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Basic Science
4 IPD

Vani Marindani
130112090058

BASIC SCIENCE IPD- Vani Marindani 1301-1209-0058

BASIC SCIENCE IPD- Vani Marindani 1301-1209-0058

BASIC SCIENCE
CARDIOLOGY
HEART
- Location of the heart : bentuk cone
# Besar : sebesar kepalan tangan, 12 cm x 9 cm x 6 cm , 250g pada wanita,
300g pada pria.
# Terdapat di diafragma, dekat garis tengah thoracic cavity
# Terletak di mediastinum : jaringan yg memanjang dari sternum ke vertebral
column di antara paru2.
# Sekitar 2/3 dari jantung terdapat di sebelah kiri dari midline
# Titik akhir dari jantung : apex : directed anteriorly, inferiorly, & to the left
# Broad Portion dari jantung : base : directed posteriorly, superiorly, & to the
right.
- Berdasarkan Apex & Base, jantung memiliki beberapa surfaces dan borders
# Surface :
Anterior surface : deep to the sternum & ribs
Inferior surface : a. Part of the heart between the apex & right border
b. Rest mostly on the diaphragm
# Border :
Right border : faces the right lung & extends from inferior surface to the base
Left border : faces the left lung & extends from the base to the apex
- Pericardium :
# Membran / selaput yg mengelilingi & melindungi jantung
# Mempertahankan jantung di posisinya di mediastinum dengan tetap dapat
bergerak untuk vigorous & kontraksi
# Terdiri dari 2 bagian :
1. Superficial : fibrous pericardium : keras, tdk elastis, dense irreguler
CT
a. Menyerupai kantung yg menempel pada diafragma
b. Its opening end berdifusi dgn CT dari pembuluh darah yg
masuk & meninggalkan jantung
c. Fungsi : mencegah overstreching jantung, untuk proteksi,
mempertahankan jantung di mediastinum.
2. Deeper : serous pericardium : tipis, membran yg lebih lembut, dan
membentuk 2 lapisan mengelilingi jantung
a. Parietal layer (outer) : berdifusi dgn fibrous pericardium
b. Visceral layer (inner) : melekat erat di permukaan jantung
epicardium
c. Diantara parietal layer & viseral layer : Pericardial cavity
d. Pericardial cavity mengandung pericardial fluid : slippery
secretion of the pericardial cell that reduces friction
between the membranes as the heart moves.
- Layers of The Heart Wall :
Terdiri dari 3 lapisan :
a. Epicardium (Visceral layer of the serous pericardium) : external layer
Composed of mesothelium & delicate Cl- yg memberikan textur lembut,
licin, thd permukaan paling luar dari jantung.
b. Myocardium (middle layer)
o Cardiac muscle tissue
o Merupakan bagian terbesar dari jantung
BASIC SCIENCE IPD- Vani Marindani 1301-1209-0058

o Untuk pumping action


c. Endocardium : selaput tipis endothelium yg terdapat di atas dari lapisan
tipis CT
Fungsi : provides a smooth lining for the chambers of the heart, covers the
valves (katup) of the heart
Berkelanjutan dgn endothelium lining of the large blood vessel attached to
the heart
-

Chambers of The Heart : 4 chambers


2 Atria superior
2 Ventricle : Inferior
# Di permukaan anterior auricle (wrinkled pouchlike)
Mirip telinga anjing
Meningkatkan kapasitas dari atrium sehingga dapat menahan darah darah
dalam volume yg besar
# Sulci :
Series og grooves
Mengandung coronary blood vessels & variable amount of fat
Setiap sulcus menandai external boundary di antara 2 ruangan di jantung
a. Coronary Sulcus (deep) :
1. encircles most of the heart
2. marks the boundary between superior atria & inferior ventricles
b. Anterior Interventricular Sulcus
1. Shallow groove on the anterior surface of the heart
2. Marks the boundary between the right & left ventricles
c. Posterior Interventricular Sulcus
1. Marks the boundary between the ventricles on the posterior of the
heart

RIGHT ATRIUM
- Menerima darah dari 5 vena
1. Vena Cava Superior
2. Vena Cava Inferior
3. Coronary Sinus
4. Anterior cardiac vein
5. Vena cordis minimae
- Posterior wall dari right atrium : smooth
- Anterior wall dari right atrium : rough adanya muscular ridges pectinate
muscles extend from auricle
- Diantara right & left atrium interatrial septum : ada oval depression
Fossa ovalis
- Fossa ovalis merupakan bekas / sisa dari Foramen Ovale : opening in the
interatrial septum of the fetal heart that normally closes soon after birth
- Darah dari right atrium ke right ventricle melalui Tricuspid value
a. Consist of 3 leaflets or cusps
b. Composed of dense CT coveted by endocardium
RIGHT VENTRICLE
- Form most of the anterior surface of the heart
- Contain a series of ridges yg dibentuk oleh raised bundles of cardiac muscle
fibers trabecuklae carnae untuk convey part of the conduction system
BASIC SCIENCE IPD- Vani Marindani 1301-1209-0058

Cusps of the tricuspid valve are connected to tendon like cords chordae
tendinae connected to cone-shaped trabeculae carnae called papillary
muscles
Dipisahkan dengan left ventricle oleh interventricular septum
Blood passes from the right ventricle through the polmunary valve ke
pulmonary trunk : Right Pulmonary Arteries &Left Pulmonary Arteries

LEFT ATRIUM
- Form most of the base of the heart
- Menerima darah dari paru2 melalui Pulmonary Veins
a. Posterior wall : smooth
b. Anterior wall : smooth, because pectinate muscle are confined to the
auricle of the left atrium
- Blood passes from the left atrium into the left ventricle through bicuspid valve
- Mitral Refers to its resemblence (mirip) to the bishops miter, which is two
shaped
LEFT VENTRICLE
- Forms apex of the heart
- Contain trabeculae carnae & chordae tendinae yg terikat pada cups di bicuspid
valves to papillary muscles
- Blood passes from left ventricle through aortic valve ke ascending (largest
artery in the body) aorta
- Beberapa bagian darah di aorta masuk ke coronary arteries (branch form the
ascending aorta) & carry blood to the heart wall
- Remainder of the blood passes into the arch of the aorta & descending aorta
sbgnya membawa darah ke seluruh tubuh ( Thoracic aorta & Abdominal aorta)
- During fetal life, ductus arteriousus shunts blood from the pulmonary trunk
into aorta
- Ductus Arteriosus normally closes shortly after birth, leaving a remnant
ligamentum arteriosum, which connects the arch of the aorta
Coronary Arteries
a. Right & left
b. Bercabang dari ascending aorta & mensuplai darah O2 ke myocardium
- Left Coronary Artery
a. Passes inferior to the left auricle
b. Divides into the anterior interventriculer & circlumflex branch
- Right Coronary Artery
a. Gives small atrial branches that the supply the right atrium
b. Continues inferior to the right auricle
c. Divides into the posterior interventricular & marginal branch
- Anterior Interventricular Branch (Left Anterior descending)
a. Memanjang di anterior interventricular sulcus
b. Supplies oxygenated blood to the walls of both ventricles
- Circlumflex Branch
a. Terdapat di Coronary Sulcus
b. Supplies oxygenated blood to the walls of the left ventricle & Left atrium
- Posterior Interventricular Branch
a. Posterior interventricular Sulcus
b. Supplies the walls of the of the two ventricles with oxygenated
BASIC SCIENCE IPD- Vani Marindani 1301-1209-0058

- Right Marginal Branch


a. In the Coronary Sulcus
b. Carries oxygenated blood to the Myocardium of the right ventricle
CORONARY VEINS
- Great cardiac Vein
a. Anterior Interventricular Sulcus
b. Drain the area of the heart supplied by the left coronary artery (Left &
Right Ventricles and left atrium)
- Middle Cardiac Vein
a. Posterior interventricular sulcus
b. Drain the area of the heart supplied by the posterior interventricular branch
of the right coronary artery (left &right ventricles)
- Small Cardiac vein
a. In the Coronary Sulcus
b. Drain the right atrium & right ventricle
- Anterior Cardiac Vein
a. Drain the right ventricle & open directly into the right atrium
Action Potensial & Contraction Of Contractile Fibers
Contactile Fibers have a stable resting membrane potensial ( -90 mV)
1. Depolarization
Threshold
Voltage gated fast Na+ channels
terbuka
Na+ masuk ke sitosol ( krn sitosol contractile fiber lebih
(-) daripada interstitial fluid & Na- > di interstitial fluid)
Menghasilkan rapid
depolarization
Dalam beberapa millisecond, Na+ channels
tertutup, inflow Na+ menurun

2. Plateau maintain depolarization


Voltage gated slow Ca2+ channels di
Sarcolemmaterbuka
Ca2+ masuk ke sitosol
Kenaikan konsentrasi Ca2+ merangsang

- kontraksi
Beberapa saat sebelum plateau phase, beberapa voltage gated K+ channel
terbuka & K+ keluar dari kontractile fiber
- Plateau phase ditopang adanya balance antara Ca2+ dan K+
- Plateau phase : 0,25 s
- Membran potensial contractile fiber close to 0 mV
3. Repolarization
Voltage gated K+ channel
terbuka
BASIC SCIENCE IPD- Vani Marindani 1301-1209-0058

Ca2+ channels di SR
& Sarcolema tertutup

K+

keluar,

memperbaiki

resting membran potensial ke


90 mV

Cardiac Conduction System


- Source of rhytmical activity network of specialized cardiac muscle fibers
(autorhyritmic fibers)
- Autorhyritmic fibers generate action potensial that triggers heart contraction
mempunyai 2 fungsi :
a. Pace maker mengatur rhythm dari electrical excitation yg
mengakibatkan kontraksi jantung
b. Membentuk conduction system jaringan dari specialized cardiac muscle
fibers that provide a path for each cycle of cardiac excitation to progress
through the heart

CONDUCTION SYSTEM
1. Jantung tereksitasi pada Sinoatrial Node (SA) yg berlokasi di dinding atrium
kanan sebelah bawah dari opening vena cava superior, SA node tidak
mempunyai resting potensial yg stabil. SA Node mengulang depolarisasi untuk
mencapai threshold dengan spontan pacemaker potensial, jika mencapai
threshold maka akan membangkitkan potensial aksi yang berpropagasi menuju
kedua atrium melalui gap junction di intercalated discs di atrial muscle fiber
atrium berkontraksi.
2. Kemudian potensial aksi menacapai Atrioventricular (AV) node berlokasi
di interatrial septum, bagian depan dari opening coronary sinus.
3. Potensial aksi masuk ke atrioventricular bundle (bundle og His) tempat ini
merupakan suatu tempat dimana potensial aksi dapat berkonduksi dari atria ke
ventricle.
4. Potensial aksi kemudian masuk ke right & left bundle branches memanjang
dari interventricular septum ke apex.
5. Large diameter purkinje fiber mengkonduksi potensial aksi dari apex naik ke
remainder of the ventricular myocardium ventricle kontraksi darah
masuk ke semilunar valves
- Autorhytmic fiber in the SA Node would initiate an action potensial about
every 0,6 second 100 times / minute.
NERVOUS SYSTEM CONTROL of THE HEART
Simpatis Dan Parasimpatis
Competitive situations heart rate may climb
- Proprioceptor ( monitor limb & muscle ) send nerve impulses at an increased
frequency to cucer
a. Propioceptor input mayor stimulus for the quick rise in heart rate that
occurs at onset of physical activity
- Chemoreceptor monitor chemical changes in the blood
- Baroreseptor monitor the stretching of mayor arteries & vein caused by
pressure of the blood flow
a. Baroreseptor yg berlokasi di arch of aorta & carotid arteries detect
changes in blood pressure & provide input to cardiovasculer center when it
change
BASIC SCIENCE IPD- Vani Marindani 1301-1209-0058

Symphatetic Neuron extend from medula oblongata into the spinal cord
- Di Thoracic region dari spinal cord, cardiac accelerator nerve keluar menuju
SA dan AV node & sebagian besar Myocardium.
Pumping Action of the heart (triggered by chest pain)
Cardiac output : volume darah yang dikeluarkan ventrikel kiri (atau kanan) ke aorta
(atau pulmonary trunk) setiap menit
Cardiac Output = Stroke Volume X Heart rate
Stroke Volume : volume darah yg dikeluarkan sekali kontraksi
Faktor2 yg meregulasi stroke volume dan memastikan ventrikel kiri dan kanan
memompa darah dgn jml yg sama:
1. Preload : effect of stretching
Besarnya stretching dr otot jantung mempengaruhi besarnya kontraksi. Preload
sebading dgn end-diastolic volume (EDV), shg smk besar EDV semakin kuat
kontraksi berikutnya
2. Contractility : kekuatan dari kontraksi setiap preload
3. Afterload : tekanan sebelum katup semilunar terbuka
Makin besar afterload makin kecil stroke volume
Normal Myocardial Contraction & Relaxation
Contractile cells : myocyte myofiber (group of myocytes), held by surrounding
collagen
Myocyte
- sarcolemma : plasma membrane invaginate to form T-tubule
- Sarcoplasmic reticulum ryanodine receptor & SERCA2
- Mitochondria
- L-type calcium channel
Contractile protein : actin(thin filament), myosin(thick filament), titin(anchoring
myosin to Z-lines), also there are troponin, tropomyosin
Microanatomy of Heart Cells
Characteristic
Ventricular
Atrial Myocyte
Myocyte
Shape
Long & narrow
Elliptical
Length, m
60-140
About 20
Diameter, m
About 20
5-6
Volume, cubic m
15.000-45.000
About 500
T tubules
Plentiful
Rare or none
Intercalated disc
Prominent end-toSide-to-side as well
end transmission
as end-to- end
transmission
General Appearance Mitochondria &
Bundles of atrial
sacrcomere very
tissue separated by
abundant;
wide area of
rectangular
collagen
branching bundles
w/little interstitial
collagen
BASIC SCIENCE IPD- Vani Marindani 1301-1209-0058

Mechanism Cardiac Contraction-Relaxation Cycle


Depolarization waves causes opening of voltage-sensitive L-type Ca channels

Ca entry & causes release Ca release from SR via Ca release channel (ryanodine
receptor)

Ca bind to troponin C

Change formation of tropomyosin to uncover active site for myosin


ATP Hydrolysis
Myosin head attaches to actin

Strong binding state

Power stroke

Actin filament displaced

ATP binds

Head detaches

Weak binding states


Phospholamban inhibit SERCA2

Phosphorylated (induced by -adrenergic)

Deinhibited

Activates SERCA2

Reuptake Ca into SR
Cardiac cycle
1. LV contraction (isovolumic contraction & maximal ejection)
2. LV relaxation (start of relax & reduced ejection ; isovolumic relaxation)
3. LV filling ( LV filling, rapid phase; slow LV filling; Atrial systole or booster)
Contractile Performance of The Intact Heart
3 determinants of myocardial performance
1. loading condition (preload & afterload; Frank-Starling mechanism)
Preload : load present before contraction has started, at the end of diastole
Afterload : systolic load on LV after it has started to contract or the wall stress during
LV ejection
Frank-Starlings Law of heart interlinked preload & afterload in LV volume
(preload) leads to contractile function in turn will systolic BP & hence afterload
Laplace law
BASIC SCIENCE IPD- Vani Marindani 1301-1209-0058

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Wall stress =
Means :
- the larger the LV, the greate of its radius, the greater is wall stress
- At any given radius (LV size) the greater the pressure developed by LV, the
greater the wall stress
2. contractile state inherent capacity of myocardium to contract independently of
changes in preload or afterload
interaction Ca & contractile protein

Increase inotropic state, means a greater rate of contraction to reac a greater peak
force

Increase rates of relaxation


3. HR
Heart rate & force-frequency relationship : HR progressively enhances the dorce off
ventricular contraction, but too rapid will decrease force
CO = SV X HR

BASIC SCIENCE IPD- Vani Marindani 1301-1209-0058

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GASTRO-ENTEROHEPATOLOGY
STOMACH
Anatomi
J-shaped
Terbagi menjadi 4 bagian :

Cardia : superior opening of the stomach

Fundus : rounded portion superior to & to the left of


cardia

Body : inferior dr fundus & central portion

Pylorus : berhubungan dgn duodenum

Pyloric antrum : terhubung dgn body of stomach

Pyloric canal : terhubung dgn duodenum


Concave medial border : lesser curvature
Convex lateral border : greater curvature
Histologi
Lapisan2 :
Mucosa : simple columnar epithelium, lamina propria, muscularis mucosae
Submucosa : areolar CT
Muscularis : 3 lapisan otot polos (longitudinal, circular, oblique hanya
terdapat di body of stomach)
Serosa : simple squamous epithelium dan areolar CT
Exocrine gland
Mucous neck cells : mucus
Parietal cells : menghasilkan factor intrinsic (utk penyerapan Vit B12) dan
HCL
Chief cells : mensekresi pepsinogen dan gastric lipase
Enteroendocrine : G cells mensekresi hormone gastrin u/ stimulasi kerja
lambung; terdapat di pyloric antrum
Physiology
Fungsi : serve as mixing chamber & holding reservoir
Structure
Mucosa
Chief cells

Activity

Result

Secrete
pepsinogen

Pepsin, the activated form, breaks down protein into


peptides

Secrete
lipase
Parietal cells

gastric Split triglycerides into fatty acids & monoglycerides

Secrete HCl

Kills microbe in food, denature protein, convert


pepsinogen into pepsin

Secrete intrinsic Needed for absorption of Vit B12, which is used in


factor
RBC formation

BASIC SCIENCE IPD- Vani Marindani 1301-1209-0058

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Surface
Secrete mucous
mucous cell
&
mucous Absorption
neck cells

Form a protective barrier that prevents digestion of


stomach wall
Small quantity of water, ions, short-chain fatty acids, &
some drug enter the bloodstream

G cells

Secrete gastrin

Muscularis

Mixing waves

Stimulate parietal cell to secrete HCl & chief cells to


secrete pepsinogen; contract lower esophageal
sphincter, increases motility of stomach & release
pyloric sphincter
Macerate food & mix it w/gastric juice, forming chyme

Pyloric
sphincter

Peristaltis
Opens to permit
passage
of
chyme
into
duodenum

Forces chyme thru pyyloric sphincter


Regulate passage of chyme from stomach to
duodenum, prevent breakflow of chyme from
duodenum to stomach

BASIC SCIENCE IPD- Vani Marindani 1301-1209-0058

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SMALL INTESTINE
Anatomy
A.Duodenum
- first & shortest (25cm) part of small intestine, also the widest part &most fixed
part
- C-shaped, around head of pancreas
- Begin at pylorus & end @ duodenojejunal junction
- Partial retroperitoneal
- Divided into 4 parts
Superior (1st part) : short (5cm) & lies anterolateral to the body of L1
vertebrae
Descending (2nd part) : longer (7-10cm) & descends along the right sides
of L1-L3 vertebrae
Horizontal (3rd part) : (6-8 cm) long & crosses the L3 vertebrae
Ascending (4th part) : short (5cm) & begins @ left of the L3 vertebrae &
rises superiorly as for as the superior border of L3 vertebrae
Vascularization
Artery duodenal arteries, arise from celiac trunk & superior mesenteric artery
Vein : follow the arteries & drain into portal vein some directly & others indirectly,
thru superior mesenteric & splenic vein
Lymphatic follow the arteries
- Anterior lymphatic vessels : pancreaticoduodenal LN & pyloric LN
- Posterior lymphatic vessels : superior mesenteric LN & celiac LN
Nerve Vagus, Greater, & Lesser (abdominopelvic) splanchnic nerve
B. Jejunum & Ileum
Total long : 6-7m jejunum 2/5 & ileum 3/5
Jejunum
- begin @ duodenojejunal flexure
- in left upper quadrants
Ileum
- ends @ iliocecal junction
- in right lower quadrants
Vascularization
Artery Superior mesenteric artery Sending 15-18 branches to jejunum & ileum
Arterial arches Vasa recta
Vein superior mesenteric vein splenic vein portal vein
Lymphatic
- specialized @ intestinal villi lacteals (for absoprtion fat)
lacteal Lymphatic plexuses @ wall of jejunum & ileum Lymph vessel @
layer of mesentery : into
juxtaintestinal LN : close to intestinal wall
mesenteric LN : scattered among arterial arcades
superior central nodes : along the proximal part of SMA
note :
- from mesenteric LN drain into superior mesenteric LN
- from terminal ileum follow ileal branch to ileocolic LN
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Nerve
- sympathetic : originate from T8-T10 segment of spinal cord
presynapsis synapse w/postsynapstic neuron in celiac & superior
mesenteric (prevertebra) ganglia
- parasympathetic : from posterior vagal trunks
presynapsis synapse w/postsynaptic neuron in myenteric & submucosal
plexus
Histology
1. Mucuos membrane
Macros : series of permanent fold/plicae circularis (terdiri atas mukosa dan
submucosa, berbentuk semilunar, sirkular, spiral) ciri jejunum
Micros : intestinal villi (p =0.5-1.5mm), duodenum leaf shaped; ileum fingers
like
Between the villi are small openings intestinal glands/glands of lieberkuhn
Intestinal gland
- Stem cell
- Enterocyte (absorptive cell) : tall columnar cell (inti lonjong pd stengah bag
basal); @ the apex striated (brush) border, merupakan microvilli
Mikrovili :
Juluran silindris sitoplasma apikal
Terdiri atas membran sel yg membungkus filamen2 aktin di pusat
Ukuran : 1m x 0.1 m
F(x) : memperluas permukaan kontak antara permukaan usus dengan
makanan
- Goblet cell : less abundant in duodenum, makin banyak ke arah ileum;
menghasilkan glikoprotein asam u/melindungi dan melapisi usus
- Paneths cell : in the basal portion; serosa eksokrin dgn granule sekresi di bag
apeks sitoplasma; produce lysozyme (for killing bacteria)
- Sel M (lipatan mikro)
Sel epitel khusus di atas folikel limpoid dari peyers patches
Ditandai dengan banyak sekali sumur (pit) pada permukaan apikal dan
invaginasi badan sel dan permukaan lateral o/limpoid intraepitel
F(x) : fungsi immunologis
- Endocrine cells :
Ciri sistem neuroendokrin difus
2 kelompok : terbuka (apeks sel dgn mikrovili berkontak lumen organ) &
tertutup (apeks sel ditutupi sel epitel lain)
S cell secretin
K cell gastric inhibitory polypeptide
L cell glucagon-like peptide I
I cell cholecystokinin (CCK)
Mo cell motilin (for stimulate motility)
Dikendalikan susunan saraf & hormon
Lamina Propria
- Loose CT w/blood & lymph vessels, nerve fiber
- Smooth muscle
- Peyers patches (aggregates of lymphoid nodules)
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Muscularis mucosa
2. Submucosa : duodenal/Brunners gland production alkaline (pH 8.1-9.3)
3. Muscularis
- Internal : circular
- External : longitudinal
4. Adventitia & serosa
Note :
Lamina propria & submukosa peyers patches (kelompok limfonoduli; terdiri atas
10-200 nodul; terdapat 30 patches pd manusia)
Pembuluh darah
Menembus muscularis externa Membentuk pleksus di submucosa Cabang2
melalui muscularis mucosaa & lamina propria ke dalam vili Menyusun kapiler
tepat di bawah epitel Ujung vilus venul Vena pleksus submucosa
Pembuluh limfe
Dimulai dari tabung buntu pada pusat vili Ke lamina propria diatas muscularis
mucosa, dimana membentuk pleksus Submucosa Mengitari limfonoduli
Saraf
- Dibentuk kelompok intrinsik & ekstrinsik
- Intrinsik:
dibentuk kelompok neuron yg membentuk plexus Auerbach (terdapat di
antara lapisan longitudinal luar dan circular dalam muskularis) dan pleksus
submucous (Meissner)
neuron kemoreseptor & mekanoreseptor
efektor
f(x) : bertanggung jawab atas kontraksi usus yg terjadi tanpa pengaruh
saraf ekstrinsik
- ekstrinsik :
parasimpatis (merangsang otot polos) & simpatis ( menekan otot polos)
Sel enteroendokrin utama dalam saluran cerna
Jenis sel &
Hormon yang dihasilkan
lokasi
A-lambung
Glucagon
G-pilorus
Gastrin
S-usus kecil
Sekretin
K-usus kecil
L-usus kecil
I-usus kecil
D-pilorus,
duodenum
Mo-usus kecil
EC-saluran

Polipeptide yg menghambat
gastrik (GIP)
Substansi mirip glucagon
(glisentin)
Kolesistokinin
Somatostatin
Motilin
Serotonin, substansi P

Fungsi Utama
Glikogenolisis hepatik
Merangsang sekresi asam lambung
Sekresi bikarbonat pankreas dan bilier
serta air
Inhibisi sekresi asam lambung
Glikogenolisis hepatik
Sekresi enzym pankreas, kontraksi
kandung empedu
Hambatan setempat dari sel endokrin
lain
Penignkatan motilitas usus
Peningkatan motilitas usus

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cerna
D1-saluran
Polipeptida intestinal
cerna
vasoaktif(VIP)
D1-saluran
Polipeptida intestinal
cerna
vasoaktif(VIP)
PHYSIOLOGY OF SMALL INTESTINE

Sekresi ion & air, peningkatan motilitas


usus
Sekresi ion & air, peningkatan motilitas
usus

Movement
I. PROPULSIVE MOVEMENT - PERISTALTIS
Causes the food to move forward along the tract at appropriate rate to
accommodate digestion and absorption
Process : a contractile ring appears around the gut then it moves forward
sliding forward along the tube
Stimulation : the usual stimulus for intestinal peristaltis is distension of the gut.
Process : large amount of food collects at any point in the gut
stretching the wall of the gut stimulate enteric nervous system to
contract the gut wall 2-3 cm behind this point contractile ring appears
initiates peristaltic movement.
Other stimuli : chemical or physical irritation of the epithelial in the gut &
parasympathetic nervous signal.
Peristaltis is the inherent properties of many syncytial smooth muscle tube can
also occur in the esophagus, bile duct, glandular ducts, ureters, etc.
Effectual peristaltic reflex requires an active myenteric plexus.
Peristaltic Reflex = Myenteric reflex
- Is a complex pattern of peristaltic movement.
- Direction : it normally dies out rapidly in the orad (arah mulut) direction while
continuing for a considerable distance toward the anus. It is because the
myenteric plexus is polarized in anal direction (Peristaltic Reflex)
- Mech: peritstaltis normally begins on the orad side of the distended segment
moves toward the distended segment push the intestinal contents in the anal
direction for 5-10 cm before dying out. At the same time, the gut sometimes
relaxes several cm downward toward the anus (called receptive relaxation)
allowing the food to be propelled more easily anally than orad.
- The peristaltic reflex plus the anal direction of movement of peristaltic is called
the Law of the Gut
Propulsive Movements (Peristaltis) of Small Intestine
Chyme is propelled through the small intestine by peristaltic waves occur at
any part of the small intestine.
Normally :
- Velocity: 0,5-2 cm/sec, faster in the proximal intestine & slower in
terminal intestine.
- Very weak & usually die out after traveling only 3-5 cm, very rarely
farther than 10cm
- Net forward movement of chyme along the small intestine 1cm/min 35 hours is required for passage of chyme from the pylorus to ileocecal
valve.
The function of peristaltic :
- to cause progression of chyme toward ileocecal valve
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- to spread out the chyme along intestinal mucosa


Propulsive movement of small intestine is also helped by the segmentation
movement (lihat di bawah)
Control of Peristaltis :
(1) Neural control : Peristaltic activity after meal,due to
- Gastroenteric reflex initiated by distension of the stomach, conducted
principally by myenteric plexus from the stomach along the wall of small
intestine
- Stretching of the duodenal wall in the beginning of chyme enter the
duodenum
(2) Hormonal control
- Peristaltic activity : Gastrin, Cholecystokinin (CCK), Insulin, Motilin,
and Serotonin.
Peristaltic activity : Secretin & Glucagon

Peristaltic Rush
- intense irritation of the intestinal mucosa (e.g. severe infectious diarrhea)
cause powerful & rapid peristaltsis (i.e. the Peristaltic Rush) sweeping the
contents of the small intestine to the colon relieving the small intestine of
irritating chyme & excessive distension.
- Initiated by :
partly by nervous reflexes that involves the autonomic nervous system
& brain stem
partly by intrinsic enhancement of myenteric plexus reflexes within the
gut itself.
Movement caused by the muscularis mucosa & muscle fiber
- muscularis mucosa :
cause short folds appear in intestinal mucosa surface area exposed to
chyme absorption
individual fiber of these muscle extend to intestinal villi cause them
contract intermittently (shortening elongating - shortening) milk the
chyme
- these mucosal & villous contraction are initiated mainly by local nervous
reflexes in the submucosal nerve plexus initiated by chyme.

II. MIXING MOVEMENT


Mixing movement differ in different part of the alimentary tract, i.e:
(1) In some areas, the peristaltic contraction themselves cause most of the mixing
especially when forward progression of the intestinal contents is blocked
by a spinchter.
(2) At the other times, local intermittent constrictive contractions occur every few
cm in the gut wall usually last only 5-30 seconds at one segment then
new constriction occur at the other point in the gut chopping & shearing the
contents.
Mixing Contraction (Segmentation contractions) of Small Intestine
Mixing movement in the small intestine = localized concentric contraction
(segmentation contraction)
Process:
a portion of small intestine become distended with the chyme
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stretching the intestinal wall

elicits localized concentric contraction spaced at interval along the intestine

contraction cause segmentation of the small intestine (that is they divide the intestine
into spaced segments that have the appearance of chain of sausage)

as one set of segmentation relaxes, a new set often begins but the contraction this time
occur mainly at the new points between the previous contraction

The segmentation contractions chop the chime 2-3 times per minute promoting
progressive mixing of food with small intestine secretion

The maximum frequency of the segmentation contraction in small intestine is


determined by the frequency of electrical slow waves in the intestinal wall.
This frequency normally is not over 12 times of contraction per minute in
the duodenum and proximal jejunum.
In the terminal ileum frequency = 8-9/min
The excitation stimulus mainly from the myenteric plexus.

FUNCTION OF THE ILEOCECAL VALVE


Principal function of the ileocecal valve is to prevent backflow of fecal content
from the colon into the small intestine.

The ileocecal valve itself protrudes into the lumen of the cecum and
therefore is forcefully closed when excess pressure builds up in the cecum &
tries to push cecal contents backward against the valve lips.
The wall of the ileum for several cm immediately upstream from the ileocecal
valve has thickened circular muscle called ileocecal spihincter.
Normally : sphincter remains mildly constricted & slows emptying of ileal
contents into the cecum
Immediately after meal : gastroileal reflex intensifies peristaltis of the ileum
emptying ileal content
Resistance to emptying at the ileoecal valve prolongs the stay of chyme in the
ileum fascilitates absorption.
Secretion
I. Mucus Secretion by Bruners Gland in Duodenum
Brunners gland is located in the wall of upper duodenum, mainly between
pylorus of stomach & papilla of Vater where the pancreatic secretion & bile
empty into duodenum.
Brunner gland secretes large anount of alkanline mucus, in response to :
1) Tactile or irritating stimuli on duodenal mucosa
2) Vagal stimulation
3) GI hormone, specially secretin.
The function of the mucus :
o protect duodenal wall from digestion by highly acidic gastric juice
o contains >> bicarbonate ion add to the bicarbonate ion from pancreatic
juice & liver bile neutralize HCl from gastric juice.
Control of secretion :
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Inhibited by sympathetic n.s : very excitable person tend to have peptic


ulcer in this area
II. Secretion of Intestinal Digestive Juices by Crypt of Lieberkuhn
Crypt of Lieberkuhn are small pits located over the entire surface of small
intestine, lies between intestinal villi.
Surface of intestinal villi & crypts are covered by epithelium composed of 2
types of cell:
1) moderate number of goblet cell secretes mucus lubricate &
protect intestinal surface
2) large number of enterocytes
in the crypts : secretes >> water & electrolytes
in villis surface : reabsorb water & electrolytes along with
digested product.
Intestinal secretions : 1800ml/day; pure extracelular fluid; slightly alkaline pH
7.5-8.0
F(x) : watery vehicle for absorption of substances from chyme when it comes
in contact w/villi
The exact mechanism of secretion of water fluid by crypts is not known, but
believed to involve :
1. active secretion of chloride ion to the crypts
2. active secretion of bicarbonate ion.
All of the above cause drag of the sodium ion thru membrane into secreted
fluid osmotic movement of water
Digestive enzyme in the small intestine secretion : secreted by the enterocytes
of the mucosa especially those that cover the villi contain digestive enzyme
that digest specific food substace when they are being absorbed through the
epithelium. The enzymes are :
1) Several peptidase split small peptides into amino acids, i.e :
aminopeptidase & dipeptidase
2) Sucrase : split sucrose glucose & lactose
3) Maltase : split maltose glucose
4) Lactase : split lactose glucose & galactose
5) -dextrinase : split -dextrin glucose
6) Small amount of intestinal Lipase : split neutral fat glycerol & fatty
acids
7) Nucleosidase & Phosphatase : split nucleotides nitrogen bases,
pentose & phosphate
Regulation of small intestine secretion : local enteric nervous reflexes, especially
reflex initiated by tactile or irritative stimuli from the chyme in intestine.
Note:
Epithelial cells deep in the crypts of lieberkuhn continually undergo mitosis & new
cells migrate along the basement membrane upward out of the crypts toward tips of
villi replacing villi epithelium & also forming new digestive enzyme
Digestion
Carbohydrate
By pancreatic amylase
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Digestion : occured within 15-30 min after the chyme empties from stomach
into duodenum & mixed w/pancreatic juice
Generally, CH are almost totally converted into maltose and/or other very
small glucose polymers before passing beyond duodenum or upper jejunum
By intestinal epithelial enzyme
Lactase, sucrase, maltase, -dextrinase : splitting lactose, sucrose, maltose into
monosaccharides located in enterocytes covering intestinal microvilli brush
border
sucrose glucose & lactose
maltose glucose
lactose glucose & galactose
So, final products are monosaccahrides water soluble & absorbed immediately
into portal blood

Protein
By pancreatic secretions
most protein digestion occurs in upper small intestine in the duodenum &
jejunum by pancreatic proteolytic enzymes
enzymes : trypsin, chymotrypsin, carboxypolipeptidase, proelastase
trypsin & chymotrypsin : split protein molecules into small polypeptides
carboxypolypeptidase : cleaves individual amino acid from carboxyl ends of
polypeptides
proelastase (convert into elastase) : digest elastin fibers that partially hold
meat together
Only small percentage protein are digested all the way to their constituent amino acids
by pancreatic juices, most remain as dipeptides & tripeptides
By peptidases in enterocytes
mainly in duodenum & jejunum @ villi of small intestine
enzymes : aminopolypeptidase & dipeptidase
F(x) : splitting remaining larger polypeptides into tripeptides & dipeptides & a
few into amino acids

Both amino acid + dipeptides & tripeptides transported thru membrane into interior of
enterocytes

Inside cytosol of enterocytes are multiple other peptidases that are specific for
remaining types of linkages bween amino acid

All last dipeptides & tripeptides are digested into single AA

Pass on thru of underneath side of enterocyte into the blood


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Fats
In stomach : by lingual lipase taht is secreted by lingual gland in mouth & swallowed
w/ the saliva but, essentially all fat digestion occurs in the small intestine
Emulsification of fat by bile acids & lecithin
emulsification of fat (by bile that containing bile salts & lecithin) : break the
fat globules into small sizes so that the water soluble digestive enzymes can
act on globule surface
bile salts & lecithin

Polar part : soluble in water & remaining : soluble in fat (dissolve in surface layer of
fat globules)

Polar part projecting outward

Soluble in the surrounding watery fluid

Decrease interfacial tension of fat

Becomes nonmiscible fluid

That on agitation, can be broken up into many vary minute particles for more easily
F(x) of bile salts & lecithin : make the fat globules readily fragmentable by agitation
of water in the small bowel so if agitation diameter fat globules decrease
increase total surface area lipase easily to act
By pancreatic lipase
digest within 1 minutes all triglycerides
intestine also have enteric lipase unimportant

Absorption
Absorptive Surface of the Small intestine Mucosal Villi
1. Valvulae Conniventes (or folds of Kerckring)
It is folds on the mucosal surface
surface area of absorptive mucosa 3 folds.
Especially well developed in the duodenum and jejunum protrude 8
mm to the lumen.
2. Million of small Villi

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Located on the epithelial suface of the small intestine all the way down to
the ileocecal valve. The distribution less profuse in the distal small intestine.
Projects 1mm from the surface of the mucosa
total absorptive area another 10 folds
3. Brush border
Consist of as many as 1000 microvili 1m length & 0,1 m diameter
protruding into chyme
total absorptive area another 20 folds
Extending from the epithelial cell bodies to each microvillus are multiple
actin filament that contract rhythmically to cause continual movement of
microvilli & constantly exposed to new quantities of intestinal fluid.
The combination of the folds of Kerckring, villi, & microvilli increase the total
absorptive area 1000 folds.

Absorption Capacity
Absorption from the small intestine each day consist of :
- several hundreds of darbohydrate
- 100 grams fat
- 50-100 grams ion
- 50-100 grams amino acids
- 7-8 L of water
Absorption capacity of normal intestine:
- several kg carbohydrate per day - 500 g fat per day
- 500 700 g protein per day
20L water per day
I. Absorption of Water
Isosmotic Absorption
Water is transported through the intestinal membrane entirely by diffusion this
diffusion obeys the usual law of Osmosis.
When the chyme is dilute enough, water is absorbed through the intestinal mucosa
to the blood of the villi almost entirely by osmosis.
When hyperosmotic solutions are discharged from the stomach to duodenum,
water is transported from plasma to chyme chyme is isosmotic with plasma.
II. Absorption of Ions
Active transport of Na+ ion
Na+ ion transported to the epithelial (absorptive) cell via diffusion & secondary
active transport.
Once inside the epithelial cell, the Na+ are actively transported out of the
epithelial cells through the basal & side wall (basolateral) of these cells to
paracellular space by Basolateral Sodium-Potassium pump (Na+/K+ ATPase).
Part of the sodium ion is absorbed along with chloride ions. i.e. : the negatively
charged chloride ions are mainly passively dragged by the positive electrical
charges of Na.
Transport of Other Ion
Absorption of negatively charged ion such as : chloride, iodide, and nitrate ion
in the duodenum & jejunum occur mainly by diffusion, that is passively follow the
sodium ion or be actively transported.
Absorption of calcium, iron, potassium, magnesium & phosphate ion active
transport mechanism.
Absorption of Bicarbonate
The bicarbonate ion in an indirect way as follow:
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Na+ is absorbed moderate amount of H + is secreted to the lumen of gut in


exchange for Na+ H+ + HCO3- H2CO3 H2O + CO2, the water remains as a
part of chyme in intestine, CO2 is readily absorbed into blood & subsequently
expired through the lung.
This is so called : Active absorption of Bicarbonate ion.
The epithelial surfaces of villi in the ileum as well as on all surface of large
intestine have special capability to bicarbonate ion in exchange of chloride ion.
III.Absorption of Nutrients
A. Absorption of carbohydrate
Essentially, all the carbohydrate absorbed in the food are in the form of
monosaccharide, only a small fraction & almost none as larger carbohydrate
compound.
Glucose : 80% because it is the final digestion product of our most
abundant carbohydrate food, i.e. the starches.
Galactose & Fructose : 20%
Virtually, all the monosaccharides pass from the lumen through the apical
membrane via facilitated diffusion or secondary active transport.
(1) Absorption of Glucose & Galactose : Sodium co-transport Mechanism
(secondary active transport)
The transport protein for transport of Na+ has 3 binding sites : 1 for
glucose, 2 for Na+ unless all three sites are filled, neither substance is
transported, so when 2Na+ is transported to the absorptive cell, 1 molecule
of glucose is also transported to the cell with the same direction (therefore,
it is a symporter) .
Galactose compete the glucose to ride the same symporter.
Once inside the epithelial cell, other transport proteins & enzymes cause
facilitated diffusion of glucose through cells basolateral membrane
paracellular space into the blood
(2) Absorption of Fructose
Fructose transport does not occur by the sodium co-transport mechanism
Fructose is transported by facilitated diffusion all the way through intestinal
epithelium but not coupled with sodium transport.
Much of fructose on entering the epithelial cell becomes phosphorylated
converted to glucose transported in the form of glucose.
B Absorption of Protein
Proteins after digestion are absorbed through the luminal membranes of the
intestinal epithelial cells in the form of dipeptide, tripeptide, & a few amino
acids.
Mechanism of transport :
(1) Absorption of Amino Acids
Most proteins are absorbed as amino acid in duodenum & jejunum
Amino acids are transported by secondary active transport with Na + (in the
same way as glucose)
(2) Absorption of Dipeptides & Tripeptides
Absorption of dipeptide & tripeptide occur by the H+ symporter
Peptides then hydrolyzes inside the cell amino acids
Amino acids move out the absorptive cells via diffusion enter capillary of the
villus

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Both the monosaccharides & amino acid transported in the blood to the liver by
hepatic portal system.
C Absorption of Fat

When fat is digested to form monoglycerides & FFA, they become dissolved
in the central lipid portions of bile micelles.

All dietary lipid are absorbed via simple diffusion.


(1) Absorption of Micelles
the micelles perform a ferrying function in fat absorption
In the presence of the abundance micelles, about 97% of fat is absorbed,
in the absence of bile micelles, only 40 50% is absorbed
Mech :
In the form of micelles, monoglycerides & free fatty acid (esp.LCFA) are carried to
the surface of the microvilli of intestinal cell brush border

penetrate to the recess among the moving, agitating microvilli

monoglycerides & FFA diffuse immediately out of micelles diffuse into the interior
of epithelial cell.

After entering the epithelial cell, the fatty acids & monoglycerides are taken up by the
cell SER

In SER, they are mainly used to form new triglycerides

Triglycerides aggregates into globules along with phospholipid & cholesterol &
coated with protein chylomicron

chylomicrons leave the epithelial cell through the base of epithelial cell by exocytosis

Chylomicrons flow upward through lymphatic system empty into circulating blood
(2) Absorption of short chain fatty acid : direct diffusion without converting into
micelles.
Small quantities of short & medium chain fatty acids are absorbed directly into
the portal blood rather than being converted into triglycerides & absorbed by
way of lymphatic system
This is because : the short chain fatty acid are more water soluble than long
chain fatty acids this allow direct diffusion of short chain fatty acid from
intestinal epithelial cell directly into the capillary blood of intestinal villi.
D. Absorption of Vitamin
Fat soluble vitamin (A,D,E,K) are included with ingested dietary lipid in
micelles & are absorbed via simple diffusion
Most water soluble vitamin (B & C), also absorbed via simple diffusion
Vit.B12 combined with intrinsic factor produce by stomach the
combination is absorbed in the ileum via active transport mechanism.

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LARGE INTESTINE
Consists of
1. Cecum
2. Appendix
3. Ascending, transverse, descending & sigmoid colon
4. Rectum
5. Anal canal
Features
*Omental appendices : small, fatty, omentum like projections
*Three teniae coli (thickened band of SM representing most of longitudinal coat)
Mesocolic : which transverse & sigmoid mesocolons attach
Omental : which omental appendices attach
Free : which neither mesocolons nor omental appendices are attached
*Haustra : sacculation of the wall of the colon bween teniae
*A much greater caliber
Cecum & Appendix
Cecum :
*Blind intestinal pouch, 7.5 in length & breadth
* Located in right lower quadrants, lies in the iliac fossa inferior to the junction of
terminal ileum & cecum
Appendix
- Blind intestinal diverticulum (6-10cm in length)
- Contain masses of lymphoid tissue
- Vascularization
*Artery :
Cecum : Ileocolic artery
Appendix : appendicular artery
* Vein : ileocolic vein
*Lymphatic : LN in mesoappendix to ileocolic LN
*Nerve :
Sympathetic : originate from lower thoracic of spinal cord
Parasympathetic : from vagus nerve
Colon
Ascending colon
- Passes superiorly on right side of abdominal cavity from cecum to right lobe of liver
turn to lef @ right colic flexure
- Covered by peritoneum anteriorly
Vascularization
Arteries : ileocolic & right colic arteries
Veins : ileocolic & right colic veins
Lymphatic : epicolic & paracolic LN
Nerve : from superior mesenteric plexus
Transverse colon
- 45 cm in long
- Third, longest, most mobile part of large intestine
- from right colic flexure to left colic flexure & bends inferiorly to bcomes descending
colon
Vascularization
arteries : middle colic artery
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veins : SMV
lymphatic : middle colic LN
nerve : superior mesenteric nerve plexus
Descending Colon
- secondarily retroperitoneal position bween left colic flexure & left iliac fossa
- peritoneum covers the colon anteriorly & laterally & bind it to posterior abdominal
wall
Sigmoid Colon
- S-shaped loop of variable length (40 cm)
- Extend from iliac fossa to S3 segments, where it join w/rectum
- Termination of teniae coli (15 cm from anus) rectosigmoid junction
Vascularization of Descending & Sigmoid colon
Arteries : Left colic & sigmoid arteries
Veins : inferior mesenteric vein
Lymphatic vessel : pass to epicolic & paracolic LN
Nerve
Sympathetic : from lumbar splanchnic nerves, superior mesenteric plexus,
periarterial plexus
Parasympathetic : from pelvic splancnic nerve via inferior hypogastric (pelvic)
plexus & nerves
Rectum
- Fixed (primarily retroperitoneal & subperitoneal) terminal part of large intestine
- Continuos w/sigmoid colon @ level S3 vertebrae
- Continuos inferiorly w/anal canal
- 3 sharp lateral flexures of the rectum (superior, intermediate, inferior)
- 3 internal folding (transverse rectal folds): 2 on left & 1 on right
- Ampulla of the rectum : dilated terminal part of the rectum, lying directly superior to
& supported by the pelvic diaphragm (levator ani) & anococcygeal ligament
- Peritoneum covers :
the anterior & lateral surfaces of the superior third of the rectum
only anterior surface of the middle third
no surface of inferior third
Vascularization
arteries
superior rectal artery supplies proximal part of rectum
right & left middle rectal arteries supplies middle & inferior parts of the rectum
inferior rectal arteries supply anorectal junction & anal canal
Veins
Superior rectal veins : drain into portal venous vein
Middle & inferior rectal veins : drain into systemic vein
Rectal venous plexus :
- Internal rectal venous plexus : deep to mucosa of anorectal junction
- External rectal venous plexus : external to muscular wall of rectum
Lymphatic
Superior half into lumbar (caval/aortic) LN
Inferior half sacral LN
From distal ampulla internal iliac LN
Nerve
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Sympathetic : from lumbar spinal cord, via lumbar splanchnic nerves &
hypogastric/pelvic plexuses
Parasympathetic : from S2-4 spinal cord level, via pelvic splanchnic nerves & left
& right inferior hypogastriv plesux

Anal Canal
- Extend from superior aspect of pelvic diaphragm to the anus
- 2.5-3.5 cm long
- Internal anal sphincter
Involuntary sphincter, superior 2/3 of anal canal
Thickening of circular muscle layer
- External anal sphincter
voluntary ; inferior 2/3 of anal canal
Supplied mainly by S4 thru inferior rectal nerve
- Superior half longitudinal ridges, called anal columns (contain terminal branches
of superior rectal artery & vein)
- Inferior ends of anal column are joined by anal valves
- Superior of valve anal sinuses
- Pectinate line divide anal canal
Superior : visceral, derived from hindgut
Inferior : somatic, from embryonic proctodeum
Vascularization
Arteries :
Superior rectal artery : supply anal canal superior to pectinate muscle
2 inferior rectal artery : supply inferior part of anal canal
Middle rectal artery
Veins
Internal rectal venous plexus drain in both direction from the lvel of the
pectinate muscle
Superior rectal vein & portal vein from superior to the pectinate line
Inferior rectal vein inferior pectinate line
Middle rectal vein drain muscularis externa of ampulla & form anastomoses
w/superior & inferior rectal vein
Lymphatic
Superior to pectinate line into internal iliac LN common iliac & lumbar LN
Inferior to pectinate line into superficially inguinal LN
Nerve
Superior pectinate line inferior hypogastric plexus (sympathetic,
parasympathetic, visceral afferent fiber)
Inferior pectinate line inferior anal (rectal) nerve, branches of pudendal nerve
Histology
Kelenjar usus panjang2, banyak sel goblet, sel2 absorptif, sedikit sel
enteroendokrin
Mucosa
- Epitel pelapis silindris, mikrovili pendek, tidak teratur
- Lamina propria : kaya akan limfosit dan limfonoduli meluas ke submucosa
Submucosa
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Muscularis
- Longitudinal & circular
- Serat2 lapisan longitudinal tergabung dalam 3 pita tebal memanjang tenia
koli
Serosa
- appendiks epiploika ( tonjol2 kecil bertangkai terdiri atas jaringan lemak)
2 cm di atas muara anus:
-epitel berlapis gepeng
-lamina propria : terdapat pleksus vena2 besar bisa hemorrhoid
Physiology
1. Movement of Colon
Mixing movement (Haustration)
Propulsive movements-Mass movement : Modified peristaltic take over
propulsive role ffrom transverse colon sigmoid ( usually occur 1-3 x/day, most
abundant for 15 min during the first hour after eating breakfast)
Defecation reflex
Intrinsic reflex(weak)
mediated by local eneteric nervous system in rectal wall when feces in rectum

Distention of wall

Afferent signals

Myenteric plexus

Initiate peristaltic waves in descending colon, sigmoid, rectum

Forcing feces toward anus

Internal anal sphincter relax

If external anal aphincter also consciously (voluntary relax)

defecation
Parasympathetic reflex
Nerve endings in rectum is stimulated

Involve a sacral segment in spinal cord

Parasympathetic nerve fiber in pelvic nerve

Descending colon, sigmoid, rectum & anus

- Greatly intensify peristaltic wave


- Relaxed internal anal sphincter
- Convert intrinsic reflex from weak to powerful
taking a deep breath
closure of glottis
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contraction of abdominal wall

Increase pressure in abdominal cavity

Forcing fecal content in rectum to cause a new reflex


2. Secretion only mucus (+ small bicarbonate from few nonmucuos secreting cells
between mucus cell)
3. Absorption : water & electrolytes
PERITONEUM
- Is the largest serous membrane of the body
- Consist of simple squamous epithelium + areolar CT
- Divided into
1. Parietal peritoneum : lines the wall of abdominopelvic cavity
2. Visceral peritoneum : covers some organs in the cavity & is their serosa
- Space bween them : peritoneal cavity
- Retropertinoeal covered by peritoneum only on their anterior surfaces;
kidney & pancreas
- 5 major peritoneal folds
a. Greater omentum
o Drapes over transverse colon & coil small intestine like fatty apron
o Double sheet total 4 layer
o Contain adipose tissue & lymph nodes
b. Falciform ligament
o Attaches liver to anterior abdominal wall & diaphragm
c. Lesser omentum
o Suspends stomach & duodenum from liver
o Contain some lymph nodes
d. Mesentery
o Binds small intestine to posterior abdominal wall
e. Mesocolon
o Binds large intestine to posterior abdominal wall
o Carries blood & lymph vessel to intestines

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LIVER
Anatomy
- Largest organ after skin
- Weight : 1500 g; 2.5% body weight
- Occupy almost Right Hypochondrium & epigastrium
- Extents into Left hypochondrium, inferior to the diaphragm
Surface, Peritoneal Reflections, & Relationship of the Liver
Diaphragmatic surface
- anterior, superior, some posterior
- convex, smooth, dome-shaped
- related to concavity of inferior surface of diaphragm
- subphrenic recesses
bween diaphragm & anterior & superior aspect of diaphragmatic surface of
the liver
separated into R & L by falciform ligament
- subhepatic space : portion of supracolic compartment of peritoneal cavity
immediately inferior to the liver
- hepatorenal recess (hepatorenal pouch; Morison pouch)
posterosuperior extension of subhepatic space, lying bween R part of
visceral surface of liver & R kidney & suprarenal gland
Gravity dependent; fluid from omental bursa flow into this recess
Communicates anteriorly w/right subphrenic recess
- Covered w/visceral peritoneum, except bare area of liver
Demarcated by the reflection of peritoneum from diaphragm to as its
anterior & posterior layer of coronary ligament
Meet on the right to form right triangular ligament
Near apex of wedge shaped liver : meet to form left triangular ligament
Visceral surface
- Concave, posteroinferior
- Covered w/peritoneum, except @ fossa for gallbladder & porta hepatis
- Bears multiple fissure & impression
Right sagital fissure : formed anteriorly by fossa for the gallbladder &
posteriorly by groove for vena cava
Left sagital fissure : formed anteriorly by fissure for ligamentum teres
(round ligament) & posteriorly by fissure for ligamentum venosum
Linked centrally by porta hepatis & form letter H
- Impressions
Right side of anterior aspect of the stomach (gastric & pyloric area)
Superior part of duodenum (duodenal area)
Lesser omentum (extends into the fissures for the ligamentum venosum)
Gallbladder
Right colic flexure & Right transverse colon
Right kidney & suprarenal gland
- Round ligament fibrous remnant of umbilical vein
- Ligamentum venosum fibrous remnant of fetal ductus venosus
- Lesser omentum enclose portal triad
Hepatoduodenal ligament : passes from liver to the lesser curvature
w/stomach & the first 2 cm of superior part of duodenum
Hepatogastric ligament :
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Anatomical Lobes of the Liver


- Divide into 2 anatomically lobes & 2 accessory lobes
- 2 anatomical : right lobe & left lobe
Separated by falciform ligament & left sagital fissure
- 2 accessory lobe : caudate (posterosuperior) & quadrate
ligament(anteroinferior)
Separated by R & L sagital fissures
Functional subdivisions of the liver
- Right & left liver right liver larger
- Each part receives its own primary branch of hepatic artery & portal v ein &
is drained by its own hepatic duct
- Caudate lobe
Considered a third liver
Vascularization is independent of bifurcation of portal triad (it receives
vessels from both bundles)
Drained by one or two small hepatic vein directly into IVC
- Liver can be further divided into 4 division & then 8 surgically resectable
hepatic segment each served by a secondary or tertiary branch of portal
triad
Vascularization
- Dual blood supply dominant venous & lesser arterial one
- Portal vein :
75-80% of blood to liver
Containing >40% oxygen than blood returning to heart
Carries all nutrient absorbed by GIT (except lipid) to sinusoid of liver
Short, wide vein
formed by superior mesenteric & splenic vein posterior to the neck of
pancreas & ascend anterior to IVC
- arterial blood from Hepatic Artery(branch from celiac trunk)

Branches into common hepatic artery & hepatic artery proper


Note :
@ or close to porta hepatis, hepatic artery & portal vein divide into Right & Left
Branches supply R & L liver

Each, branches into secondary branches supply medial & lateral division of R & L
liver

Tertiary branching supply 7-8 hepatic segments


Vein : Collecting vein Central vein IVC
Lymphatic
1. superficial : in subperitoneal fibrous capsule of liver
2. deep : in CT, which accompany ramifications of portal triad & hepatic vein
most of lymph is formed in the perisinusoidal spaces (of Disse)

Drains into deep lymphatic in the surrounding intralobular portal triad


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Superficial in anterior aspect of diaphragmatic & visceral surface of liver & deep
lymphatic vessel accompanying portal triad converge toward porta hepatis

Hepatic lymph nodes

Celiac lymph nodes

Chyle cistern
(dilated sac @ inferior end of thoracic duct)
Superficial lymphatic from posterior aspect of diaphragmatic & visceral surface drain
toward bare area of liver

Phrenic lymph nodes


Or
Join deep lymph that accompanying hepatic vein converging on IVC

Posterior mediastinal lymph nodes

Right lymphatic & thoracic duct


Another route
- from posterior surface of the left lobe toward esophageal hiatus left gastric
lymph nodes
- from anterior central diaphragmatic surfaces along the falciform ligament
parasternal lymph nodes
- along the round ligament og the liver to the umbilicus & lymphatic of the
anterior abdominal wall
nerve
- derived from hepatic plexus
- consist of symphatetic from celiac plexus & parasympathetic from the anterior
& posterior vagal nerve
Histology
Stroma
- dibungkus simpai tipis CT (kapsula Glisson) yg menebal di hilum
- jalinan serat retikular halus menunjang hepatosit & sel endotel sinusoid
dari lobulus hati
Lobulus hati
- komponen utama : sel hati atau hepatosit
- epitel ini berkelompok membentuk lempeng2 satuan struktural lobulus
hati
- lobulus hati
poligonal; 0.7 x 2 mm
berkontak, pd beberapa daerah dibatasi CT ygmengandung duktus biliaris,
lymph, saraf, & pembuluh darah celah portal, dihuni triad portal
- triad portal
3-6 buah per lobulus
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Venul : darah asal vena mesenterika superior + inferior & vena lienalis
arteriol : dari trunkus seliakus & aorta abdominalis
duktus : dilapisi epitel kuboid, membawa cairan empedu
lymph
- Hepatosit
Radier, membentuk lapisan setebal 1-2 sel seperti batu bata
Eosinophilic, byk mitochondria & retikulum endoplasma
Byk mikrovili; 1-2 inti bulat dgn 1-2 nucleoli
Lisosom & badan golgi
Lempeng sel mengarah dari tepian lobulus ke pusat & beranastomosis scr
bebas, membentuk sperti labirin dan busa
Celah antara lempeng : kapiler sinusoid
- Sinusoid
Celah di anata lempeng hepatosit mengandung kapiler
Endotel membentuk lapisan tidak utuh
Sel endotel dipisahkan dari hepatosit o/celah Disse, mengandung mikrovili
dari hepatosit, memudahkan untuk pertukaran makromolekul
Dikelilingi serat retikular
Sel kupffer
Sel penimbun lemak (Ito)/stellate cell mengumpulkan vitamin A yg msk
dr luar sbg ester retinil dlm tetes lipid
Bermuara ke vena sentralis
Lobulus hati klasik
- Darah mengalir dr tepi ke pusat terjadi perbedaan kejadian di sel2
perilobular dan sel2 sentrolobular
Lobulus portal
- Portal triad sentral
- Mencurahkan empedu ke pusatnya
- Mengandung bagian dari 3 lobulus dati yg berdekatan
- Pada setiap ujung terdapat central vein
Asinus hati (rappaport)
- Terletak pada daerah 2 lobulus
- Pusat cabang2 terminal dari portal vein, cabang asteri & sebuah duktus
biliaris
Pembagian berdasarkan kedekatan dgn vena distribusi
- Zona I : plg dkt dgn pembuluh; plg pertama dipengaruhi oleh atau mengubah
darah yg masuk
- Zona II
- Zona III
Aliran darah
- 80% dr vena porta : rendah oksigen, kaya nutrien
- 20% dr arteri hepatika : kaya oksigen
- Sistem vena porta
Vena porta Venul porta (cbg interlobular) Vena distribusi Vena ceruk
SinusoidVena sentralis (sentrolobular) Vena sublobularis Vena
hepatika IVC
- Sistem arteri
Arteri hepatika Arteri interlobularSinusoid
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Aliran empedu
Bile canaliculi Bile ductules Bile duct Right and left hepatic ductCommon
hepatic duct + cystic duct Common bile duct
PANCREAS
Anatomy
- Elongated, accessory digestive gland
- Lies retroperitoneally & transverse across the posterior abdominal wall,
posterior to the stomach bween the duodenum on the right & spleen on the left
- Produces :
Exocrine secretion (pancreatic juice) : enter the duodenum thru main &
accessory pancreatic duct
Endocrine secretion (glucagon, insulin from pancreatic islet) : enter the
blood
- Divided into :
Head of the pancreas
o Expanded part of the gland that is embraced by the C-shaped curved of
duodenum to the right of SM vessels
o Attaches to medial aspect of descending & horizontal part of
duodenum
o Uncinate process projection from inferior part of pancreatic head,
extends medially to the left, posterior to SMA
o Rests posteriorly on the IVC, right renal artery & vein, left renal vein
Neck of the pancreas
o Short (1.5-2 cm) & overlies the superior mesenteric vessel
o Anterior surface of the neck,covered w/peritoneum
o SMV joins splenic vein posterior to the neck to form portal vein
Body of pancreas
o Lies to the left of SM vessels, passing over the aorta & L2 vertebra,
posterior to the omental bursa
o Anterior surface is covered by peritoneum and lies in the floor of
omental bursa & forms part of the stomach bed
o Posterior surface is devoid of peritoneum & contact w/aorta, SMA, left
suprarenal gland, left kidney & renal vessels
Tail of the pancreas
o Lies anterior to left kidney
o Relatuvely mobile & passes between the layers of splenorenal ligament
w/splenic vessels
o Tip of the tail is usually blunted & turned superiorly
- Main pancreatic duct
Begin in the tail of pancreas
Runs thru parenchyma of gland to the pancreatic head turn inferiorly &
closely related to bile duct
Main pancreatic duct + bile duct hepatopancreatic ampulla (of Vater),
open into duodenum @ major duodenal papilla
Sphinter of pancreatic duct, bile duct, hepatopancreatic sphincter (of Oddi)
smooth muscle sphincter
- Accessory pancreatic duct
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Open into duodenum @ minor duodenal papilla


Usually, (60%) communicates w/ main pancreatic duct
Vascularization
Arteries
Splenic artery supply body & tail
Anterior & posterior superior pancreaticoduodenal arteries (branch of
gastroduodenal artery) and anterior & posterior inferior
pancreaticoduodenal arteries (branch of SMA) supply head
Vein : pancreatic vein splenic & SMV (most to splenic)
Lymphatic :
Most end in pancreaticosplenic LN
Pyloric LN
Efferent vessel drain into Superior mesenteric LN or celiac LN via hepatic LN
Nerve : derived from vagus & abdominopelvic splanchnic nerve
Parasympathetic & sympathetic : from celiac plexus & superior mesenteric
plexus
Parasympathetic fiber are secretomotor, but pancreatic secretion is mainly
mediated by secretin & cholecystokinin
Histology
- Adlh campuran kelenjar eksokrin dan endokrin yg memproduksi enzyme dan
hormon pencernaan
- Enzym dari sel eksokrin
- Hormon pulau2 langerhans
- Ditutpi simpai tipis jaringan ikat yg mencabangkan septa ke bagian dalamnya
memisahkan lobuli pankreas
- Asinus dikelilingi lamina basal + serat2 retikular halus
- Memiliki jalinen kapiler luas
Eksokrin
- Kelenjar asinar kompleks serupa kel parotis
- Bagian awal duktus interkalaris menjulur ke dalam lumen asini
- Inti dikelilingi sitoplasma pucat bagian sel centroacinar, yg merupakan
bagian intraasinar dr duktus interkalaris
- Duktus interkalaris berubah menjadi dektus interlobularis (dilapis epitel
silindris)
- Tidak ada duktus striata
- Terdiri dari beberapa sel serosa yg mengelilingi lumen terpolarisasi, inti
bulat, merupakan sel2 penghasil protein; jmlh granul zymogen bervariasi
- Produce air, ion, tripsinogen, kimotripsinogen, karboksipeptidase,
ribonuklease, deoksiribonuklease, triasilgliserol lipase, fosfolipase A2,
elastase, amilase
- Sekresi dikendalikan :
Sekretin : merangsang sekresi yg banyak cairan, kurang enzym, kaya
bicarbonat; disekresi oleh sel duktus bukan asinar
F(x) : menetralisir asam
Kolesistokinin : merangsang sekret yg tidak begitu banyak tetapi kaya
enzim terutama mempengaruhi proses pengeluaran granul zymogen
vagus

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BILIARY DUCT & GALLBLADDER


Bile Duct
Anatomy
- Forms in the free edge of the lesser omentum by the unio of cystic duct &
common hepatic duct
- Length 5-15cm
- Descend posterior to the superior part of duodenum & lies in the groove on
posterior surface of the head of pancreas
- On the left side of descending part of the duodenum contact w/main
pancreatic duct hepatopancreatic ampulla major duodenal papilla
- Circular muscle around distal end of the bile duct is thickened to form the
spinchter of the bile duct
Vascularization
Arteries
Cystic artery : supply proximal part of duct
Right hepatic artery : supply middle part of duct
Posterior superior pancreaticoduodenal artery & gastroduodenal artery :
supply retroduodenal part of duct
Vein
Proximal part of bile duct & hepatic duct directly enter liver
Posterior superior pancreaticoduodenal vein drain distal part of duct
into portal vein
Lymphatic
Cystic LN
Node of omental foramen
Hepatic LN
Histology
Hepatic duct, cystic duct, common bile duct
1. Mucosa
Simple columnar epithelium
Lamina propria : thin, surrounding w/smooth muscle

Makin ke duodenum, makin menebal

Di bagian intramural membentuk sphincter of Oddi


Gallbladder
Anatomy
- 7-10 cm long, lies in the fossa for gallbladder on visceral surfaces of liver
- Body of gallbladder lies anterior to duodenum
- Neck & cystic duct are immediately superior to duodenum
- Peritoneum completely surround fundus gallbladder & binds its body & neck
to the liver
- Hepatic surface of gallbladder attaches to liver by CT of fibrous capsule of
liver
- Has 3 parts :

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Fundus : wide end of organ, projects from inferior border of the liver & is
usually located at the tip of the right 9th costal cartilage in MCL
Body : contacts the visceral surface of the liver, transverse colon, &
superior part of duodenum
Neck : narrow & tapered; directed toward the porta hepatis; it makes Sshaped bend & joins the cystic duct
- Cystic duct (3-4 cm in long) connect neck of gallbladder to common hepatic
duct
- Mucosa of the neck spiral into spiral fold helps keep cystic duct open
Vascularization
Arteries Cystic artery, arises from right hepatic artery
Veins
cystic vein : draining the neck gallbladder & cystic ductenter liver directly
or thru portal vein
vein from fundus & body of gallbladder directly into visceral surface of
liver hepatic sinusoid
Lymphatic : hepatic LN & cystic LN celial LN
Nerve
Celiac plexus : sympathetic & visceral afferent (pain) fiber
Vagus nerve : parasympathetic
Right phrenic nerve : somatic afferent fiber
Histology
- Berbentuk avokad, melekat di bwh permukaan hati
- Menampung 30-50 ml empedu
- Berhubungan dengan hati dengan cystic duct
Dinding kantung empedu
- Simple columnar epithelium
- Lamina propria
- Selapis otot polos
- Selapis jaringan ikat perimuscular yg berkembang baik
- Membran serosa
Mucosa
- Berlipat2 jelas saat kosong
- Epitel : mengandung byk mitochondria, inti si 1/3 bagian basal sel; apikal
banyak mikrovili
- Dekat duktus sistikus : epitel berlekuk ke lamina propria membentuk kelenjar
tubuloasinar dengan lumen lebar penghasil mukus
Muscular
- Tipis, kebanyakan otot polos tersusun di sekitar lingkaran kandung empedu
Adventitia & serosa
- Jaringan ikat mengikat permukaan superior
- Serosa permukaan berlawanan
Fungsi kantung empedu : menyimpan & memekatinya dengan menyerap airnya
melepaskan ke saluran cerna bergantung transpor aktif natrium dalam epitel
Kontraksi diinduksi o/kolesistokinin dirangsang adanya lemak

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PHYSIOLOGY OF LIVER & GALLBLADDER


The main function of the liver & hepatocytes
Function
processes involve
Protein metabolism

synthesis &secretion of albumin


Synthesis of plasma protein
Formation of urea from ammonia
Deamination of amino acids
Synthesis coagulation factors
e.g factors V,VII,IX,X & protrombhin
metabolism of polypeptide hormone

fat metabolism

formation of lipoprotein & fatty acids


synthesis cholesterol
conversion of cholesterol to bile salts
conversion of carbohydrate & protein to
fat
ketogenesis
gluconeogenesis
synthesis & breakdown of glycogen

carbohydrate metabolism
bile secretion

production of bile salts


elimination of bilirubin

storage

glycogen
vitamin (A & B12)

biotransformation and
detoxification

of drugs & exogenous substance


gonadal hormone
aldosterone
glucocorticoid
nitrogrnous gut toxins

protection

filtration of portal blood


removal of bacteria/antigens by kupfer
cells

haematopoiesis

the fetal liver is the majorsource of


blood cells

BILE PRODUCTION
Hati mengeluarkan empedu (bile) sebanyak 600-1200 ml/hari
Function of bile acid
1. Cholesterol metabolism
a. reduction in excess cholesterol
o through degradation of cholesterol to bile acids
o by solubilization of cholesterol in the bile
b. regulation of cholesterol synthesis in the liver and intestine
c. regulation of cholesterol output into the bile

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o 3-,7-bile acids inhibit secretion


o 3-,12-bile acids increase secretion
2. Digestion and resorption of dietary fats
a. by formation of micelles
b. by stabilization and activation of enzymes
(e. g. pancreatic lipase, phospholipase A2,pancreatic cholesterol esterase)
3. Effects on the bile flow due to osmotic water movement
4. Effects on bile secretion
a. monohydroxy bile acids function cholestatically
b. dihydroxy and trihydroxy bile acids have a choleretical effect
5. Emulsification of fat-soluble vitamins
6. Stimulation of intestinal motility
Bile
Bile components.
- electrolytes,
- bile salts (bile acids),
- cholesterol,
- lecithin (phosphatidylcholine),
- bilirubin diglucuronide,
- steroid hormones, medications etc.
pathway
(1.)Bile acid uptake at the sinusoidal membrane surface is achieved
o Actively by several Na+-dependent (NTCP) as well as Na+-independent
(OATP) carrier proteins
o passively by facilitated biological diffusion or free physical diffusion
processes.
(2.)Bile acid release occurs at the biliary membrane surface in the canaliculi
either actively, facilitated by
o ATP-driven carrier glycoproteins such as MRP2 (also called cMRP or
MOAT) and
o hBSEP (human bile salt export pump ), identical to cBAT (canalicular bile
acid transporter).
o by exocytosis of intracellularly derived mixed vesicles,
o with the help of a potential-dependent membrane carrier.
(3.)Bile acid uptake at the mucosal surface of the enterocytes proceeds
o actively either through Na+-dependent carrier systems in the ileum or by free
diffusion in the ileum and colon.
The gall bladder and upper small intestine serve as mechanical stores with the
ability to drive the circulation of the bile pool by peristaltic action.
The bile acids become bound chiefly to albumin or HDL for transport in the
blood.
Incorporation into HDL is effected by apolipoproteins A1 and A2.
Uptake into the hepatocytes
is mediated by a membrane-specific transport system
This influx process is predominantly an active transport mechanism against an
electrochemical gradient. Energy is supplied by Na+/K+-ATPase.
Intracellular transport of bile acids to the biliary pole of the hepatocytes follows
after their binding to cytosolic proteins: free bile acids would be damaging to
subcellular structures because of their amphiphilic nature and detergent activity.
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Control of bile secretion and release


1. Secretin : produced by duodenum, stimulate bile secretion by the liver
2. Cholecystokinin: produced by duodenum, stimulate gall bladder to contract,
thereby releasing bile into duodenum
3. Vagal nerve stimulation : causes gallbladder to contract, thereb releasing bile
into duodenum.
The gallbladder stores & concentrate bile
Bile continually secreted by the liver & flows to gallbladder, where 40-70 ml of
bile can be stored
While bile in the gallbladder, water & electrolyte are absorbed
Bile salts & pigments become as much as 5-10 times more concentrated
PHYSIOLOGY OF BILE
Bile : fluid secreted by the liver, concentrated in gallbladder, and poured to the small
intestine via bile duct.
Chief constituent : conjugated bile salt, cholesterol, phospholipid, bilirubin, &
electrolytes
Function :
- helps in emulsification, absorption, digestion of fats
- alkalinize the intestinal content
Bile Acid : any of the steroid acid derived from the cholesterol
Bile salt : glycine or taurine conjugate of bile acids formed in the liver &
secreted in the bile.
Bile Acids Metabolism
1) Formation of bile acids from cholesterol
- Occurs in the hepatocytes : mostly pericentral hepatocytes
- This process convert the highly insoluble cholesterol to the water soluble bile
acid. Steps :
1. hydroxylation of cholesterol by the enzyme 7-hydroxylase
2. epimerization : conversion of -orientation to - orientation 3
hydroxyl group
- the process yields primary bile acids :
1. chenodoxycholic acid
2. cholic acid
- when these primary bile acid enter the distal small intestine or the colon, they
can be acted by the bacterial enzymes to yield secondary bile acids :
1. lithocholic acid from chenodoxycholic acid
2. deoxycholic acid from cholic acid
3. ursodeocholic acid.
- The most important conversion is litocholic acid & deoxycholic acid
Lithocholic acid is cytotoxic in high concentration
- very little ursodeoxycholic acid is formed in humans . It is formed by
epimerization of the 7 hydroxyl group.
2) Bile acid conjugation
- Following hepatic synthesis :
Primary bile acid secondary bile acid
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glycine & taurine

Returned to
liver

conjugated bile salt

PRIMARY BILE ACID


The primary bile acids are formed in the hepatocytes as liver-specific degradation
products of cholesterol due to the action of microsomal, peroxisomal and
mitochondrial enzymes; they are linked to cytosolic proteins
The two primary bile acids represent 60-90% of the total bile acid production:

Biosynthesis of the two primary bile acids is followed by conjugation of their


carboxylic group with the amino group of either glycine or taurine, mediated by a
cytoplasmic enzyme.
By means of this conjugation, the primary bile acids, which initially are barely
water-soluble, become anions and are thus rendered hydrophilic.
In this way four conjugated bile acids are formed:

SECONDARY BILE ACID

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The secondary bile acids result from the activity of anaerobic intestinal
microorganisms in the ileum, caecum and colon. bacteria can deconjugate both
primary and secondary bile acids, making them more lipophilic
This is followed by 7-dehydroxylation of :
- cholic acid deoxycholic acid
- chenodeoxycholic acid lithocholic acid,
- 7-dehydrogenation and oxidation of chenodeoxycholic acid also yield
ketolithocholic acid
Unconjugated bile acids can be considered "damaged" and can be passively
absorbed across the wall of the intestine
Secondary bile acid :

The secondary bile acids become partially (30-50%) absorbed in the intestine,

They then travel through the portal vein back to the liver, where they are
reconjugated in the hepatocyte

following reconjugation with glycine or taurine in the liver, they excreted into the
canaliculi.

The bile thus contains a mixture of primary and secondary bile acids & therefore,
all bile acids secreted by the hepatocyte are in their conjugated forms.
The conjugated bile salt are more water soluble and structurally can be actively
transported across the canalicular membrane
Deoxycholic acid as a secondary bile acid is likewise an end-product; it enters
the enterohepatic circulation without further modification.
(re) Conjugation of the secondary bile acids in the liver yields the following four
conjugated bile acids:

TERTIARY BILE ACIDS


The tertiary bile acids are formed in the liver as well as in the gut.
- Intestinally absorbed lithocholic acid is enzymatically converted to
sulpholithocholic acid in the liver.
- Ketolithocholic acid is transformed to (hypercholeretic) ursodeoxycholic acid
in both the intestine and the liver.
When passing through the canaliculi, UDC is partly reabsorbed by epithelial cells
and returned to the liver via the blood circulation (cholehepatic shunt).
The tertiary bile acids:
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The bile acids may be further modified by enzymatic reactions. The enzymes
involved have been found in the liver, intestine and kidney.
By their action, conjugated and unconjugated primary or secondary bile acids may
become bound to sulphuric acid, glucuronic acid or glucose. A further
improvement in water-solubility can be obtained by sulphation or glucuronidation.
lithocholic acid can be sulfated, particularly if present in abnormally high
concentrations This increases the hydrophilicity of the molecule and is
therefore believed to reduce its cytotoxic effects

Regulation of bile biosynthesis of bile acid


Regulation of the biosynthesis of bile acids :
- through feedback by the respective daily loss quota (predominantly)
- by HMGCoA reductase and 7-hydroxylase, which are themselves chiefly
adjusted by ursodeoxycholic acid.
Bile acids exert feedback inhibition on cholesterol 7 -hydroxylase,
such that when return of bile acids from the intestine is high, the
synthesis of new primary bile acids is reduced.
With advancing age, bile acid synthesis in the liver decreases and excretion of
cholesterol in the bile increases.
The terms bile acids and bile salts are interchangeable.
Bile Acids Composition
1. Canalicular bile

The secretion of bile begins when bile acids are actively secreted across the
canalicular membrane.

Canalicular bile is transiently hyperosmotic However, the tight junctions that


delineate the canaliculus are relatively permeable, and so water is drawn into the
canaliculus to balance this, along with plasma cations to maintain electrical
neutrality.

The composition of canalicular bile is also modified by the active secretion of


additional substrates from the hepatocyte itself. The composition are :
-

Conjugated bilirubin - Gluthathione

Cholesterol

Glucose, amino acids, urea - Xenobiotics

Cations : e.g. Calcium

- Phosphatidylcholine

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2. Ductular bile

The bile ductules (canal of hering) are lined by cholangiocytes, which are
columnar epithelial cells specialized to modify bile composition.

The tight junctions linking the cholangiocytes are much less permeable than those
linking hepatocytes. They are freely permeable to water, but are only selectively
permeable to electrolytes and impermeant to larger solutes bile rapidly
becomes isotonic

Modification :

glucose is actively reabsorbed and returned to the bloodstream.

glutathione is hydrolyzed to its constituent amino acids by the apically-fixed


enzyme, gamma glutamyltranspeptidase (GGT)

The reuptake of glucose and amino acids is likely important in preventing


bacterial overgrowth in the biliary tree, by limiting nutrient availability.

Overgrowth of bacteria in the bile ductules has potentially serious


consequences because bacterial enzymes can deconjugate bilirubin,
yielding a product that can form a highly insoluble salt with calcium that is
present in the bile pigment stone.

the cholangiocytes secrete bicarbonate in response to secretin

Sodium ions follow paracellularly to maintain electrical neutrality, in turn


drawing additional water into the bile and increasing its volume and flow.
Thus, bile becomes slightly alkaline.

the ductules secrete IgA molecules into the bile

The composition of ductular bile :

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3. Hepatic bile
Hepatic bile refers to the bile that emerges from the liver in the common hepatic
duct, prior to further modification by gallbladder storage
The large bile ducts are thought to have little ability to modify bile composition,
other than by adding mucus that presumably serves a protective and lubricating
role. Thus, the composition of hepatic bile reflects that which emerges from the
ductules
liver synthesizes 200400 mg of bile acids per day

Enterohepatic Circulation of Bile Acid


Intestinal Uptake Mechanisms
Bile acids secreted into the gut lumen are initially entirely in conjugated form.

Because these conjugated bile acids are ionized, they cannot cross the wall of
the intestine passively.

The reabsorption of conjugated bilirubin via the process of secondary active


transport.

The transporter :
1) sodium-coupled transporter,i.e. the apical sodium-dependent bile salt
transporter or ASBT.

ASBT expression in the intestine is limited to epithelial cells in the


terminal ileum.

Thus, conjugated bile acids remain with the meal in the lumen until the
nutrients are absorbed.

2) OST is present at the basolateral domain of ileal epithelial cells

Only a minor portion of the bile acid pool spills over into the colon in health.

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Hepatocyte transport mechanism

Bile acids returned to the liver, either in conjugated or unconjugated form, leave
the portal circulation in the sinusoids bound to albumin and then are specifically
taken up across the basolateral membrane of the periportal hepatocytes.

The transporter are :

Table 111. Hepatocyte Transporters

Name

Location

Substrate/function

Sodium taurocholate
cotransporting
polypeptide (NTCP)

Basolateral
membrane

Uptake of conjugated bile acids from blood

Organic anion
transporting protein
(OATP)

Basolateral
membrane

Uptake of bile acids and xenobiotics from


blood

Bile salt export pump


(BSEP)

Canalicular
membrane

Secretion of conjugated bile acids into bile

Multidrug resistance
protein 3 (MDR3)

Canalicular
membrane

"Flippase" that adds phosphatidylcholine to


bile

Multidrug resistance
protein 1 (MDR1)

Canalicular
membrane

Secretion of hydrophobic cationic drugs into


bile

ABC5/ABC8

Canalicular
membrane

Secretion of cholesterol into bile

Multiple organic anion


transport protein
(cMOAT, MRP2)

Canalicular
membrane

Secretion of sulfated lithocholic acid and


conjugated bilirubin into bile

Regulation of bile secretion motor function of gallbladder & biliary system


1. determinants of gallbladder pressure & filling
- whether hepatic bile will enter the gallbladder, or be secreted directly to the
intestine, depends on interrelationship between 3 pressures :
(a) hepatic secretion pressure
(b) sphincter of Oddi pressure
(c) receptive relaxation of gallbladder
gallbladder contraction & sphincter of Oddi contraction

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BILIRUBIN METABOLISM ( liat bagan)

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DRUGS & HORMONE METABOLISM


The liver metabolized drugs & hormone via biotransformation in 3 stages :
phase 1 : oxidation
- major reaction involved is hydroxylation, catalyzed by members of a class of
enzymes referred to as monooxygenases or cytochrome P450s.
- Hydroxylation may terminate the action of drug,

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In addition to hydroxylation, these enzymes catalyze a wide range of


reactions, including those involving deamination, dehalogenation,
desulfuration, epoxidation, peroxygenation, and reduction.
phase 2 : conjugation
- the hydroxylated or other compounds produced in phase 1 are converted by
specific enzymes to various polar metabolites by conjugation with glucuronic
acid, sulfate, acetate, glutathione, or certain amino acids, or by methylation.
Phase 3 : elimination
The overall purpose of the two phases metabolism of xenobiotics is to increase
their water solubility (polarity) and thus excretion from the body.
Very hydrophobic xenobiotics would persist in adipose tissue
In certain cases, phase 1 metabolic reactions
- convert xenobiotics from inactive to biologically active compounds.
- convert the active compounds to less active or inactive forms prior to
conjugation.

PHASE 1
The reaction catalyzed by a monooxygenase (cytochrome P450) is as follows:
RH (drugs) + O2 + NADPH + H+
R-OH + H2O +NADP
OR
Reduced cytochrome P450
oxidized cytochrome P450
RH + O2

R-OH + H2O

PHASE II
Five Types of Phase 2 Reactions Are Described Here
1. Glucuronidation

UDP-glucuronic acid is the glucuronyl donor,

variety of glucuronosyltransferases, present in both the endoplasmic reticulum


and cytosol, are the catalysts.

Molecules such as 2-acetylaminofluorene (a carcinogen), aniline, benzoic


acid, meprobamate (a tranquilizer), phenol, and many steroids are excreted as
glucuronides.

the most frequent conjugation reaction.

2. Sulfation
Some alcohols, arylamines, and phenols are sulfated.

the sulfate donor in these and other biologic sulfation reactions (eg, sulfation
of steroids, glycosaminoglycans, glycolipids, and glycoproteins) is adenosine
3'-phosphate-5'-phosphosulfate (PAPS)

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3. Conjugation with Glutathione (gsh)

Glutathione (-glutamyl-cysteinylglycine) is a tripeptide consisting of


glutamic acid, cysteine, and glycine

A number of potentially toxic electrophilic xenobiotics (such as certain


carcinogens) are conjugated to the nucleophilic GSH in reactions that can be
represented as follows:
R (electrolic xenobiotic)+ GSH

R-S-G

Enzim untuk katalisisnya : glutathione S-transferases found in liver cytosol


and in lower amounts in other tissues.

If the potentially toxic xenobiotics were not conjugated to GSH, they would be
free to combine covalently with DNA, RNA, or cell protein and could thus
lead to serious cell damage.

GSH

defense mechanism

Other reaction
Acetylation
Acetylation is represented by
X + Acetyl-CoA

Acetyl-X + CoA

catalyzed by acetyltransferases present in the cytosol of various tissues,


particularly liver

Slow acetylators are more subject to certain toxic effects.

Methylation
A few xenobiotics are subject to methylation by methyltransferases, employing Sadenosylmethionine as the methyl donor.

PHYSIOLOGY OF PANCREAS
PANCREATIC SECRETION
Product of pancreatic secretion = Pancreatic Juice
Pancreatic juice is a mixture of :
- Pancreatic enzymes secreted by pancreatic acini
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Large volume of sodium bicarbonate solution secreted by small ductule


& larger ducts leading from the acini.
Pancreatic juice is secreted most abundantly in response to the presence of chyme
in the upper portion of small intestine.
I. Pancreatic Digestive Enzymes
Enzyme for digestion of protein
The most important of the pancreatic enzymes for digesting proteins are : Trypsin,
Chymotrypsin & Carboxypolypeptidase.
1) Trypsin & Chymotrypsin : split whole & partially digested protein
various sizes of polypeptide (but not cause release of individual amino acids)
2) Carboxypolypeptidase : split some peptides individual amino acids
(completing digestion of some proteins all the way to amino acids state)
The proteolytic enzymes are in the inactive forms when first synthesized in the
pancreatic cells, i.e. Trypsinogen, chymotrypsinogen, & procarboxypolypeptidase
become activated only after they are secreted into intestinal tract.
Trypsinogen is activated by enterokinase (secreted by intestinal mucosa) or
autocatalytically activated by trypsin that has already been formed from
previously secreted trypsinogen.
Chymotrypsinogen, Procarboxypolypeptidase is activated by trypsin
Enzyme for digestion of carbohydrate
Pancreatic enzyme for digesting carbohydrates is : pancreatic amylase :
hydrolyzes starches, glycogen, & most other carbohydrate (except cellulose)
form mostly disaccharides (maltose) & a few trisaccharides (maltotriose) & dextrin.
Enzyme for digestion of fat
The main enzymes for fat digestion are :
2. Pancreatic Lipase : hydrolyzing neutral fat fatty acids & monoglycerides
3. Cholesterol Esterase : hydrolysis of cholesterol esters
4. Phospholipase : splits fatty acids from phospholipids
Enzyme for digestion of Nucleic Acids (Nuclease)
1. Ribonuclease : split RNA nucleotide
2. Deoxyribonuclease : split DNA nucleotide
Secretion of Trypsin Inhibitor
IMPORTANT: proteolytic enzyme of the pancreatic juice must not become
activated until after they have been secreted to intestine because : trypsin &
other enzymes would digest the pancreatic itself.
Fortunately the same cell that secretes proteolytic enzymes into the acini of
pancreas secrete simultaneously another substance called Trypsin Inhibitor
prevents activation of trypsin directly & other enzymes indirectly.
II. Secretion of Bicarbonate Ion
Bicarbonate ion & water are secreted mainly by the epithelial cells of ductules &
duct that lead from acini.
Basic steps in secretion of bicarbonate ion :
1) CO2 diffuse to the interior of the cell from blood, then :
CO2 + H2O H2CO3 HCO3- + H+
2) Bicarbonate ion (HCO3-) are actively transported in association with Na+ through
the luminal border of the cell into the lumen of the duct.
3) H+ are exchanged for Na+ through the blood border of the cell by secondary
active transport process supplies Na+
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4) The overall movement of H + & Na+ ions from the blood into the duct lumen
creates osmotic pressure gradient osmosis of water to the pancreatic duct
forming an almost isosmotic bicarbonate solution.
Regulation Of Pancreatic Secretion
3 Basic stimuli are important in causing pancreatic secretion :
1. Acetylcholine : release from parasympathetic n.s.
2. Cholecystokinin : secreted by duodenal & upper jejunal mucosa
3. Secretin : secreted by duodenal & upper jejunal mucosa when theres highly
acid food enters small intestine.
Acetylcholine & Cholecystokinin stimulate the acinar cell to produce
large quantity of digestive enzyme but relatively small quantities of
water & electrolytes without the water, most of the enzyme remain
temporarily stored in the acini & ducts until more fluid secretion comes to
wash them into the duodenum.
Secretin : >>water & electrolytes (sodium bicarbonate)
Pancreatic secretion normally results from the combined effects of the multiple basic
stimuli, not from one alone.
Phases of Pancreatic Secretion
Occurs in 3 phases :
1) Cephalic phase
- nervous signal acetylcholine release by vagus nerve moderate
amounts of enzymes secreted into the pancreatic acini (20% after meal)
- little of the pancreatic secretion flows immediately through the pancreatic
duct to the intestine because only small amount of water & electrolyte are
secreted.
2) Gastric phase
- continuation of nervous stimulation secretion of pancreatic juice (510% after meal)
- only small amount of the juice reach the duodenum
3) Intestinal phase
- after chyme leaves the stomach & enters the small intestine, pancreatic
secretion becomes copious, mainly in response to hormone secretin.
Secretin simulates secretion of copious quantities of Bicarbonate ion neutralize
acidic stomach chyme.
Cholecystokinin (CCK)
Release of CCK especially caused by presence of proteoses & peptone
(product of partial protein digestion) & Long chain Fatty Acid (LCFA) in
chyme.
CCK absorbed into blood stimulate mainly release of more pancreatic
enzyme by the acinar cell.

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GINJAL DAN HIPERTENSI GUS


KIDNEY
Anatomy
- retroperitoneal
- @level T12-L3 vertebrae
- Right kidney slightly inferior to the left kidney bcoz of liver
- 10 x 5 x 2.5cm
- Each kidney has :
anterior & posterior surfaces
medial & lateral margin
superior & inferior poles
- Superior : diaphragm
- Inferior : quadratus lumborum muscle
- Right kidney related to liver, duodenum, & ascending colon
- Left kidney related to the stomach, spleen, pancreas, jejunum, & descending colon
- @hilum (anterior to posterior) : renal vein-renal artery-renal pelvis entrance to
renal sinus
- renal pelvis : flatenned, funnel-shaped expansion of superior end of ureter
apex of renal pelvis is continuos w/ureter
receives 2-3 major calices each divides into 2-3 minor calices each id
indented by renal papilla (apex of renal pyramid, from which urine is excreted)
- vasculature
arteries from renal arteries (arise @ IV disc L1-L2)
divides close to hilum into segmental arteries:
o superior (apical) segment supplied by superior (apical) segmental artery
o anterosuperior segments supplied by anterosuperior segmental artery
o anteroinferior segments supplied by anteroinferior segmental artery
o inferior segment supplied by inferior segmental artery
o posterior segment supplied by posterior segmental artery
note :
4 arteri plg atas berasal dari anterior branch of renal artery
Posterior segment berasal dari posterior branch of renal artery
Renal artery 5 segmental arteries Interlobar artery arcuate artery
Interlobular artery Afferent arterioles Glomerulus Efferent arterioles
Peritubular capillaries Interlobular vein Arcuate vein Interlobar vein
Renal vein IVC
Veins
left renal vein also receives :left suprarenal vein, left gonadal (testicular or
ovarian) vein, & communication w/ ascending lumbar vein
lymphatic
right and left lumbar (caval & aortic)lymph nodes
Nerve
Arise from renal nerve plexus (from abdominopelvic splanchnic nerve) & consist
of symphatetic & parasymphatetic
Histology
- Kidney can be divided into :
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Outer cortex

Inner medulla : 10-18 medullary pyramid (medullary rays penetrate cortex)

- Each kidney is composed of 1-4 million nephrons


- 2 type of nephron : cortical & juxtamedullary nephron
- Nephron, consist of :

Renal corpuscles : glomerulus & Bowmans capsule

Renal tubules :prximal convoluted tubule, loop of henle, distal convoluted tubule,
collecting tubule & duct

Renal Corpuscles consists of :


Glomerulus : capillary w/fenestrated endothelial cell
glomerular (Bowman's) capsule
visceral layer : podocytes cell, have primary processes seconday processes
(pedicles) di antaranya filtration slit
the parietal layer :simple squamous epithelium + basal lamina + a thin layer of
reticular fibers
Note : between them urinary space
- Pole : vascular pole & urinary pole
- Glomerular Filtration Membrane :

Podocytes

Basement Membrane (~0.1m), consist of :


o Lamina rarae : fibronectin charge barrier
o Lamina densa : type IV collagen + laminin + (-)charge proteoglycan heparan
sulfate physical barrier
o Lamina rarae : fibronectin charge barrier

Endothelial cell of glamerular capillaries

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- So, particles > 10 nm in diameter and negatively charged proteins (X) across
mesangial cells :@ wall of glomerular capillaries & extraglomerular (form part JGA);
contractile and have receptors for angiotensin II & ANP
Proximal Convoluted Tubule
- cuboidal, or low columnar

have acidophilic cytoplasm numerous mitochondria

have microvilli

- longer than the DCT


- wide lumen
Henle's Loop
- consisting of :

a thick descending limb (60m) similar w/DCT

a thin descending limb (12m) squamous epithelial cell

a thin ascending limb squamous epithelial cell

a thick ascending limb similar to DCT

Distal Convoluted Tubule


- lined with simple cuboidal epithelium
- have no brush border, no apical canaliculi, and smaller cells, more nuclei are seen
- @ close contact w/afferent arteriole modified into columnar cell macula densa
cells
Collecting Tubules & Ducts
- collecting tubules (d= 40m) : lined with cuboidal epithelium
- deeper into the medulla increase in height until bcomz columnar
- have electron-lucent cytoplasm with few organelles.
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Juxtaglomerular Apparatus
- Consist of :
1. JG cells modified smooth muscle cells of afferent arterioles; secrete renin
2. Macula densa
3. Extraglomerular mesangial cells or lacis cell

PHYSIOLOGY OF KIDNEY
Urine Formation
Rates are which different substances are excreted in urine represent the sum of :
- Glomerular filtration
- Reabsorption of substances from renal tubules into the blood
- Secretion of substances from blood into renal tubules
Urinary excretion rate = filtration rate - reabsorption rate + secretion rate
4 hypothetical substances :
1. Panel A : substance is freely filtered by glomerular capilaries, neither
reabsorbed bor secreted
Cth : creatinine
Excretion rate = filtration rate
2. Panel B : substance is freely filtered but is also partially reabsorbed from
tubules back into blood
Cth : electrolytes
Excretion rate = filtration rate reabsorption rate
3. Panel C : substance is freely filtered but is not excreted into urine because all
the filtered substance is reabsorbed from tubules back to the blood
Cth : amino acids & glucose
4. Panel D : substance is freely filtered & is not reabsorbed, but additional
quantities of this substance are secreted from peritubular capillaries blood into
renal tubules
Rapidly cleared from the blood & excreted in large amounts in urine
Cth : certain foreign subtances & drugs
Excretion rate = filtration rate + tubular secretion rate
Each of process~glomerular filtration, tubular reabsorption or secretion~ is
regulated according to the need of body
Ex : when sodium is excess in the body rate at which sodium is filtered increase &
a smaller fraction is reabsorbed. So, increased urinary excretion of sodium
Why are large amounts of solutes filtered & then reabsorbed by kidney?
1. High GFR allows kidney to rapidly remove waste product from body that
depend primarily on glomerular filtration for their excretion
Most waste products are poorly reabsorbed by tubules & therefore depend
on a high GFR for effective removal from body
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2. High GFR allows all the body fluids to be filtered & processed by the kidney
many times each day
Plasma volume = 3L, GFR = 180L/day entire plasma can be filtered &
procesed about 60x/days allows kidney to precisely & rapidly control
volume & composition of body fluids
Glomerular Filtration
Composition of Glomerular Filtrate
Filtered fluid (glomerular filtrate) is protein-free & devoid of cellular elements,
including RBC
u/ salts & organic molecules similar to concentrations in the plasma
Exception include a few low-molecular weight substances such as calcium & fatty
acids are not freely filtered bcoz partially bound to plasma proteins
GFR: 125 ml/min or 180 L/day
Fraction renal plasma flow that is filtered (filtration fraction) about 0.2 means that
20% of plasma flowing thru kidney is filtered thru glomerular capillaries
Filtration fraction = GFR/Renal Plasma flow
Glomerular Capillary Membrane
3 layers :
- Endothelium of capillary
High filtration rate across glomerular capillary membrane is due to special
characteristic endothelium is perforated by thousands of small holes called
fenestrae .
Note : although fenestration are relatively large, endothelial are endowed
w/fixed negative charges hinder passage of plasma proteins
- Basement membrane
consist of meshwork of collagen & proteoglycans fibrillae that have large
spaces thru which can filter large amounts of water & small solutes
effectively prevents filtration of plasma proteins, bcoz of strong negative
electrical charges associated w/proteoglycans
- Layer of epithelial cells (podocytes)
Not continuos but have long footlike processes (podocytes) that encircle
the outer capilaries
Separated by gap slit process thru which glomerular filtrate moves
Also have negative charges provide additional restriction to filtration
plasma protein
Negatively charged large molecules are filtered less easily than positively charged
molecules of equal molecular sizes
diameter albumin: 6 nanometer, pores glomerular membrane : 8 nanometer
albumin restricted from filtration bcoz of its negative charge & electrostatic repulsion
exerted by negative charges of glomerular capilary wall proteoglycans
In certain kidney disease, there are loss of negatively charge can be proteinuria
Determinants of GFR
By :
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1. Sum of hydrostatic & colloid osmotic forces across the glomerular membrane
net filtration pressure
2. Glomerular capillary filtration coefficient, Kf
GFR = Kf x Net filtration pressure
Net filtration pressure : sum of hydrostatic & colloid osmotic forces that either favor
or oppose filtration across the glomerular capillaries, include :
- Hydrostatic pressure inside glomerular capillaries (glomerular hydrostatic
pressure PG) promotes filtration
- Hydrostatic pressure in Bowmans capsule (PB) opposes filtration
- Colloid osmotic pressure of the glomerular capillary plasma protein ( G)
opposes filtration
- Colloid osmotic pressure of the protein in Bowmans capsule promotes
filtration
(under normal condition, concentration protein in glomerular filtrate is so low
that the colloid osmotic pressure of bowman capsule fluid is considered to be
zero)

GFR = Kf X (PG PB G + B)
*Increased GFR Coefficient Increases GFR
KF : a measure of the product of the hydraulic conductivity & surface area of
glomerular capillaries; cannot be measured directly but it is estimated by :
Kf = GFR /Net filtration pressure
Calculated about 12.5 ml/min/mmHg of filtration pressure or 4.2 ml/min/mmHg per
100 gr of kidney weight compared w/other tissue is only about 0.01 ml/min/mmHg
per 100 gr
SO, this high Kf for glomerular capillaries contributes tremendously to their rapid rate
of fluid filtration
Note: do not provide a primary mechanism for normal da-to-day regulation of GFR
*Increased Bowmans Capsule Hydrostatic Pressure Decreases GFR
*Increased Glomerular Capillary Colloid Osmotic pressure Decreases GFR
As blood passes from afferent arteriole thru glomerular capillaries to efferent arteriole
plasma protein concentration increases about 20%
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Why?

Bcoz about 1/5 fluid in capillaries filter into Bowmans capsule thereby concentrating
glomerular plasma protein that are not filtered
Normal colloid osmotic pressure of plasma entering glomerular capillaries : 28 mmHg
rises to 38 mmHg by the time the blood reaches efferent end of capilaries, so
average colloid osmotic pressure of glomerular capillary plasma protein is 32mmHg
2 factors that influence glomerular capillaries colloid osmotic pressure :
- arterial plasma colloid osmotic pressure if increase, increasing glomerular
capillary colloid osmotic pressure
- fraction plasma filtered by the glomerular capillaries (filtration fraction) if
increase, concentrates plasma protein & raises the glomerular colloid osmotic
pressure
consequently, even w/a constant glomerular hydrostatic pressure, a greater rate o
fblood flow into the glomerulus tends to increase GFR, & a lower rate of blood flow
into glomerulus tends to decrease GFR
*Increased Glomerular Capillary Hydrostatic Pressure Increases GFR
primary means for physiological regulation of GFR
Determined by :
- arterial pressure glomerular
hydrostatic pressure GFR
- afferent arteriolar resistan ce
glomerular hydrostatic pressure
- efferent arteriolar resistance
glomerular hydrostatic pressure
note : if constriction efferent arterioles is
severe (>3x) in colloid osmotic pressure
exceed the increase in glomerular
hydrostatic pressure net force for
filtration decreases reduction GFR
Renal Blood Flow
70 kg man blood flow to kidney : 1100ml/min or 22% of CO high blood flow
comparing other organs
Why? Bcoz to supply enough plasma for the high rates of glomerular filtration that
are necessary for precise regulation of body fluid volume & solute concentrations
Determined by pressure gradient across the renal vasculature (difference bween renal
artery & renal vein hydrostatic pressure), divided by the total renal vascular resistance
Renal blood flow =

renal artery pressurerenal vein pressure


total renal vascular resistance

Note
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renal artery pressure : equal to systemic arterial pressure


renal vein pressure : average 3-4mmHg under most condition
total vascular resistance : sum of resistance in individual vasculature
segments, including arteries, arterioles, capillaries, & veins
most of renal vascular resistance resides in 3 major segments :
o interlobular arteries
o afferent arterioles
o efferent arterioles
control by sympathetic nervous system, hormones, local internal renal
control mechanism
although changes in arterial pressure have some influence on renal blood flow, the
kidney have effective mechanism for maintaining RBF & GFRrelatively constant over
an arterial pressure range bween 80-170mmHg autoregulation
renal cortex receives most of kidney blood flow
renal medulla only 1-2% of total renal blood flow
Physiologic Control of Glomerular Filtration & Renal Blood Flow
Sympathetic Nervous System Activstion Decreases GFR
- all blood vessel of kidney is innervated by sympathetic nerve fiber
- activation constriction renal arterioles decreases renal blood flow
decrease GFR
- important in reducing GFR during severe, acute disturbances, lasting for a few
minutes to a few hours, such as : defense reaction, brain ischemia, or severe
hemorrhage
Hormonal & Autacoid Control

Norepinephrine, Epinephrine, & Endothelin constrict renal blood vessel &


decrease GFR
- NE, epinephrine released by adrenal
- Endothelin released by damages vascular endothelial cell
Angiotensin II constrict efferent arterioles Increase glomerular hydrostatic
pressure
- F(x) :
help to prevent decreases in glomerular hydrostatic pressure & GFR
efferent arterioles constrict decrease renal blood flow decreased flow
thru peritubular capillaries increases reabsorption of sodium & water
restore BV & BP
preserve GFR maintain a normal excretion of metabolic waste product
(urea & creatinine)
Endothelial-Derived NO decrease renal vascular resistance & increase GFR
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Prostaglandins & Bradykinin increase GFR


- PGE2, PGI2, bradykinin : cause vasodilation & increased RBF & GFR
Autoregulation of GFR & Renal Blood Flow
feedback mechanism intrinsic to kidney normally keep renal blood flow & GFR
relatively constant despite marked changes in arterial BP
not 100% perfect, but they do prevent potentially large changes in GFR & renal
excretion of water & solutes
F(x) :
- Maintain delivery of oxygen & nutrients to the tissue at normal level
- Remove waste product of metabolism
Changes : as low as 75mmHg or an increase as high as 160mmHg
Cth :
Normal GFR : 180 L/day, tubular reabsorption : 178.5 L/day 1.5L/day of fluid to
be excreted in urine
If there are increase BP (from 100 to 125mmHg) increase GFR 25% (from180 to
225L/day) If tubular reabsorption remained constant 178.5 increase urine flow
to 46.5L/day increase urine more than 30-fold!!
In reality, such change in BP exert much less of an effect bcoz of :
- Renal autoregulation preent large changes in GFR that would otherwise occur
- Additional adaptive mechanism in renal tubules that allow them to increase
their reabsorption rate when GFR rises glomerulotubular balance
Role of Tubuloglomerular Feedback in Autoregulation of
GFR
Kidney have feedback mechanism changes in sodium
chloride @macula densa w/the control af renal arteriolar
resistance
This help to ensure a relatively constant delivery of sodium
chloride to distal tubule & helps to prevent spurious
fluctuations in renal excretion
Has 2 components :
- Afferent arteriolar feedback mechanism
- Efferent arteriolar feedback mechanism
depend on special anatomical arrangement of
juxtaglomerular complex (macula densa + juxtaglomerular
cells)
Myogenic Autoregulation of Renal Blood Flow & GFR
- Mechanism : Ability of BV to resist stretching during increased arterial
pressure myogenic mechanism
- Respond to increased wall tension or wall stretch by contraction of vascular
SM prevent overdistention of vessel & by raising vascular resistance, help
to prevent excessive increases in RBF & GFR when arterial pressure increases
Tambahan
- High protein intake increase RBF & GFR
Mech :

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High protein meals Increase release amino acids into the blood
Reabsorbed in proximal tubule Reabsorbed together w/sodium
Decreased sodium delivery to macula densaElicit tubuloglomerular
feedback-mediated decrease in resistance afferent arterioles Raise RBF &
GFR
High glucose increase RBF & GFR (w/same mechanism w/protein)

Reabsorption & Secretion


Urine excretion = glomerular filtration tubular reabsorption + tubular secretion
Tubular reabsorption is quantitatively large & selective :
- quantitatively large a small change in glomerular filtration or tubular
reabsorption can potentiaaly cause a relatively large change in urine excretion
ex:<<10% in tubular reabsorption from 178.5 to 160.7 L/day would
increase urine volume from 1.5 to 19.3 L/day (if GFR remained constant)
- selective : depend on substance (table 27.1)
Proximal Tubular Reabsorption
- 65 % sodium & water, & slightly lower percentage of filtered chloride
-

High capacity for reabsorption


why? Bcoz highly metabolic &
have large numbers of
mitochondria to support potent
active transport process
Also have :
extensive brush border on
luminal (apical) side
extensive labyrinth of
intercellular & basal channels
All of these, provide extensive
membrane seurface area on luminal
& basolateral sides
sodium reabsorption :
extensive membrane surface
loaded w/protein carrier
molecules co-transport (@luminal membrane)
counter transport (w/hydrogen)
sodium-potassiumATPase pump major forces for reabsorption of sodium,
chloride & water...But there are different mechanism in early & late portion of
proximal tubule
1st half : by co-transport w/glucose, amino acid, other solutes
2nd half : by co-transport w/chloride ion
Concentration sodium @ proximal tubule & total osmolarity remains
relatively constant water permeability also high
Glucose, amino acid, bicarbonate much more avidly reabsorbed
decrease concentration
Creatinine increase concentration (bcoz less permeable)
Total solute concentration ~remains same all along proximal tubule~
Proximal tubule also important for :

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secretion or organic acids & base, such as bile salts, oxalate, urate, &
catecholamine so, excretion = filtration + secretion w/lack reabsorption
rapid excretion
secretion drug or toxins penicillin or salicylates
secretion para-aminohippuric acid (PAH)

Loop of Henle
Descending part of thin segment no brush border, few mitochondria, minimal level
of metabolic activity
- highly permeable to water 20% of filtered water
- moderately permeable to : urea & sodium
Thick segment of Loop of Henle
- have high metabolic activity
- capable of active reabsorption of sodium, chloride, potassium
- thick ascending limb : reabsorption of calcium, bicarbonate, magnesium
- @basolateral membrane Na/K ATPase pump
- low intracellular sodium concentration provide a favorable gradient for
movement from tubular fluid into cell
- @ luminal membrane :
mediated by 1-sodium, 2-chloride,1-potassium co-transporter uses
potential energy released by downhill diffusion of sodium into the cell to
drive the reabsorption of potassium into the cell against a concentration
gradient
sodium-hydrogen counter-transport mechanism sodium reabsorption &
hydrogen secretion
- There is also significant paracellular reansorption of cation : Mg++, Ca++,
Na+, K+ bcoz slight (+) charge in tubular lumen relative to interstitial fluid
(why? Bcoz in 1-sodium, 2-chloride, 1-potassium cotransporter, there is slight
backleak of potassium into lumen +8 mV)
- Thick ascending limb : impermeable to
water very dilute

Distal tubule
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Very first part forms juxtaglomerular complex that provide feedback


control og GFR & blood flow
- Next early part : for reabsorption avidly reabsorb sodium, potassium,
chloride, but impermeable to water
- Called diluting segment
Late Distal Tubule & Cortical Collecting Tubule
Composed of :
- Principal cell
F(x) : reabsorb sodium & water & secrete potassium
By sodium-potassium ATPase pump in basolateral membrane maintain
low sodium concentration inside the cell & favors sodium diffusion into
the cell thru the special channel
Secretion potassium involved 2 steps:
o Potassium enter the cells bcoz sodium-potassium ATPase maintain
high intracellular potassium concentration
o Once in the cell, potassium diffuses down its concentration gradient
across the luminal membrane into tubular fluid
- Intercalated cell
Reabsorb potassium & secrete hydrogen
Secrete hydrogen : by hydrogen ATPase transport mechanism
Hydrogen is generated by action of carbonic anhydrase on water & CO2

Form carbonic acid

Dissociates into hydrogen & bicarbonate ion

Hydrogen ion secreted into lumen


Note : for each hydrogen secreted, a
bicarbonate ion bcomes available for
reabsorption across the basolateral
membrane
Characteristic of late distal tubule &
cortical collecting tubule:
o Almost completely impermeable
to urea
o Reabsorb sodium ion & the rate is
controlled by hormone, especially
aldosteron & by other factor such
as concentration potassium ion
o Intercalated cells avidly secrete
hydrogen ion by active hydrogen ATPase mechanism
o Permeability to water controlled by ADH, if ADH , tubular
segment permeable (vise versa)
-

Medullary Collecting Duct


- Reabsorb less than 10% of filtered water & sodium
- Epithelial cell : cuboidal in shape; smooth surfaces; few mitochondria
- Characteristic
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Permeability to water controlled by ADH


Permeable to urea reabsorption
Secreting hydrogen ions against a large concentration as also occurs in
cortical collecting duct

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REGULATION OF TUBULAR REABSORPTION


Glomerulotubular Balance
- Intrinsic ability of tubules to increase their reabsorption rate in response to
increased tubular load (increased tubular inflow) glomerulotubular balance
- Ex : if GFR increase from 125 to 150ml/min proximal tubular reabsorption
also increases from 81 ml/min (65% of GFR) to 97.5 ml/min (65% of GFR)
- Also occur in other tubular segment, especially loop of Henle mechanism
unclear, but may bu due partly changes in physical forces in the tubule &
surrounding renal interstitium
- F(x) : helps to prevent overloading of distal tubular segments when GFR
increase & act as second line to buffer the effect of spontaneous changes in
GFR on urine output (first line: autoregulatory mech)
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Peritubular Capillary & Renal Interstitial Fluid Physical Forces


changes in peritubular capillary reabsorption can in turn influence the hydrostatic &
collooid osmotic pressure of the renal interstitium & reabsorption of water & solutes
fromrenal tubules
As glomerular filtrate passes thru renal tubules 99% of water & most of solutes are
reabsorb.
Fluid & electrolyte are reabsorbed from tubules into renal interstitium & from there
into
peritubullar capillary normal
rate = 124
ml/min
Net reabsorptive force sum of :
- Hydrostatic pressure inside the peritubullar capillaries (peritubular hydrostatic
pressure, Pc ) oppose reabsorption
- Hydrostatic pressure in renal intertitium (Pif) favors reabsorption
- Colloid osmotic pressure of peritubular capillary plasma protein (c) favors
reabsorption
- Colloid osmotic pressure of protein in the renal interstitium (if) oppose
reabsorption

Net reabsorptive force = 32 + 6 13- 15


= 10 mmHg similar to that found in glomerular capillaries but in
opposite direction
Kf high hydraulic conductivity large surface area of capillaries
12.4ml/min/mmHg
Regulation :
- Peritubullar capillary hydrostatic pressure by arterial pressure & resistance
of afferent & efferent arterioles
arterial pressure peritubullar capillary hydrostatic pressure
reabsorption rate
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resistance of either afferent or efferent arterioles peritubular capillary


hydrostatic pressure reabsorption rate
Colloid osmotic pressure of peritubular capillaries
Systemic plasma colloid osmotic pressure peritubular capillary
colloid osmotic pressure reabsorption rate
filtration fraction concentrated plasma protein peritubular
capillary reabsorption rate

Effect of Arterial Pressure on Urine Output ~pressure-natriuresis & pressurediuresis mechanism~


- Increasing arterial pressure bween 75-160 mmmHg slight effect on RBF &
GFR if autoregulation is impaired larger increase of GFR
- Increase renal arterial pressure decreases percentage of filtered load of
sodium & water that is reabsorbed by tubules
- Increase renal arterial pressure Reduces angiotensin II formation
decresed tubular sodium reabsorption
Hormonal Control

Sympathetic Nervous System


- Activation decrease sodium & water excretion by constricting renal
arterioles, thereby reducing GFR
- Also increases sodium reabsorption in proximal tubule & the thick ascending
limb of the loop of henle
- Also stimulate renin release & angiotensin II formation adds overall effect
to increase tubular reabsorption & decrease renal excretion of sodium
+an
Mechanism of reabsorption
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Active transport need energy


1. Primary active transport : melawan electrochemical gradient, butuh sumber
energy
Ex : reabsorpsi Na+ melalui Na+/K+ ATPase pump
2. Secondary active transport : uphill diffusion yg terfasilitasi karena perubahan
electrochemical gradient yang disebabkan primary active transport substansi
molekul, butuh carrier molekul
Ex : glucosa yg masuk ke dalam sel melalui co-transport glucose Na (countertranspor)
3. Pinocytosis for reabsorption of protein
Ex : reabsorpsi protein di proximal tubule. Protein attaches to brush border
invaginates into cell, vesicle is formed containing the protein protein inside
the cell digested into AA reabsorbed thru basolateral membrane into
interstitial fluid
Passive transport
Ex : water reabsorption by osmosis is coupled mainly to sodium reabsorption

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Regulation of ECF Osmolarity &Sodium (Na+) Concentration


Osmolarity = total concentration of solutes in ECF
Determined by : total amount of solute/ECF volume
ECF Na+ concentration & osmolarity are regulated by the amount of extracellular
water Body water is controlled by :
- Fluid intake
- Renal excretion of water controlled by multiple factor that influence
glomerular filtration & tubular reabsorption
ADH controls urine concentration
- Plasma osmolarity & sodium concentration are regulated bya powerful
feedback system that alter renal excretion of water independently of the rate of
solute excretion primary effector is ADH
- Mech :
osmolarity of body fliuds above normal (the solute is too cencentrated)

Stimulates ADH secretion from posterior pituitary

Increased permeability of distal tubules & collecting duct to water

Allow large amounts of water to be reabsorbes

urine volume but does not markedly alter the renal excretion of the solutes
Thus, the rate of ADH secretion determines to a large extent, whether the
kidney excretes a dilute or concentrated urine
Formation of Dilute & Concentrated Urine
- When there is excess water in the body , & body osmolarity is reduced, the
kidney can excrete urine w/ an osmolarity as low as 50 mOsm/L
(concentration only about 1/6 osmolaroty of normal ECF)
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Cenversely, when there is deficient of water & ECF osmolarity is high, the
kidney can excrete urine w/concentration of 1200-1400 mOsm/L
Renal Mechanism for Excreting a Dilute Urine
When there is a large excess of water in the body, the kidney can excrete as much as
20 L/day of dilute urine w/concentration as low as 50 mOsm/L continuing
reabsorp solutes while failing to reabsorp amounts of water in distal parts of nephron
Mechanism :
@ Proximal tubule
- As fluid flows thru the proximal tubule, solutes & water are reabsorbed in
equal proportion little change in osmolarity occurs proximal tubule
remain isoosmotic to the plasma, w/an osmolarity of about 300 mOsm/L
@ Descending Loop of Henle
- As fluid passes down the descending loop of Henle, water is reabsorbed by
osmosis & tubular fluid reaches equilibrium w/surrounding interstitial fluid of
medulla intersitial fluid of medulla is very hypertonic about 2-4 x
osmolarity of original glomerular filtrate
- Therefore, tubular fluid becomes more concentrated as it flow into inner
medulla

@ Ascending Loop of Henle


- In the thick segment, Na+, K+, Cl- are avidly reabsorbed
- This portion of tubular segment is impermeable to water even in the presence
of large amount of ADH
- Therefore , tubular fluid becomes more dilute as it flow up the ascending loop
of Henle into the early distal tubule
- The osmolarity decrease progressively to about 100 mOsm/L by the time the
fluids enter the early distal tubular segments
- Thus regardless whether ADH is present or absent, fluid leaving the early
distal tubular segments is hypoosmotic
@ Distal & Collecting Tubule
- As the dilute fluid in the early distal tubule pass to the late distal convoluted
tubule, cortical collecting duct, & collecting duct, theres additional

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reabsorption of naCl in the absence of ADH, this portion of tubule is also


impermeable to water
- Thus, the additional reabsorption of solute causes th etubular fluid to become
even more dilute decreasing its osmolarity to aas low as 50 mOsm/L

Failure of water reabsorption & the continued reabsorption of solutes large volume
of dilute urine
Renal Mechanism for Excreting & Concentrated Urine
When there is a water deficit in the body, the kidney forms a concentrated urine by
continuing to excrete solutes while increase water reabsorption & decrease volume of
urine formed
Human kidney can produce a maximal urine concentration of 12001400mOsm/L (4-5x osmolaroty of the plasma)
~Obligatory Urine Volume~
- Maximal concentrating ability of the kidney dictates how much urine volume
must be excreted each day to rid the body of waste product of metabolism &
ions that are ingested
- A normal 70kg human must excrete 600mOsm of solutes each day if max
urine concentrating ability is 1200mOsm/L the minimal volume of urine that
must be excreted is :
600/1200 mOsm/L = 0.5 L/day
thus minimal loss of volume in the urine contributes to dehydration, along
w/water loss from the skin, respiratory tract, & GIT when water is not
available to drink
Basic requirement for forming concentrated urine :
1. High level of ADH
High level of ADH increase permeability the distal tubule & collecting duct
to water allowing these tubular segments to avidly reabsorbed water
2. High Osmolarity of the Renal medullary Intersitial Fluid
Provides osmotic gradient necessary for water reabsorption to occur in the
presence of high level ADH
Renal medullary interstitial fluid becomes hyperosmotic because of the countercurrent
mechanism
- Depend on special anatomical arrangement of loop of henle & vasa recta
- Descending limb of loop of Henle flow from cortex to medulla, meanwhile,
ascending limb flow from medulla to cortex, thus fluid flowing in one tube
runs counter (opposite) to fluid flowing in the nearby parallel tube
countercurrent flow
- Gives net effect of adding more & more solute to the medulla in excess of
water w/sufficient time, this process gradually traps solutes in the in
medulla & multiplies the concentration gradient established by active pumping
of ions out of thick ascending limb of loop of Henle raising the interstitial
fluid osmolarity to 1200-1400 mOsm/L
Major factors that contribute to countercurrent mechanism buildup pf solute
concentration into renal medulla are :
- Active transport of Na+ & co-transport of k+, Cl-, & other ion from thick
ascending limb of loop of Henle medullary interstitium
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Active traansport of ions from collecting ducts medullary interstitium


Facilitated diffusion of large amount of urea from inner medullary collecting
duct medullary interstitium
Diffusion of only small amounts of water from the medullary tubules into the
medullary interstitium, for less than the reabsorption of solutes into medulla
by interstitium

Steps2

Countercurrent multiplier : repetitive reabsorption of NaCl by thick ascending loop &


continued inflow of NaCl from proximal tubule into loop of Henle keeps adding to
the newly arrive NaCl multiplying its concentration in medullary interstitium
There are special features of renal medullary blood flow that contribute to the
preservation of high solute concentration in medullary interstitium :
- Medullary blood flow is low (5% of total renal blood flow)
Sufficient to supply metabolic meeds
Helps to minimize solute loss from medullary interstitium
- The vasa recta serve as countercurrent exchanges
Minimizing washout of solutes from the medullary interstitium
Although there is large amount of fluid & solute exchange across vasa
recta, there is little net dilution of the concentration of interstitial fluid at
each level of renal medulla because of the U-shape of vasa racta
capillaries, which act as the countercurrent exchanges
Mechanism :
@proximal tubule
- Osmolarity of the fluid remains about the same as the glomerular filtrate :
300mOsm/L, because tubular membrane is permeable both to water &
electrolyte
@Descending loop of Henle
- Osmolarity of the fluid flowing thru descending loop gradually until its
equal to that of the surrounding interstitial ~ 1200 mOsm/L when blood
concentration of ADH is high
@Ascending Loop of Henle-Thin
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The thin ascending limb is essentially impermeable to water but reabsorbs


some NaCl because of high concentration of naCl in the tubular fluid
owing to water removal from descending liio of henle, theres some passive
diffusion of NaCl to medullary interstitium
- Some of urea absorbed into medullary intersttial from collecting duct also
diffesus into the ascending limb returning urea to the tubular system &
helping to prevent its washing out from renal medulla
this urea recycling is an assitional mechanism that contributes to the
hyperosmotic renal medulla
@Thick Ascending Loop of Henle
- The thick part of ascending loop of henle is virtually impermeable to water,
but large amounts of Na, cl, K, & other ions are actively transported from the
tubule into medullary interstitium
- The tubular fluid osmolarity is falling to concentration of 100 mOsm/L
@Early Distal Tubule
- =thick ascending loop
@Late Distal tubule & Cortical Collecting Tubules
- Osmolarity of the fluid depend on the level of ADH
Increase ADH : these tubules are highly permeable to water & sugnificant
amount of water is reabsorbed
The fact that these large amount of water are reabsorbed into the cortex,
rather than into the renal medulla helps to preserve the high medullary
interstitial fluid osmolarity
- Urea is not very permeant in this part of nephron increase urea
concentration as water is reabsorbed
@Inner Medullary Collecting Duct
- Concentration of fluid in inner medullary collecting duct depends on :
ADH
Osmolarity of medullary interstitium established by the countercurrent
mech.
- Increase ADH largely permeable to water water diffuses from the tubule
into the intersitium until osmotic equilibrium is reached (~1200-1400
mOsm/L) produced very concentrated but small volume of urine
- Increase water reabsorption increase urea concentration in the tubular fluid
urea diffuses out of the tubule into renal interstitium
This diffusion is greatly facilitated by specific urea transporter. One of
these urea transporter, UT-AI is activated by ADH
The absorption of urea into renal medulla contributes to the high
osmolarity of medullary intersitium & high concentrating ability of kidney

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The kidney can, when needed excrete a highly concentrated urine that contains little
NaCl this is due to high concentration of other solutes, esp. Of water product such
as urea & creatinine
Control of ECF Osmolarity & Na Concentration
- Plasma Na concentration = 140-145 mEq/L, average =142 mEq/L
- Plasma osmolarity = 300mOsm/L (about 282 mOsm/L when corrected for
interionic action) 2-3% bcoz Na+ & its associated anions accounts for
94% of the solute in ECF compartments, palsma osmolarity (Posm) can be
approximately roughly as :
Posm = 2.1 x plama sodium concentration
- Although multiple mechanism control the amount of Na+ & water excretion
by the kidney, 2 primary system are esp involved in regulating ECF osmolarity
& Na+ concentration :
Osmoreceptor ADH system
o ADH release is also controlled by cardiovascular reflexes that respond
to decrease in BP &/or BV, including
o Arterial baroreceptor reflex
o Cardiopulmonary reflex
o These reflex pathways originate inhigh preswsure regions of the
circulation, such as aortic arch & carotid sinus & in low pressure
region, esp the cardiac atria
o Path :
Afferent stimuli are carried by the vagus & glossopharyngeal nerve

Nuclei of tractus solitarius

Projection from these nuclei relays signals to the hypothalamic nuclei


that control ADH synthesis & secretion

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Thirst mechanism
o Kidney minimize fluid loss during water deficits thru osmoreceptorADH feedback system, adequate fluid intake is necessary to
counterbalance fluid loss does occur thru sweating & breathing & GIT
o Centers for thirst in CNS located anterolaterally in the preoptic
nucleus

o Treshold for osmolar stimulus of drinking when Na concentration


increase only 2 mEq/L above normal
o Mechanism
Thirst stimuli

Stimulate neuron at thirat center


(osmoreceptor cell)

Activate thirst mechanis

Drinking behavior
Regulation of Electrolytes
Kalium
Extracellular fluid K+ concentration =
4.2 0.3 mEq/L
Total body K+ :
- 98% intracellular
- 2 % extracellular
Maintenance of K+ balance :
- Excretion of K+ by the kidney
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- Control of K+ distribution between extra & intracellular compartment


Regulation of internal K+ distribution
1. Insulin stimulates K+ uptake into cells
2. Aldosterone activity of Na+/K+ ATPase K+ uptake into cells
3. -adrenergic stimulation K+ uptake into cells
4. Acid base balances
Acidosis (H+) activity Na+/K+ ATPase cellular uptake of K+
5. Cell lysis release K+ into extracelular compartment
6. Strenous exercise release K+ from skeletal muscle into ECF
7. ECF osmolarity osmotic flow of water out of cells intracellular K+
promotes diffusion of K+ out of cells
Overview K+ excretion :
- Rate of K+ filtration
= GFR x plama K+
= 180 l/day x 4.2 mEq/L
= 756 mEq/L
- Rate of K+ reabsorption by tubules
65% of filtered K= is reabsorbed in the proximal tubule
25-30% is reabsorbed in loop of henle, esp in thick ascending part
- Rate of K+ secretion by the tubule
In distal & collecting tubules
High K intakes required extrasecretion of K is achieved almost entirely
by secretion of K+ into distal & collecting tubules (vise versa)
Mechanism of K+ secretion :
- Uptake of K+ from the interstitial fluid into the cell by Na+/K+ ATPase in the
basolateral membrane of the cell
- Passive diffusion of K+ from interior of cell into tubular fluid
Na+/K+ ATPase pump creates a high intracelular K+ concentration
provided driving force for passive diffusion
Luminal membrane of the cells os highly permeable to K+ there are
special channel that are specifically permeable to K+
Control of K+ secretion :
- Activity of Na+/K+ ATPase pump
- Electrochemical gradient for K+ secretion from blood into tubular lumen
- Permeability of luminal membrane
When severe K+ depletion cessation of K+ secretion & net reabsorption of K+ in
late distal & collecting tubule
Reabsorption occur in the intercalated tubules :H+/K+ATPase located in luminal
membrane
- Reabsorbs K+ in exchange for H+ secreted into tubular lumen
- K+ then diffuses thru basolateral membrane of cell into the blood
Most important factor that stimulate K+ secretion by the principal cells
ECF K+
- Stimulates Na+/K+ATPase pump K+ uptake across basolateral membrane
K+ diffusion across luminal membrane into tubule
- K+ gradient from renal interstitial fluid to the interior of epithelial cells
decrease backleakage of K+ from inside cell thru basolateral membrane
- Stimulate aldosteron secretion by adrenal cortex stimulates K+ secretion
aldosteron stimulates K+ secretion
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- Stimulates Na+/K+ATPase pump K+ uptake across basolateral membrane


- permeability o fluminal membrane for K+
Distal tubular flow rate stimulate K+secretion
- K+ is secreted into tubular fluid the luminal concentration on K+
driving force for K+ diffusion across lumianl membrane decrease w/
tubular flow rate, secreted k+ is continuosly flushed down the tubule rise in
tubular concentration become minimizes
Acid Base Balance
Hydrogen ion : single free proton released from a hydrogen atom molecules
containing hydrogen atom acids
- Base : ion or molecule that can accept a hydrogen ion (HCO3-,HPO4-)
Strong : reacts rapidly & strongly w/H+ ex: OH
Weak : bind w/ H+ much more weakly ex: HCO3- Acid
Strong : rapidly dissociates & release especially large amount of H+ in
solution Ex: Hcl
Weak : less tendency to dissociate their ionn & therefore release H+ w/less
vigor
H+ concentration of body fluid normally kept @ a low level (compared w/other ion)
so, its customary to express H+ concentration on a logarithm scale, using pH units

Acidosis : < 7.4


Alkalosis : > 7.4
*@ intracellular fluid, the pH is lower bcoz metabolism of cells produces acids.
Hypoxia & poor blod flow acid accumulation
Defenses Against Changes in H+ Concentration
3 primary systems that regulate H+ concentration in body fluids to prevent acidosis or
alkalosis:
1. The chemical acid-base buffer system of body fluids
Immediate (within a fraction of second) combine w/ acid or base to
prevent excessive changes in H+ concentration
Cannot eliminate H+ or add them to body, but only keep them tied up until
balance can be re-established
2. Respiratory center
Act a few minute
Regulates removal of CO2, (& therefore H2CO3) from ECF
3. Kidney
The first two lines (buffer & respiratory) keep the H+ concentration from
changing too much until the more slowly responding third line of defense
(kidney) can eliminate the excess acid or base from body (urine)
Duration : hours-severeal days
Most powerfull
I.Buffer System
Any substance that can reversibly bind hydrogen ion (H+)
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In this example, H+ combines w/buffer to form weak acid


When H+ >> shift to right
H+ << shift to left
Types of Buffer
A. Bicarbonate Buffer System most important; contain water solution that
contain 2 ingredients
Weak acids/H2CO3
Formed by CO2 & H2O

slow & exceedings small amounts of H2CO3 are formed unless the
enzyme carbonic anhydrase is present
Carbonic anhydrase abundant in wall of lung alveoli (when CO2
released) & epithelial cell of renal tubule
Bicarbonate salt NaHCO3
NAHCO3 ionizes completely to form bicarbonate ion & Na

Because of weak dissociation of H2CO3, concentration of H+ is


extremely small
When strong acid (HCl) is added to buffer solution the increased H+
released from HCl is buffered by HCO3 form weak acid (H2CO3) H2O
+ CO2 stimulate respiration to remove excess CO2
When strong base (NaOH)
OH- from NaOH react w/H2CO3 form weak base NaHCO3
Pada saat bersamaan H2CO3 menurun (karena bereaksi dgn NaOH)
menyebabkan banyak CO2 + H2O H2CO3

decreased CO2 inhibit respiration & decrease rate of CO2 respiration


Increased HCO3- excretion of renal
B. Phosphate Buffer System not important as an ECF buffer, it plays a major
role in buffering renal tubular fluid & intracellular fluid
Main element H2PO4- & HPO42When strong acid is added
Produce weak acid & decrease in pH is minimized
When strong base is added
Produce weak base & only slight increase in pH
Note :
pK = 6.8 (not far from norml pH) allow the system operate near its max
buffering power
Especially important in tubular kidney, bcoz :
o Phosphate greatly in tubule
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o pH tubular fluid < pH ECF, so closer to pK


Also important in ICF
C. Protein
Important intracellular buffer & the most plentiful buffer in the body bcoz
of their high concentration, especially within the cells
pK = fairly close 7.4
approx 60-70% of total chemical buffering in body fluid is inside cells,
most is from intracellular buffer
slightly amount diffusion H+ & HCO3- thru cell membrane (require
several hours) & CO2 diffusion (rapid) pH intracellular changes in ECF
pH
buffer system (intracellular , protein) help to prevent changes in pH of
ECF
ex :
II.Respiratory Regulation
Second line of defenses control of ECF CO2 concentration
ventilation eliminates CO2 from ECF H+ concentration (vise versa)
CO2 is formed continually in body by intracellular metabolic process
If rate of metabolic formation CO2

pCO2 in ECF

rate of pulmonary ventilation

pCO2

CO2 concentration <<

<< H2CO3 H+ + HCO3


pH
(negative feedback for ventilation)
Kesimpulan :
1. Changes in either pulmonary ventilation or rate of CO2 formation change
pCO2
2. H+ concentration affect the rate of alveolar ventilation
3. Respiratory system act as negative feedback controller of H+ concentration

III.Renal Control
Kidney control acid base balance by excreting :
- Acidic urine
reduce the amount of acid in ECF
formed by secretion of large hydrogen ion in tubular
- Basic urine
Removes base from ECF
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Large number of HCO3- are filtered continously into tubule


Renal :
- Excretion of nonvolatile acid (80mEq)
- Prevent loss of bicarbonate in urine each day kidney filter 4320 mEq
bicarbonate under normal condition, almost all of this is absorbed
- Hydrogen ion secretion from tubule each day, total 4400 mEq hydrogen ion
secreted into tubules :
4320 for reabsorption HCO3- (krn direabsorpsinya dalam bentuk
H2CO3
80 must be secreted to rid the body of nonvolatile acid
Thus kidney regulates ECF hydrogen ion by 3 fundamental mechanism :
1. Secretion of H+
2. Reabsorption of filtered HCO33. Production of new HCO3Reabsorption Bicarbonate Ion
- Location : in all tubules, except ascending & descending thin limbs of loop of
Henle
- For each bicarbonate reabsorption, there must be a hydrogen ion secretion
Secretion of hydrogen ion
Location : Epithelial cells of proximal tubule, thick ascending loop of Henle & early
distal tubule
By : sodium-hydrogen counter transport
process reabsorption
HCO3- (hasil filtrasi)

Combine w/H+

H2CO3

H2O + CO2

CO2 can move easily across tubular


membrane (di dlam tubular cell mengalami
process seperti mechanism secretion H+
Primary active secretion of H+ in
intercalated cell of late distal & collecting
tubule (5%)
Process, ada 2 step :
1. Dissolved CO2 combine w/H2O H2CO3
2. H2CO3 HCO3- + H+ H+ by primary active transport secrete into
tubular lumen

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Production of new HCO3Ketika H+ yg disekresikan berlebih


- Hanya sedikit yg bisa diekskresikan dalam bentuk ionic (H+) dalam urine
krn pH minimal urine 4.5
- Sisanya akan di buffer dgn phosphate atau ammonia (bisa juga dgn urate &
citrate, tapi ini kurang berperan)
Phosphate buffer
Mech :
H+ yg disekresikan menuju tubular lumen

Combine w/HPO42- atau buffer lain

H2PO4(dieksresikan dlm bentuk NaH2PO4)


Sementara HCO3- yg dihasilkan pada saat tubular cell mensekresi H+ disebut new
bicarbonate
Pada kondisi normal, banyak phosphate yg terfiltrasi direabsorpsi kembali sehingga
hanya 30-40 mEq yg tersedia untuk buffering system

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Ammonia Buffer
More important than phosphate
Consist of :
- Ammonia (NH3)
- Ammonium ion (NH4+)
Glutamine actively transported into epithelial cells of proximal tubule, thick
ascending limbs of loop of henle & distal tubule
Dissociate into 2 HCO3- + 2 NH4+ NH4+ secreted into lumen by co-transport in
exchange for sodium
In collecting tubule, addition of NH4+ occurs in diffeent mechanism :
H+ yg disekresikan + NH3 NH4+ (secreted)
Collecting duct permeable to NH3 but less permeable to NH4, for each NH4
excreted, a new HCO3- is generated & added to blood
So, when H+ , stimulate renal glutamine metabolism

REGULATION OF RENAL TUBULAR HYDROGEN ION SECRETION


- Alkalosis = HCO3- excretion , NH4+ & titrable acid not excreted
- Acidosis = HCO3- excretion , NH4+ & titrable acid largely excreted
- Respiratory acidosis pCO2 akan pCO2 di tubular cell H+ formation
secretion

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RENAL CORRECTION OF ACIDOSIS & ALKALOSIS

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ACIDOSIS
- when the ratio of HCO3 to CO2 in the extracellular fluid decreases
decreasing pH.
If this ratio decreases because of a fall in HCO3 metabolic acidosis.
o Compensations include increased ventilation rate, which reduces
PCO2 , and renal compensation, which, by adding new bicarbonate to
the extracellular fluid, helps minimize the initial fall in extracellular
HCO3- concentration
If the pH falls because of an increase in PCO2 respiratory acidosis.
o compensatory response is an increase in plasma HCO3-, caused by the
addition of new bicarbonate to the extracellular fluid by the kidneys.
ALKALOSIS
- respiratory alkalosis
The cause of the alkalosis : is a decrease in plasma PCO2 , caused by
hyperventilation
Compensatory response to a primary reduction in PCO2 in respiratory
alkalosis is a reduction in plasma HCO3 - concentration,caused by
increased renal excretion of HCO3
- metabolic alkalosis
The cause of metabolic alkalosis, however, is a rise in the extracellular
fluid HCO3 concentration.
Compensations are decreased ventilation, which raises PCO2 , and
increased renal HCO3 - excretion, which helps compensate for the initial
rise in extracellular fluid HCO3 - concentration
Clinical causes of Acid-Base Disorders
- Respiratory acidosis caused by decrease ventilation & increase pCO2
Dpt terjadi dr kondisi patologis yg merusak respiratory center/ penurunan
kemampuan untuk eliminasi CO2
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Respiratory alkalosis caused by increase ventilation & decrease pCO2


Rarely from physical pathologic condition (usually @ high altitude,
decrease O2)
Psychoneurosis
metabolic acidosis : refers to all other types of acidosis besides those caused
by excess CO2 in the body fluids.
Cause :
o failure of the kidneys to excrete metabolic acids normally formed in
the body
o formation of excess quantities of metabolic acids in the body
o addition of metabolic acids to the body by ingestion or infusion of
acids
o loss of base from the body fluids, which has the same effect as adding
an acid to the body fluids.
Renal tubular acidosis defek sekresi H+ atau reabsorpsi HCO3 Diarrhea loss of sodium bicarbonate into feces
Vomit loss of bicarbonate
DM acetoacetic acid increase
CRF
Metabolic alkalosis caused by increase ECF bicarbonae concentration
@ increase HCO3- or decrease H+ not common
Diuretics GFR Na+ absorption H+ secretion
aldosteron promote Na+ reabsorption H+ secretion
Vomit of gastric contents loss of HCL from gastric loss of acid from
ECF
Ingestion alkaline drugs sodium bicarbonate

Hormonal Regulation
Renin-Angiotensin- Aldosteron System
Smooth muscle cells in afferent arterioles are site os synthesis, storage, & release of
renin
3 factors stimulate renin secretion :
a. Perfusion pressure decrease stimulate baroreceptor in afferent arteriole
b. Sympathetic nerve activity increase increase renin
c. Delivery of NaCl to macula densa stimulate secretion renin
Angiotensinogen in liver
Renin secretion

Angiotensin I
ACE
Angiotensin II

Aldosteron in adrenal cortex


Angiotensin II has several important physiologic functions, include :
- Stimulation of aldosteron secretion by adrenal cortex
- Arteriolar vasoconstriction, which increase BP
- Stimulation ADH secretion & thirst
- Enhancement of NaCl resorption by proximal tubule
Aldosteron
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Stimulation by angiotensin II, increase plasma K+


Function :
Decrease NaCl excretion by stimulating its resorption by thick ascending
limb of loop of Henle, distal tubule & collecting duct
Increase reabsorption of water increase BV
Increase excretion of K+

Atrial Natriuretic Peptide


- Store & produce by atrial myocyte
- Stimulate by atrial stretch as would occur w/positive Na+ balance n ECF
volume expansion
- Antagonize function w/RAA system
- Action :
Vasodilation of afferent & vasoconstriction of efferent arteriole of
glomerulus increase GFR
Inhibition of renin secretion by afferent arteriole
Inhibition aldosteron secretion by glomerulosa cells of adrenal cortex
Mech :
o Acts on juxtaglomerular cells to inhibit renin secretion & thereby
decrease angiotensin II induced aldosteron secretion
o Acts on glomerulosa cells of adrenal cortex to inhibit aldosteron
secretion
Inhibition of Na Cl resorption by collecting suct which is also caused in
part by reduced levels of aldosterone
also acts on the collecting duct cells inhibit Na channel in apical
membrane decrease na resorption. This effect occurs presominantly in
medullary portion of collecting duct
inhibition of ADH secretion by posterior pituuitary & ADH action on
collecting duct. This decrease water resorption by collecting duct & thus
increase excretion of water in urine
Antidiuretic Hormone (ADH)/Vasopressin
- synthesized neuroendocrine cells located within supraoptic &
paraventricular nuclei of hypothalamus
- stored nerve terminal located in neurohypophysis
- ADH large volume of urine
- ADH small volume of urine
- Secretion is regulated by :
Osmotic control
o Osmoreceptor : cells located in hypothalamus but distinct from those
that synthesized ADH
o These cells sense some changes in body fluid osmolality by either
shrinking of swelling
o Osmoreceptor respond : solute that are effective osmoles (ex: NaCl) &
ineffective solute (ex: urea) little effect
o Osmolality body fluid stimulate osmoreceptor synthesize ADH
Hemodynamic control
o Decrease BV or arterial pressure also stimulate ADH secretion
o Receptor activated by this response are locatd in :
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o Low-pressure (left atrium & pulmonary vessels)


o High pressure (aortic arch n carotid sinus)
o Signal from these receptor are carried in afferent fibers of vagus &
glossopharyngeal nerve brainstem to ADH secretory cells
- Sensitivity of baroreceptor system is less than that of osmoreceptor 5-10%
decrease in BV or arterial pressure is required b4 ADH secretion is stimulated
- Primary action :
Incrase permeability of collecting duct to water
ADH receptor on basolateral membrane of principal cells

Intracellular vesicles containing water channels (aquaporins) are inserted into apical
membrane via exocytosis
- Removal of ADH water channels are retrieved from apical membrane via
endocytosis
- ADH also increase permeability of terminal portion of inner medullary
collecting duct to urea
Calcitriol
Active form of vit D, help regulate Ca hemostasis
Erythropoietin
Stimulate production RBC
BLOOD PRESSURE & REGULATION
Blood pressure tekanan hidrostatik yang dihasilkan oleh darah pd dinding
pembuluh darah
Mean arterial blood pressure (BP) is total product of cardiac output (CO) & total
peripheral resistance (TPR)
BP = CO x TPR
Cardiac output = stroke volume (SV) x heart rate (HR)
Stroke volume, determined by
LV filling volume preload
force of contraction contractility
resistance LV must overcome to eject blood into aorta
2 component :
- systole : terjadi pada akhir stroke output ventrikel kiri jantung ventrikel
jantung berkontraksi, stlh tekanan ventrikel > tekanan atrium, mitral valve
tertutup
- diastole : terjadi pada diastole ventrikel ventrikel relaksasi. Tekanan
ventrikel < tekanan aorta, aortic valve menutup
main variables :
- Extracellular fluid volume relates to CO
o Sodium intake
o Renal function & mineralocorticoid
o Inotropic ECF volume & HR
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Degree of vasoconstriction of arterial bed relates to TPR


o Sympatis
o Humoral factor vasoconstrictor (angiotensin & catecholamines) &
vaasodilator (prostaglandin & kinin)
o Local autoregulation

Mechanism to Control Blood Pressure


1. Short term
- control nervous reflex or other nervous responses
- mechanism within seconds
o Baroreceptor feedback mechanism
o CNS ischemic mechanism
o Chemoreceptor mechanism : @ arch of aorta & bifurcation of common
carotid (response to PO2 & PCO2)
Baroreceptor reflex
mediated by receptor in the walls of aortic arch & carotid sinuses
monitor changes in pressure by sensing stretch & deformation of arteries
arterial pressure rises

Baroreceptor are stimulated

Increasing transmission of impulses to CNS

Negative feedback back to circulation via ANS

BP return to normal
if higher BP rises
more baroreceptor are stretched

Greater impulse transmission rate to medulla

- Signal from carotid sinus receptor are carried by glossopharyngeal nerve (CN
IX)
- Signal from aortic arch : by vagus nerve (CN X)

Converge @ tractus solitarius in medulla

Inhibit sympathetic & excite parasympathetic


Net results :
- Decline TPR/TVR
- Reduction CO
If arterial pressure fall

Fewer impulses are transmitted to medulla

Increase in BP
After any acute fall in pressure, ex: severe hemorrhage, nervous system combine :
Cause constriction of veins & provide transfer of blood into the heart
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Cause increase in HR & contractility of heart to provide greater pumping


capacity by heart
Cause constriction of most peripheral arterioles to impede flow of blood out of
arteries

Chemoreceptor mechanism :
@ arch of aorta & bifurcation of common carotid
response to PO2 & PCO2 & H+
send impulse to CV centre & respiratory centre
output :
o sympathetic : vasoconstriction
o Rate of breathing adjustment
o
Autoregulation : ability of tissue to automatically adjust its blood flow to match its
metabolic demands
a. Physical changes
Temp vasodilation
Temp vasoconstricting
Myogenic stretch contract
Myogenic streching lessen relax
b. Vasoconstricting & vasodialting chemical
Vasodilating :
o Chemical : K+, H+, lactic acid, adenosine, Mg
o Endothelial cell : NO
o Tissue trauma/inflammation : kinin & histamine
Vasoconstrictor : thromboxane A2, superoxide radical, serotonin, &
endothelin
2. Intermediate-term control
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Exhibit significant response only after a few minutes following acute arterial
pressure change
- Mechanism :
o Stress-relaxation of vasculature when pressure in BV too high, BV
bcomes stretched n keep on stretching more & more for minutes or hours
as result pressure in vessel falls toward normal
o Capillary fluid shifted mechanism
Capillary pressure

Fluid absorbed thru capillary membrane from tissue into BV

Increase volume

Increase pressure
o Renin-Angiotensin-Aldosteron mechanism
Renin
o Released by juxtaglomerular cell in response falls of arterial
pressure
o Persist in blood = 30 min-1 hr
o Converts angiotensinogen to angiotensin I
Angiotensin I
o Conversion to AT II occurs almost in lungs, catalyzed by ACE, present
in endothelium of lung vessel
Angiotensin II
o Powerful vasocostriction
o Persist in blood = 1-2 min
o Inactivated by angiotensinase

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3. Long-term control renal regulation of water & salt output actually after
volume of fluid within vascular tone (keep ECF volume normal)
4 system involved in BR regulation
- Heart suplies pumping pressure
- BV contribute to systemic resistance
- Kidney regulate intravascular volume
- Hormones modulate function other 3 function
Heart cardiovascular centre in MO
Input :
Higher brain centre : cerebral cortex, limbic system, hypothalamus
Proprioceptor : joint movement
Chemoreceptors : blood acidity (H+), CO2, O2

Output :
Sympathetic : vasoconstriction, increase HR & contractibily
Parasympathetic : vise versa
Blood vessel
- Constricting in response to :
o Increased sympathetic
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o Abnormal regulation of vascular tone by local factor : NO, endothelin,


natriuretic factor
o Ion channel defect in contractile vascular SM
Look @ auto regulation above!!

Renal mechanism :
- Increase BP augmented urine volume (pressure diuresis) & sodium
excretion (pressure natriuresis) return BP to normal (within hours)
- Reduction GFR retention salt & water volume expansion
- Activation RAA system :
o Angiotensin II : vasoconstrictor & enhances proximal sodium
reabsorption
o Aldosteron : stimulate distal sodium reabsorption
- Sympathetic nervous system
o @arteriolar : vasoconstriction & increase in TPR
o @ proximal tubule : stimulate sodium & water reabsorption
- Endothelin : vasoconstrictor
- Renal prostaglandins antihypertensive effect
o inhibiting salt & water reabsorption
o promoting volume loss
o vasodilatation
- vasodilator system neutral lipid, PAF, NO, endothelial-based dilator system

Cardiovascular system is endowed w/feedback mechanism that continously monitor


arterial pressure
sense when pressure bcomes excessively high or low & than respond rapidly
to changes
Hormones
- aldosteron reabsorption tubular
- ADH :
o permeability of cortical & medullary collecting duct to H2O
decrease excretion H2O
o Na reabsorption by cortical collecting duct
- Natriuretic peptide
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o Promote excretion Na inhibit release of renin


o Relax afferent arteriole
Cortisol, estrogen, GH thyroid, insulin Na reabsorption
Glucagon, progesteron, n parathyroid Na reabsorption

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PULMONOLOGY
TRACHEA
Anatomy
- Trachea bifurcates @ sternal angle into main (primary) bronchi
right main bronchus : wider, shorter & runs more vertically
left main bronchus
- each of main bronchus divides into lobar bronchi (secondary bronchi), 2 on left
& 3 on right supply lobe of lung
- each of lobar bronchus divides into segmental bronchi (tertiary bronchi)
supply bronchopulmonary segments
Usually 18-20 in number (10 in right lung; 8-10 in left lung, depending on the
combining segments)
- Segmental bronchi terminal bronchioles respiratory bronchioles 2-11
alveolar ducts 5-6 alveolar sacs lined by alveoli
Histology
Trachea

Primary bronchi

pseudostratified ciliated columnar


Secondary bronchi (lobar)
epithelium

Tertiary bronchi (segmental)

large : ciliated simple columnar +goblet cell


Bronchioles

small: ciliated simple cuboidal epithelium


Terminal bronchioles

plates of cartilage menggantikan incomplete cartilages di primary bronchi dan


menghilang di distal bronchioles
cartilage , otot polos
Lapisan :
1. Epitel
2. Lamina propria : tulang rawan, otot polos, serat elastin, kel. Serosa & mukosa,
limfosit, limfonodulus
LUNGS
Anatomy
- organs of respirationf(x): is to oxygenate the blood by bringing inspired air into
close relation with the venous blood in the pulmonary capillaries.
- light, soft, and spongy, occupy the pulmonary cavities, elastic & recoil
- separated from each other by the mediastinum
- the roots of the lungs:
Pulmonary artery: superiormost on left
Superior and inferior pulmonary veins: anteriormost & inferiormost
Bronchus: middle of the posterior boundary, with the bronchial vessels
immediately surrounding
- Pleural sleeve : continuity between the parietal and the visceral layers of pleura
medial to hilum
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- hilum : root enter and leave the lung


- fissure : horizontal and oblique fissures divide the lungs into lobes
right lung : three lobes
left lung : two lobes
- @ left lung cardiac notch
- Each lung has
Apex: the blunt superior end
Three surfaces :
Costal :related to costal pleura
Mediastinal : concave, related to middle mediastinum
Diaphragmatic : form base of lung
Three borders
Anterior: costal & mediastinal surfaces meet anteriorly
Inferior:separates diaphragmatic surfaces from costal & mediastinal surfaces
Posterior :costal and mediastinal surfaces meet posteriorly;
Histology
Bronchi
- mucosa of the bronchi =mucosa of the trachea
- bronchial cartilages : more irregular in shape mkn ke bwh diganti o/ plates, or
islands, of hyaline cartilage
- lamina propria
SM layer spiralprominent near the respiratory zone
elastic fibers
mucous and serous glands
lymphocytes
Bronchioles
- d= 5 mm or less,no cartilage or glands,only scattered goblet cells
- larger bronchioles:ciliated pseudostratified columnar become ciliated simple
columnar or cuboidal epithelium in the smaller terminal bronchioles
o Clara cells secrete proteins that protect the bronchiolar lining against oxidative
pollutants and inflammation.
o neuroepithelial bodies chemoreceptors changes in gas composition
- lamina propria: smooth muscle and elastic fibers.
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Respiratory Bronchioles
- mucosa : ciliated cuboidal epithelial & Clara cell + numerous saclike alveoli @wall
- Between alveoli :ciliated cuboidal epithelium but, the cilia may be absent in more
distal portions
- Smooth muscle + elastic CT
Alveolar Ducts
- lined w/ squamous alveolar cells
- lamina propria : smooth muscle cells disappears at the distal
- elastic + reticular fibers
- open into atria : communicate with alveolar sacs
Alveoli
- d=200 m, for gas exchange
- interalveolar septum:
two thin squamous epithelial layers
capillaries& CT matrix interstitium
elastic and reticular fibers.
- Blood-air barrier:
the surface lining and cytoplasm of the alveolar cells
fused basal laminae of alveolar and endothelial cells (basement membrane)
cytoplasm of the endothelial cells
Total thickness :0.1 to 1.5 m
- 300 million alveoli : 140 m2
- Type I cells, or squamous alveolar cells
97% ;so thin (25 nm)
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Organelle around nucleus


F(x) :provide a barrier of minimal thickness that is readily permeable to gases.
- Type II cells:
3%; interspersed among the type I alveolar cells
rounded cells
vesicular or foamy cytoplasm caused by the presence of lamellar bodies
f(x) : secrete pulmonary surfactant, consists of : aqueous, proteinaceous hypophase
covered with a monomolecular phospholipid film that is primarily composed of
dipalmitoyl phosphatidylcholine and phosphatidylglycerol.
reducing the surface tension of the alveolar cells
Lung Macrophages dust cells, found in interior of the interalveolar septum and on
the surface of the alveolus
Alveolar Pores 10-15 m in diameter, f(x) : equalize air pressure in the alveoli and
promote the collateral circulation of air when a bronchiole is obstructed.

PHYSIOLOGY OF LUNG
Pulmonary ventilation (work of breathing)
Paru2 dapat dikembangkempiskan melalui 2 cara:
1. Diafragma bergerak turun naik untuk memperbesar atau memperkecil rongga
dada
Inspirasi kontraksi diafragma menarik permukaan bawah paru ke arah
bawah.
Ekspirasi diafragma mengadakan relaksasi dan sifat elastic recoil paru
(sifat elastis daya lenting paru), dinding dada, dan struktur abdominal akan
menekan paru.
2. Depresi dan elevasi tulang iga untuk memperbesar atau memperkecil diameter
anteroposterior rongga dada.
Inspirasi
- Pasa posisi istirahat, tulang rusuk miring ke bawah dengan begitu
sternum turun ke belakang kearah kolumna vertebralis
- Saat tulang rangka dielevasikan , tulang rangka langsung maju
sehingga sternum sekarang bergerak kea rah depan menjauhi spinal,
membentuk jarak anteroposterior dada kira2 20% selama inspirasi.
- Otot2 yang mengelevasikan tulang rusuk (otot inspirasi)
a. External intercostalis m. (otot utama)
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b. Sternocleidomastoid m.
Mengangkat sternum ke atas.
c. Serratus anterior m.
Mengangkat sebagian besar tulang rusuk
d. Scalenus
Mengangkat dua tulang rusuk pertama
Ekspirasi
Otot-otot yang menarik tulang rusuk ke bawah/depresi disebut otot
ekspirasi,yaitu:
a. Rectus abdominis
Mempunyai efek tarikan kea rah bawh yang sangat kuat terhadap
tulang rusuk bagian bawah
b. Internal intercostalis

~Pergerakan udara ke dalam dan keluar paru-paru & tekanan yg menyebabkan hal
tersebut~
Tekanan pleura
Tekanan pleura adalah tekanan cairan dalam ruang sempit antara pleura paru
dan pleura dinding dada.
Saat inspirasi tekanan pleura adalah -5 cmH 2O, hal ini dibutuhkan untuk
mempertahankan paru agar tetap terbuka sampai nilai istirahatnya.
Selama inspirasi, pengembangan rangka dada akan mendorong permukaan
paru dengan kekuatan yang sedikit lebih besar dan menciptakan tekanan yg
sedikit negative turun sampai rata2 -7,5 cm
Tekanan alveolus
Tekanan alveolus harus lebih besar dari tekanan pleura
Alveolar pressure = intrapleural pressure + alveolar recoil pressure.
Inspirasi
Untuk menyebabkan aliran udara dalam inspirasi maka tekanan
alveoli harus turun dibawah tekanan atm.
Ekspirasi
tekanan alveolus meningkat
Tekanan transpulmoner
Transpulmonary pressure = alveolar pressure intrapleural pressure.
Adalah perbedaan antara tekanan alveoli & tekanan pada permukaan luar paru,
dan ini adalah nilai daya elastic dalam paru (elastic recoil) yang cenderung
mengempiskan paru
Elastic recoil ditentukan oleh :
1. Daya elastic jaringan paru itu sendiri
- Elastisitas jaringan paru ditentukan oleh serat elastin & serat kolagen yang
terletak berselang seling di parenkim paru
- Pada paru mengempis serat ini berkontraksi
- Menyebabkan pengempisan paru sekitar1/3 elastisitas total
2. Daya elastic yang disebabkan oleh tegangan permukaan cairan yang
membatasi dinding bagian alveoli & ruang udara paru lainnya.
- Menyebabkan pengempisan paru sekitar 2/3 elastisitas.
Compliance paru
Nilai dimana pengembangan paru untuk setiap unit dapat meningkatkan
tekanan transpulmoner
Fibrosis paru & Area of collapsed alveoli (atelectasis) dapat menurunkan
compliance paru & meningkatkan elastic recoil
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Emphysema increases the compliance of the lungs because it destroy the


alveolar septal tissue that normally opposes lung expansion

~Surfaktan, tegangan permukaan & pengempisan/deflasi paru~


surfaktan
Surfaktan merupakan bahan aktif permukaan yaitu campuran kompleks dari
beberapa fosfolipid, protein & ion2 yang berfungsi menurunkan tegangan
permukaan.
Terdiri dari - 85% phospholipid & 75% dipalmitoyl phosphatidylcholine
-10-15% protein ( 4 spesifik protein surfactant : SP-A, SP-B,
SP-C, SP-D)
Menempati 10% dari permukaan alveoli.
Diproduksi oleh ael epitel alveolus tipe II
F(x) : menurunkan tegangan permukaan
Some pulmonary surfactant is taken back into type II cells (reuptake)
- Recycled & secreted again
- Degraded & used to synthesize other phospholipid
- Other surfactant is cleared from the alveoli by alveolar macropage,
absorption into lymphatic, or migration up to the small airways &
mucociliary escalator
Surfactant is not produced by the fetal lung until about the fourth of month
gestation & it may not be fully functional until the 7th month or later.
Hypoxia or hypoxemia, or both, may lead to a decrease in surfactant production or
an increase in surfactant destruction `
acute respiratory distress syndrome or
shock-lung syndrome

Hubungan antara tekanan di dalam alveolus dengan tegangan dinding alveolus


(wall tension) berdasarkan hukum Laplaces
Tekanan = 2 x tegangan permukaan
Radius
Dasar tegangan permukaan (surface tension)
Ketika air membentuk suatu permukaan dengan udara, maka molekul
air pada permukaan air tersebut memiliki daya tarik yang sangat kuat
satu sama lainnya sehingga permukaan air selalu berusaha untuk
berkontraksi
Surfactant membentuk permukaan hidrofobik lipid yang berkontak dengan
udara sehingga mengurangi tegangan permukaan
Semakin kecil alveolus semakin besar tekanan pengempisan yang terjadi
Semakin kecil ukuran alveoli semakin rendah tegangan permukaan
Semakin besar ukuran alveoli semakin rendah konsentrasi surfaktan sehingga
tegangan permukaan semakin besar.
~kerja pernapasan~
Kerja inspirasi dapat dibagi menjadi 3 bagian :
1. Yang dibutuhkan untuk pengembangan paru dalam melawan daya elastisitas
paru dan dada yaitu kerja compliance atau kerja elastic
V . P
- Kerja compliance =
2
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V = peningkatan volume pada saat inflasi paru


P = peningkatan tekanan intrapleura
2. Yang dibutuhkan untuk mengatasi viskositas jaringan paru dan struktur
dinding dada disebut kerja resistensi jaringan
3. Yang dibutuhkan untuk mengatasi resistensi jalan napas selama udara masuk
ke paru disebut kerja resistensi jalan napas
VOLUME & KAPASITAS PARU
Volumes
1) Tidal volume
Volume of air inspired or expired within each normal breath ; 500 ml
2) Inspiratory reverse volume
Maximum extra volume of air that can be inspired over & above the normal tidal
volume ; 3000 ml
3) Expiratory reverse volume
Maximum extra volume of air that can be expired by forceful expiration after the
end of a normal tidal expiration ; 1100 ml
4) Residual volume
Volume of air remaining in the lungs after the most forceful expiration ; 1200
ml
capacities
1) Inspiratory capacity
Tidal volume + inspiratory reserve volume
3500 ml
Amount of air a person can breath in beginning at normal expiratory level &
distending the lungs to maximum amount
2) Functional residual capacity
Expiratory reserve volume + residual volume
2300 ml
Amount of air that remain in the lung at the end of normal expiration
3) Vital capacity
IRV + TV +ERV
4600 ml
Max. amount of air a person can expel from lungs after first filling the lungs to
their max. extent & then expiring to max extent
4) Total lung capacity
VC + RV
Max. volume to which the lungs can be expanded with the greatest possible
effort
5800 ml
GAS EXCHANGE

Setelah alveoli diventilasi oleh udara segar langkah selanjutnya dalam proses
pernapasan adalah difusi oksigen dari alveoli ke pembuluh darah paru & difusi
CO2 dalam arah sebaliknya

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Fisis difusi & tekanan parsial gas

Untuk terjadinya difusi dibutuhkan sumber energy disertai dengan gerakan


molekul itu sendiri

Net diffusion => difusi gas terjadi dari daerah yang berkonsentrasi tinggi ke
daerah yg konsentrasinya rendah

Tekanan total gas pada suatu daerah berbanding langsung dengan konsentrasi
molekul-molekul gas

Kecepatan difusi (rate of diffusion) masing2 gas berbanding langsung dengan


tekanan yang ditimbulkan oleh gas itu sendiri yang disebut tekanan parsial gas
(Px)

Faktor2 yg menentukan tekanan gas yang terlarut dalam cairan

Partial pressure determined by concentration & solubility coeffisient

Henrys law

Partial pressure =

consentrationof dissolved gas


solubility coefficient

CO2 lebih mudah larut di dalam air dibandingkan O2

Tekanan uap air (vapor pressure)


Tekanan yang digunakan oleh molekul air untuk keluar menembus permukaan
Bergantung pada temperature T
aktivitas kinetic molekul akan meningkat,
kemungkinan besar molekul air akan keluar dari permukaan air masuk ke
dalam fase gas
Difusi gas ke dalam cairan
Perbedaan tekanan menyebabkan difusi netto
Difusi netto gas dari daerah yang bertekanan tinggi ke area bertekanan rendah
adalah seimbang dengan jumlah mol
Factor affect the rate of gas diffusion in fluid
1. Solubility = daya larut gas dalam cairan
S
number molecule to diffuse
2. Cross sectional area
A
total number of molecules that diffuse
3. Distance (d)
d
longer to diffuse
4. Molecular weight (MW)
5. Temperature (nilainya konstan)

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D(diffusion rate)

P A S
d MW

Difusi gas melalui jaringan


Gases highly soluble in lipid SO highly soluble in cell membrane
gas
diffuse through tissue.
Composition of alveolar air (hubungannya dengan udara atmosfer)
Alveolar air, different with atm air because :
- Alveolar air partially replaced by atm air with each breath
- O2 constantly absorbed into pulmonary blood
- CO2 constantly diffusing from pulmonary blood
- Dry atm air that enter respiratory tract is humidified before reaches alveoli
Humidification air => atm air enter respiratory passage exposed to fluids that
cover respiratory surface
water vapor dilutes all the other gases in inspired air
tekanan gas akan turun
Hanya 350 ml dari udara baru yang masuk ke dalam alveoli pada tiap kali
pernapasan normal, dan dalam jumlah yang sama udara lama dalam alveolus
dikeluarkan

Sehingga dibutuhkan banyak inspirasi untuk menukar sebagian besar udara


alveolus tesebut.
O2 concentration & partial pressure within alveoli
Controlled by
- Rate of absorption O2 into blood
- Rate entry O2 by ventilation
CO2 consentration & partial pressure within alveoli
- Peningkatan Pco2 alveolus kecepatan ekskresi CO2
- Penurunan Pco2 berbanding terbalik dengan ventilasi alveolus

Diffusion of gases through respiratory membrane


Respiratory unit include : respiratory bronchiole, alveolar duct, atria & alveoli
Respiratory membrane tdd :
1) Layer of fluid lining alveolar & containing surfactant that decrease surface
tension
2) Alveolar epithelium
3) Epithelial basement membrane
4) Interstitial space
5) Capillary basement membrane
6) Capillary endothelial membrane
Overall thickness 0.2 m 0.6 m
Total surface area = 70 m2
Total quantity blood in capillaries 60-140 ml
Diameter pulmonary capillaries 5mm, so RBC squeeze & contact with capillary
wall
O2 & CO2 no need to pass through plasma

capacity of diffusion

Factors in gas diffusion through respiratory membrane


1) Thickness of respiratory membrane
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Pada keadaan edema, gas2 tidak hanya berdifusi lewat membrane tapi
melalui cairan ini juga
rate of diffusion
2) Surface area of respiratory membrane

1/3 -1/4 normal


pertukaran gas melalui membrane terganggu bahkan
dalm keadaan istirahat sekalipun
3) Diffusion coefficient
Depend on gas solubility & inverse on molecular weight
4) Pressure difference
O2 => P in lungs > blood
CO2 => P in blood > lungs
Diffusing capacity of respiratory membran
Ability of respiratory membrane to exchange a gas between alveoli & pulmo blood
Volume of a gas that will diffuse through the membrane each minute for a partial
pressure difference of 1 mmHg
a. O2 diffusing capacity => 21 ml/min/mmHg
- Mean O2 pressure diference in resp.membran = 11 mmHg
- Perkalian tekanan ini dengan kapasitas difusi memberi hasil total kira2 230
ml difusi oksigen mealui membrane pernafasan tiap menit
- Pada keadaan kerja/exercise , kapasitas difusi O2 akan meningkat. Hal ini
terjadi karena :
Vasodilatasi capillaries yang akan meningkatkan surface area
Pertukaran yang lebih baik antara ventilasi alveoli & perfusi kapiler
alveolus dengan darah
b. CO2 diffusing capacity => never been measured, because
- CO2 berdifusi mell resp.membrane sedemikian cepatnya hingga Pco2 dalam
darah paru tidak berbeda banyak dengan Pco2 dalam alveoli
Ventilation-peRfusion ratio
VPR (VA/Q) = 0
Tidak ada ventilasi, aliran darah bagus
Udara dalam alveolus menjadi seimbang dengan CO2 & O2 darah, karena gas-gas
ini berdifusi di antara darah & udara alveolus
Po2 = 40 mmHg Pco2 = 45 mmHg
VPR = infinity
Ventilasi bagus, aliran darah tidak ada
Udara alveolus sekarang menjadi sama dengan udara inspirasi yang sudah
dilembabkan dengan demikian udara inspirasi tidak kehilangan oksigen untuk
darah dan tidak mengandung CO2
VPR = normal
Po2 alveolus = 104 mmHg

Pco2 alveolus = 40 mmHg

Physiologic shunt
Jika VPR dibawah normal , tidak terdapat cukup ventilasi untuk menyediakan
kebutuhan oksigen bagi oksigenasi aliran darah melalui kapiler alveolus

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Sehingga sebagian darah vena yg mengalir melalui kapiler paru tidak teroksgenasi
(bagian ini disebut shunted blood)
Jumlah total kuantitatif dari shunted blood disebut physioloyc shunt
Semakin besar physiologic shunt semakin besar pula jumlah darah yang tidak
teroksigenasi melalui paru

Dead space shunt


Bila VPR lebih dari normal dimana ventilasi beberapa alveoli cukup besar tetapi
aliran darah alveolus rendah
Akan ada lebih banyak oksigen dalam alveoli daripada yang dikeluarkan alveoli
oleh aliran darah
SO, ventilasi dalam alveoli tidak berharga (tidak berguna).
Selain itu ventilasi dari anatomical dead space juga tidak berguna
Jumlah dari kedua ventilasi yang tidak berguna ini disebut physiologic dead
space

REGULATION OF ACID-BASE BALANCE


Introduction
Acid substance that can donate a hydrogen ion
Base substance that can accept a hydrogen ion
Strong acid substance that is completely/almost completely
dissociated into a hydrogen ion & its corresponding/conjugate base in dilute
aqueous solution
Weak acid only slightly ionized in aqueous solution
Strong base basa yg bereaksi secara cepat dan kuat dengan H+ dan
dengan cepat menghilangkannya dari larutan
Buffer mixture of substances in aqueous solution (usually a
combination of weak acid + its conjugate base) that can reist changes in hydrogen
ion concentration when strong acids/bases are added
Body pH regulation
Hydrogen ion are the most reactive cations in body fluid that can interact with
negatively charged region of other molecules (protein)

Marked changes in protein structural conformation (hydrogen ion is necessary to


maintain membrane integrity and the speed of enzymatic reactions)

Alteration in protein behavior

Alteration in the functions of body tissues

Buffering mechanism
Chemical buffering
Chemical buffers in ECF, ICF and in bone are the 1st line defense of blood pH

change in pH but does not remove acid or base from the body
2.
Respiratory response
Respiratory system is the 2nd line defense of blood pH
1.

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Large loads of acid stimulate breathing (respiratory compensation), which removes


CO2 from the body & [H2CO3] in arterial blood

acidic shift in blood pH


3.
Renal response
Kidney are the 3rd line defense of blood pH more slowly (1-3 days)

Removing excess H- (excreted in combination with urinary buffers) ; add new


HCO3- to the ECF : also excrete the anios (phosphate, chloride, sulfate) that are
liberated from strong acids
Respiratory Regulation of pH

Dari persamaan di atas, jika terdapat CO2

H+ sehingga akan pH (shift to the right)

Stimulate peripheral chemoreceptor di aortic & carotid bodies

Stimulate center chemoreceptor di MO

Stimulate diaphragm & other respiratory muscles to contract more forcefully &
frequently (ventilation)

More CO2 exhale (persamaan shift to the lleft)

Making the blood less acidic


blood pH karena CO2

Inhibits respiratory center, inhibits ventilation

in the alkaline shift in blood pH


If pCO2 constant, rate of alveolar ventilation effects pCO2 di ECF
ventilasi pCO2 pH (ventilasi 2x pH 0,23)
ventilasi pCO2 pH (ventilasi 2x pH 0,45)
H+ concentration changing rate of alveolar ventilation
+
[H ] alveolar ventilation

pCO2
THORACIC CAVITY & THORACIC WALL
Osteocartilaginous thoracic cage :
- Sternum
- 12 pairs of ribs & costal cartilages
- 12 thoracic vertebrae & IV disc
- Diaphragm (floor of thoracic cavity)
Muscle of thoracic wall
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- Seratus posterior superior


- Seratus posterior inferior
- Levator costarum
- Internal intercostal
- External intercostal
- Transverse thoracic
Fascia of The Thoracic Wall
- Pectoral or pectoralis fascia (asso w/pectoralis major muscle)
Overlying the anterior thoracic wall : bed of the breast
- Clavipectoral fascia
Deep to pectoralis major & its fascia is another layer of deep fascia suspended
from the clavicle & investing the pectoralis minor muscle
- Endothoracic fascia
Internally lined thoracic cage
Nerves of Thoracic Wall
- 12 pairs of the thoracic spinal nerves supply the thoracic wall
- Leave IV foramina divide into
Anterior rami
o T1-T11 form intercostal nerve that run along the extent of ICS
o T12 coursing inferior to the 12th rib
Posterior rami : pass posteriorly immediate lateral to the articular processes of the
vertebrae to supply joint, muscles, & skin of the back in the thoracic region
Vasculature of Thoracic Wall
Runs in ICS paralel to ribs
ARTERY
- Derives from :
thoracic arteries : thru posterior intercostal & subcostal arteries
Subclavian artery : thru internal thoracic & supreme intercostal arteries
Axillary artery : thru superior & lateral thoracic arteries
- Intercostal arteries : thru thoracic wall bween the ribs w/ the exception @ ICS 10-11.
Each ICS is supplied by 3arteries :
A large posterior intercostal artery & its collateral branch
A small part of anterior intercostal arteries
VEINS
- 11 posterior intercostal vein & one subcostal vein on each side & anastomose
w/anterior intercostal vein
- Most posterior intercostal veins end in azygous or hemiazygous venous system
SVC
- Right superior intercostal vein : typically final tributtary of the azygos vein, before it
enter SVC
- Left superior intercostal vein : empties to left brachiocephalic veins
- Internal thoracic veins : companion veins of internal thoracic arteries
LYMPHATIC
- Drain mainly into lymph node asso w/internal thoracic arteries (parasternal nodes),
w/the heads & necks of ribs (intercostal nodes), & w/ the diaphragm
(diaphraghmatic nodes)

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Thoracic cavity : truncated cone (being narrowest superiorly, w/the circumference


increasing inferiorly & reaching its max at the junction w/the abdominal portion of
trunk
Divided into 3 major spaces :
- Central compartment/mediastinum
- 2 lateral compartment/pulmonary cavities
PLEURA
Anatomy
Each lungs invested by & enclosed in a serous pleural sac, that consist of two
continues membranes :
1. Visceral pleura : covers the lung & adherent to all its surfaces
2. Parietal pleura : lines the pulmonary cavities, adhering to thoracic wall, mediastinum,
& the diaphragm; consist of ..
Costal part : covers internal surfaces of the thoracic wall
Mediastinal part : covers the lateral aspects of the mediastinum
Diaphragmatic part : covers the superior or thoracic surface of the diaphragm on
each side of the mediastinum
Cervical pleura : extends thru superior thoracic aperture into the root of the neck,
forming a cup-shaped pleural dome over the apex of the lung
Pleural cavity
potential space bween visceral & parietal layers of the pleura
contain : a capillary layers of serous pleural fluid lubrication & allows the pleura
to slide smoothly
Lines of Pleural Reflection
- sternal line : sharp, or abrupt & occurs where the costal pleura bcomes continous
w/ mediastinal pleura anteriorly
- costal line : sharp & occurs where the costal pleura bcomes continous
w/diaphragmatic pleura inferiorly
- vertebral line : rounder, gradual reflection & occurs where the costal pleura bcomes
continous w/the mediastinal pleura posteriorly
Pulmonary Ligament bween lung & mediastinum
Costodiaphragmatic recess : where costal pleura extend into groove bween diaphragm
& chest wall
Costomediastinal recess : where the costal pleura is in contact w/mediastinal pleura
Vascularisasi
- parietal pleura
from intercostal arteries & branches internal thoracic artery
venous & lymph drainage : follow arterial supply
nerve : phrenic
- visceral pleura
bronchial arteries
venous : bronchial vein azygous & hemiazygous
lymph : drain thru superficial plexul of the lung to bronchopulmonary nodes at the
hilum
autonomic nerve supply
Histology
- mesotelium
- jaringan ikat halus kolagen & elastin; elastin bhub dgn parenkim paru
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Physiology
Pleural fluid: ultrafiltrate that originates from microvasculature of the parietal pleura
Characteristic :
volume : <20ml
- WBC : <1000/mm3
color : light yellow - glucose : same as serum level
pH : 7.37-7.43 - no organism
spec gravity : <1.016 - protein : <3gr/dl
fibrinogen (-)
pleural fluid formation
hidrostatic pressure : promotes movement of fluid out of the vessel & into
pericapillary space
colloid osmotic pressure : hinders movement of liquid out of the capillary
Starlings Equation :
Fluid movement = K ((Pc-Pic)-(COPc-COPis))
K : filtration coefficient
Pc : hidrostatic pressure in capillary
Pic : hydrostatic pressure in precapillary interstitial space
:reflection coeeficient
COP : colloid osmotic pressure
COPis : colloid osmotic pressure of pleural fluid

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HEMATO-IMMUNOLOGY
BLOOD
Darah

Plasma Darah (55%) Protein (7%)

Albumin (54%)
Globulin (38%)
Fibrinogen (7%)
Zat lain (1%)

Air (91.5%)
electrolytes
nutrient
gas
regulatory substances
waste products

Solute lain
Formed element(45%)

Platelet
150.000-400.000
WBC
5.000-10.000

neutrophils (60-70%)
lymphocytes (20-25%)
Monocytes (3-8%)
Eosinophils (2-4%)
Basophils (0.5-1.0%)

RBC
4.8-5.4 juta
Karakteristik Fisik :

Lebih padat dan lebih kental dari air, sedikit lengket

Suhu 38o C

pH 7,35 7,45

Volume 56 L (pada pria dewasa) dan 45 L (pada wanita dewasa)


Pembentukan Sel Darah (Hematopoesis)

Sistem hematopoeitik terdiri dari sumsum tulang, hati, lien, kelenjar getanh bening,
dan timus, yang merupakan tempat produksi, maturasi serta destruksi sel darah.
WAKTU
Intrauteri
ne

USIA
Selama
minggu
pertama 2 bulan
2 bulan
36 bulan
7 bulan

Birth
4 tahun
1820 tahun
> 40 tahun

LOKASI
Mesoderm yolk sac
Hati mulai berfungsi
Hematopoiesis terjadi juga di lien
Dari hati pindah ke sumsum tulang merah
Fungsi hati dan lien mulai menurun, sehingga sumsum
tulang menjadi active site hematopoiesis
Hematopoiesis secara perlahan menurun di shaft tulang
panjang
Hematopoiesis banyak ditemukan pada sternum, rib,
pelvis, vertebrae, dan skull
Sumsum tulang di sternum rib, pelvis dan vertebrae
jumlahnya sama dengan hemapoiesis jaringan dan lemak

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*Eritrosit
Anatomy RBC

RBC adalah 99 % dari sel darah

Terdapat Hb ( red color pigment, yg berfungsi sebagai oxygen carrying


protein)

Mengandung Hb sekitar 280/RBC

Bentuk: bikonkave disk

7-8 m tebal pinggir 2.5 m

Tebal tengah 0.8 m

Mature RBC gak ada nucleus ato organel

Jumlah: Male: 4.1-6 juta/L


Female: 3.9-5.5 juta/L

Life span: Male : 120 hari


Female 110 hari
Fungsi RBC

Transport O2 dan CO2


Menentukan Gol darah

RBC Senescence (Aging)


1.
Extravascular hemolisis (fagosit oleh lisosom RES)

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2.

Intravascular hemolisis (5%-10% normal RBC)

Hemoglobin Breakdown

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Hb Structure And Function

HB adalah protein pembawa oksigen yang berperan pada sifat asidofil eritrosit

Normal: male: 13,5-18g/ml, female: 12-16 g/ml

Terikat dengan 02 : oxyhemoglobine ( bright red color)

Terikat dengan CO2 : carbaminohemoglobin (dark red color)

Hb terdiri dari :
o
4 rantai polypeptide ( 2 & 2 ) yang disebut globin
o
Tiap rantai gobin berikatan dengan 1 group heme
o
Heme : red pigmented ( non protein pigment) mengandung 1 iron
atom ( ion Fe2+ yang dapat combine reversible dengan 1 molekul O2)

Fungsi HB: mengangkut oksigen dan memberikan pewarnaan pada darah


(RBC)

Berat molekul HB: 64.4 kilodalton

Sintesis: 65%: nucleater stage dan 35% saat reticulocyte stage


Ada 3 proses:
1. Iron delivery dan supply
Fe3+ di dapat ke membrane RBC melalui protein carrier (transferin)
Melewati membrane dan masuk ke sitoplasma sel
Commited to Hb sintesis dan proses lanjut ke mitokondria (ferric ion reinduced
jadi ferrous Fe2+
2. Sintesis protoporphyrins
Dimulai di mitokondria dengan formasi delta aminolevuline acid ( ala) dari
amino acid, glycine dan succinyl coenzyme A (CoA)
Dibantu oleh mitochondrial enzyme dan Ala sintetase
Dipengaruhi oleh eritropoetin dan adanya cofactor pyridoxal phosphatase (vit B6)
Intermediate heme sintesis porphyrinogens (suatu unstable tetrapyrroles yang
siap dan irreversibly oxidized untuk membentuk
oksidasi
Porphyrins (highly stable resonating molecule dan normalnya ditemkan dalam
kuantitas kecil dalam urine sehingga hasil normal RBC katabolisme)
3. Sintesis globin
Globin chain synthesis terjadi dalam RBC-Specific citoplasmic ribosome,
yang diawali dari bermacam-macam struktur gen inheritance.
Masing-masing gen merupakan hasil dari pembentukan specific polypeptide
chain.
Somatic diploid cell, termasuk RBC mengandung:
o 4
o 2
o 2 (zeta)
o 2
o 2
o 4

Pada usia 2 tahun < 2% total Hb.


o Pada fetus, 22 (HbF) merupakan major Hb.
o Produksi chain mulai secara berangsur pada prenatal dan mencapai
dewasa antara bulan ke 3 dan 6 postnatal.
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o Pada orang dewasa, Hb normal terbentuk sebagai tetramer yang


mengandung 2 globin chain dan 2 (non-) globin chain. Normal Hb
dewasa mengandung tipe Hb:
95 97% Hb HbA yang mengandung 22 chains
2 3% Hb HbA2 yang mengandung 22 chains
1 2% Hb HbF (fetal Hb) yang mengandung 22 chains
o Di sitoplasma, masing-masing globin chains berikatan dengan heme
(ferroprotoporphyrin IX) untuk membentuk Hb yang secara primer
mengandung 2 chain, 2 chain dan 4 heme group.
Eritropoeisis

Perubahan morfologi dan histologi, sesuai dengan peristiwa biokimia


perkembangan eritrosit
1. Berkurangnya volume sel
2. Terjadi kondensasi chromatin
3. Ratio N:C menurun
4. Kehilangan nucleoli
5. RNA di sitoplasma berkurang
6. Mitokondria berkurang
7. Sintesis hemoglobin meningkat namun berhenti saat telah menjadi erythrocyte
matur

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*Leukosit

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*Platelet

Aktivitas produksi platelet atau trombosit dipengaruhi oleh trhombopoietin


yang akan mengaktivkan megakaryocyte-colony-forming cells sehingga membentuk
megakarioblas, megakarioblas selanjutnya akan menjadi megakariosit (yang berisi
2000 3000 fragmen) yang akan pecah di sum-sum tulang (menjadi platelet) lalu
masuk ke sirkulasi.
Normal platelet dalam darah adalah 150.000 400.000 /L, berbentuk pipih
berdiameter 2 4 m yang memiliki beberapa vesikel tetapi tidak bernukleus. Platelet
berfungsi dalam menghentikan darah yang keluar dengan membentuk plug/sumbatan,
di dalamnya terdapat granula yang mengandung chemical promoting blood clot.
Waktu hidupnya sekitar 5 9 hari yang selanjutnya akan masuk ke spleen dan liver
untuk dimakan oleh makrofag.
Struktur
Platelet normal, apabila diwarnai menggunakan Wright stain, akan terlihat:
- daerah perifer yang berwarna biru muda hialomer
- daerah pusat pada mengandung granula merah muda granulomer.
Platelet yang terdapat di sirkulasi sekitar 70%, sedangkan sisanya akan
terampung/sequestred di hati. Fungsi utama sel darah ini adalah untuk hemostasis
sehingga bila jumlahnya <50 ribu maka akan menimbulkan ptechiae, sedangkan
jumlah <20 ribu akan terjadi pendarahan spontan.
Jika dilihat secara mikroskopis, platelet akan terbagi ke dalam 3 zona:
a. Peripheral zone yang merupakan daerah kompleks pada platelet normal
yang terdiri dari:
Glycocalyx contain protein untuk adhesi dan agregasi platelet
Platelet membrane yang memilki reseptor untuk melekat dengan
makromolekul seperti fibronektin, kolagen, vitronektin dalam plasma atau
endotelium vaskular memfasilitasi penyebaran platelet pada pembuluh
darah yang rusak dan sebagai aktivasi platelet juga pembentukan agregasi
platelet yang lebih besar.
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Glycoprotein platelet membrane berperan sebagai reseptor dan fasilitasi


transduksi; aktivitas signal sebagai respon terhadap eksternal stimuli adesi
platelet pada kolagen yang terpapar dalan subendotelium, termasuk interaksi
dari receptor membrane platelet, vWF, plasma component.
b. Cell-gel zone yang disebut juga dengan sitoskeleton; terdiri dari:
mikrotubul: mempertahankan bentuk; memiliki subunit protein tubulin;
terjadi kontraksi mikrotubul pergerakan organel-organel dan reorganisasi
yang mempermudah proses sekresi
mikrofilamen: tertanam di sitoplasma, memiliki aktin dan miosin, berfungsi
dalam merubah bentuk platelet
c. Organel zone yang bertanggungjawab untuk aktivitas metabolik pada
platelet
Granul
- granule: jumlahnya 20 200 per platelet; bersifat heparin antagonis;
mengandung platelet derived growth factor (PDGF) yang menyebabkan
proliferasi sel endotelium vaskuler, serat otot vaskular, dan fibroblas
untuk perbaikan dinding pembuluh darah yang rusak
- dense granule: berjumlah 2 -20 per platelet
- lisosom enzimhidrolitik
- fibrinogen dan vWF
Mitokondria membentuk ATP dan ADP
Dense tubular system (DTS) mencetus kontraksi platelet
Peroksisom
Chemical content of platelet; granules and major function in hemostasis
Alpha granules
Platelet Spesific proteins
Beta-thromboglobulin (-TG)
Platelet factor 4 (PF4)
Platele-derived growth factor (PDGF)
Thrombospondin
Plasma proteins
Fibrinogen
von Wilebrand factor (vWF)
Factor V
Factor VII
Fibronectin
Albumin
High-molecular-weight kininogen
(HMWK)
2 antiplasmin
Plasminogen

Function
Inhibits heparin; chemotactic; promotes
smooth muscle growth for vessel repair
Inhibits heparin
Promotes smooth muscle growth; involved
in atherosclerosis and lipid metabolism
Promotes platelet-to-platelet interaction;
mediates cell-to-cell interaction
Fibrin formation
Promotes platelet adhesion
Cofactor in fibrin formation
Cofactor in fibrin formation
Cellular adhesion molecule; promotes
platelet spreading
Uncertain
Activation of the intrinsic pathway via
contact
Inhibits plasmin
Precursor to plasmin; function in

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fibrinolysis
Dense granules
ADP (nonmetabolic)
ATP (nonmetabolic)
Calcium
Serotonin
Lysosomes
Neutral proteases
Acid hydrolase
Bacteriocidal enzymes

Promotes platelet aggregation


Uncertain
Primary and secondary messenger regulates
platelet activation/aggregation
Promotes vasoconstriction
Uncertain
Uncertain
Uncertain

HEMOSTASIS
1. Platelet adhesion:
Principal mechanism dari platelet adhesion :
vWF (von Wilbrand Factor)
collagen fibers
platelet membrane glycoprotein Ib (GPIb ; reseptor untuk vWF)
platelet adhesion terjadi saat platelet berikatan dengan kolagen dari
blood vessels damage dan dimediasi oleh vWF (suatu protein
diahsilkan dan disekresikan oleh blood vessel epithelial cell). vWF
membentuk a bridge (jembatan) diantara collagen dan platelet dengan
mengikat reseptor permukaan platelet dan collagen (vWF coonects
collagen dan platelet)
2. Platelat release reaction:
platelet menjadi active dan mengeluarkan ADP, thromboxan, dan
chemical lain dengan exocytosis.
ADP dan thromboxan menstimulasi platelet lainnya menjadi active dan
secara bertahap mengeluarkan chemical dan secara bertahap menjadi
yang lainnya menjadi active
3. platelet aggregation:
reseptor permukaan mengikat fibrinogen untuk membentuk jembatan
diantara permukaan reseptor dari pletelet yang lainnya membentuk
platelet plug
4. mengkativasi platelet express phospholipids (platelet factor III) dan
coagulation factor V , dimana adalah factor clot yang penting.

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Fig.1. Mechanism of Hemostasis


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Hemostasis
Hemostasis merupakan proses rumit tubuh menghentikan pendarahan secara spontan
dan mempertahankan darah dalam keadaan cair di dalam pembuluh darah. Tugas
utamanya adalah mempertahankan keseimbangan antara clotting dengan bleeding.
Proses ini terjadi secara cepat dan lokal yang terdiri atas proses spasme pembuluh
darah/vascular spasm, platelet plug formation, dan blood clotting.
Hemostasis dijaga oleh dua sistem utama yakni:
a. Major:
- sistem vaskular
- platelet (adesi dan agregasi)
- sistem koagulasi
- sistem fibrinolisis
b. Minor
- sistem kinin
- serine protease inhibitor
- sistem komplemen
Secara garis besar, sistem hemostasis dibagi ke dalam dua bagian yakni
primer: adesi platelet pada kolagen yang terbuka/terpapar dalam
endotelium dinding-dinding pembuluh darah (platelet plug)
aktivasi enzim untuk koagulasi protein fibrin berasal dari fibrinogen
stabilisasi fragile clot yang dibentuk pada hemostasis primer.
Hemostasis dapat dicapai melalui
- vascular spasm
- formation of platelet plug
- blood clotting (coagulation)
- Vasoconstriction
Dinding pembuluh darah rusak/sobek

Impulse pain nerveAktivasi trombosit pada titik yang rusak melepaskan seroton
Nervous reflex, local myogenic spasm
Vessel contraction

Vasokonstriksi otot-otot polos dinding pembuluh da


darah yang hilang

Formation of platelet plug


a. Mekanisme adhesi platelet
Terdapat beberapa hal yang berpengaruh dalam tahapan ini yakni
plasma, collagen fiber, dan platelet membrane glycoprotein GpIb yang
merupakan reseptor untuk vWF.
Endothelial damage

Exposed to flowing blood

Platelet move to defective site (GpIb receptor)

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Binding with vWF

vWF bridge

adhesion
penempelan akan merangsang pelepasan dense granule content
agregasi trombosit tahap awal, aktivasi platelet perubahan bentuk
platelet dari disc shape sphare with pseudopods (berfungsi untuk
meningkatkan interaksi antara platelet yang berdekatan).
b. Mekanisme agregasi
mekanisme ini merupakan interaksi antara satu platelet dengan platelet
lainnya. Prose ini akan merekrut ATP (berasal dari glikolisis), ion kalsium,
reseptor fibrinogen GP IIb & Iia
glycoprotein Iib/Iia bind with

Fibrinogen

Fibrinogen bridge
(between adjacent platelet)

Platelet aggregation
c. Mekanisme sekresi dan agregasi yang kedua
mekanisme ini terjadi secara stimultan (bersamaan); agregasi ke dua
akan muncul setelah ada sekresi.
Sekresi:
Cytoskeletal contraction & compression

Organel move to center

Granule spill their content into OCS (open canal system)


2nd aggregation:
Dense granule secretion & lysosome
(4DP, serotonin, Ca2+)

Peningkatan proses agregasi

Recruitment more platelets

Large platelet mass


d. Stabilisasi platelet plug
tahapan ini merupakan tahapan terakhir pada hemostatik primer yang
akan menghentikan pendarahan setelah pembuluh darah rusak dan akan
menghasilkan pembentukan stable platelet plug. Proses ini melibatkan
aktivitas coagulation cascade juga formation & deposition of fibrin.
Clotting/koagulasi
Proses ini merupakan reaksi kimia peningkatan pembentukan benang fibrin menjadi
bentuk gel. Proses ini melibatkan:
- Ca2+
- Enzim inaktif yang dihasilkan oleh liver
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- Molekul-molekul platelet yang dihasilkan oleh jaringan yang rusak


Secara umum proses koagulasi terbagi ke dalam 3 tahap:
a. extrinsic and intrinsic pathway terbentuk protombinase (activator of
prothrombin)
b. prothrombinase merubah prothrombin (plasma protein yang dihasilkan oleh
hati) menjadi trombin
c. trombin merubah soluble fibrinogen (protein plasma yang dihasilkan oleh hati)
menjadi fibrin insoluble sehingga terbentuk clot.
Extrinsic pathway
Cedera jaringan
Faktor jaringan

1
VII
2

VIIa
X

Xa

Ca2+

Ca2+
V
Fosfolipid trombosit
Aktivator protrombin
Protrombin

Ca2+

trombin

Keterangan:
1. Pelepasan faktor jaringan (thromboplastin):
- dilepaskan oleh jaringan yang luka
- berupa fosfolipid membran jaringan dan kompleks lipoprotein yang
mengandung enzim proteolitik yang penting
2. Aktivasi faktor X sebagai hasil peran dari faktor VII dan tissue factor:
- kompleks lipoprotein faktor jaringan bersatu dengan faktor VII menjadi
VIIa
- VIIa + faktor jaringan + Ca2+ merubah faktor X menjadi Xa.
3. Xa + V (Va) + Ca2+ membentuk aktivator protrombin:
- lalu aktivitas protrombin (thrombinase) + fosfolipid trombosit + Ca2+
merubah protrombin menjadi trombin
- terjadi proses pembekuan dengan mula-mula faktor V inaktif, namun
setelah terjadi pembekuan maka trombin akan mengaktifkan faktor V
menjadi Va, begitu seterusnya
Intrinsic pathway

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Kerusakan darah
(kontak-kolagen)
XII

XIIa

2 XI
3 IX
VII

VIIa
4

1
HMWK, prekalikrein
XI
Aktivator
Ca2+
protrombin
IXa
5
Ca2+
Ca2+
Ca2+
X
Xa

Fosfolipid trombosit V (Va)

trombin

protrombin
Ca2+

angan intrinsic pathways:


1. aktivasi faktor XII XIIa & pelepasan fosfolipid trombosit oleh darah yang
rusak/trauma
Trauma darah/berkontak dengan dinding kolagen mengubah 2 faktor:
a. faktor XII = berkontak dengan kolagen XII XIIa (proteolitik enzim)
b. trombosit = trombosit akan bersentuhan dengan kolagen berubah
bentuk/rusak sehingga trombosit melepaskan fosfolipid trombosit yang
mengandung lipoprotein
2. aktivasi faktor IX oleh XIa
XIIa merubah XI Xia dengan bantuan HMWK dan dipercepat oleh
prekalikrein
3. Faktor Xa membentuk aktovator protrombin (protrombinase)
Dengan XIa merubah IX IXa
4. Aktivasi faktor X oleh Ixa & VIIIa & Ca2+ & fosfolipid trombosit
IXa + VIIIa + Ca2+ + fosfolipid X Xa
5. Faktor Xa membentuk aktivator protrombin (protrombinase)
- Xa + V (Va) + Ca2+ + fosfolipid protrombinase
- Protrombinase protrombin menjadi trombin dengan bantuan Ca2+,
fosfolipid trombosit
- Trombin memiliki efek positif terhadap V & VIII Va & VIIIa
- Setelah terjadi pembekuan V Va
Pembentukan dan stabilisasi fibrin

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Pelepasan fibrino-peptida

Ikatan hidrogen

Fibrinogen
Trombin

Fibrin monomer
XIII
Fibrin polimer

Pengikatan
transamidase

XIIIa
Fibrin berikatan
silang

Tahapannya adalah:
1. Trombin menghidrolsis fibrinogen dengan cara melepaskan fibrinopeptida A
& B untuk membentuk fibrin monomer.
2. Melalui ikatan hidrogen secara spontan, fibrin monomer membentuk fibrin
polimer yang longgar dan insoluble (tidak larut).
3. fibrin polimer lalu distabilkan oleh XIIIa dengan pembentukan ikatan silang
yang terikat secara kovalen.

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IMMUNOLOGY
Sistem imun terdiri atas :
1. Sistem imun nonspesifik / innate
a) First lines
b) Second lines
2. Sistem imun spesifik / acquired
a) humoral
b) sellular

First line of defenses skin and mucous membranes


Physical factor
- Epidermis
- lacrimal apparatus
- Mucus
- saliva
- mucus membrane
- urine
- hair
- defecation
- cilia
Chemical Factor
sebum
lysozyme
gastric juice
vaginal secretion
Second line of defenses : internal defenses
1. Antimicrobial proteins
- interferon : menghambat replikasi virus dgn mensintesis antiviral protein di
uninfected cell
- complement : sitolisis mikroba dan contribute to inflammation
- transferring : menghambat pertumbuhan bakteri dgn menurunkan kadar besi
2. Natural Killer cell
- di limpa, nodus limfatikus, dan sumsum tulang merah
- mengeluarkan perforin u/ sitolisis dan granzymes u/ apoptosis
- hanya merusak infected cells tp microbanya dihancurkan o/fagosit
2. Phagocytes : fagositosis; neutrophil dan macrophages
5 tahap :
1. chemotaxis
2. adherens
3. ingestion
4. digestion
5. killing
4. Inflammation : redness, pain, heat, swelling, loss of function
3 tahap :
1. vasodilatasi dan peningkatan permeabilitas pembuluh darah
2. Emigrasi dari fagosit
3 perbaikan jaringan
5. Fever
memperkuat efek dari interferon
menghambat pertumbuhan mikroba
mempercepar penyembuhan

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HYPERSENSITIVITY

Perubahan aktivitas imunologi terhadap antigen yang menimbulkan respon imun yang
patologik setelah paparan ulang.
Tipe-tipe tersebut yakni:
a. tipe I/IgE mediated reactions/ reaksi anafilaksis/reaksi alergi
b. tipe II/tissue-spesific reaction
c. tipe III/immune complex-mediated injury
d. tipe IV/cell-mediated tissue destruction
Berdasarkan waktu munculnya respon imun sekunder, hipersensitivitas dibagi ke
dalam 2 macam:
- immediate hypersensitivity (terjadi dalam beberapa menit).
Anafilaksis: merupakan severe immediate hypersensitivity, dapat dalam
bentuk general (gatal, eritema, muntah-muntah, kram perut, diare,
kesulitan bernafas, edema laring, vascular collapse menyebabkan
respiratory distress) atau dalam bentuk lokal (anafilaktik kutaneus).
- delayed (terjadi beberapa jam hingga beberapa hari)
Tipe I (IgE-mediated reaction)
Pada tipe ini terdapat ciri uama yakni produksi IgE setelah terpapar antigen. Sebagian
besar alergi tipe ini disebabkan oleh faktor lingkungan sehingga bersifat alergik
(alergen: agen yang menyebabkan respon alergi, kemungkinan berupa protein).
Reaksi tipe ini disebut juga dengan reaksi cepat/ reaksi alergi/anafilaksis (ana: jauh
dari; phylaxis: perlindungan); contohnya: rhinitis allergy, asma.
Tugas IgE
- Paparan terhadap alergen produksi IgE oleh sel B paparan berulang
sensitized.
- IgE (dan IgG4) berikatan dengan reseptor Fc pada sel mast (sehingga disebut
antibody cytotropic karena dapat berikatan pada permukaan sel). Reagin
merupakan skin sensitizing antibody yang terkadang disebut cytotropic
antibody.
- Pada individu yang tersensitisasi kemudian terpapar ulang alergen, maka akan
menyebabkan cross-linking 2 reseptor kompleks IgE-Fc dan mulai melakukan
degranulasi juga melepaskan produk-produk sel mast.
Mekanisme IgE-mediated hypersensitivity
Degranulasi mast cell modulasi respon inflamasi akut. Pada proses ini yang paling
berpengaruh adalah histamin. Pengaruh histamin:
a. H1 receptor: meningkatkan permeabilitas postkapiler venula, kontraksi otot
polos, vasokonstriksi pulmonar, mencetus sekresi mukosa, kemotaksis lekosit,
produksi prostaglandin di paru-paru.
b. H2 receptor: mencetus sekresi asam lambung, mencetus sekresi mukosa,
meningkatkan level cAMP di sel, kemokin lekosit, aktivasi suppressor T-cell
(menekan produksi histamin dari sel mast dan basofil negative feed back
loop sehingga dapat menghentikan degranulasi).
Individu yang memiliki kerentanan terhadap alergi disebut atopic individual yang
memiliki beberapa kemungkinan latarbelakang seperti berikut:
- konsentrasi IgE yang lebih tinggi
- memiliki reseptor Fc lebih banyak pada mastosit
- berkurangnya fungsi salah satu limfosit-T (contohnya: defisiensi IgE-spesific
suppressor cells).
Reaksi alergi juga dapat terjadi pada sekstem saraf otonom yakni termasuk mediatormediator biokimia (epinefrin, asetilkolin) mengendalikan perilaku sel target pada
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jaringan tuan rumah (melepaskan mediator-mediator inflamasi dari sel mast dan
mengendalikan derajat respon tiap sel target terhadap mediator-mediator inflamasi)
Pada reaksi hipersensitivitas tipe I (reaksi alergi) terdapat beberapa tahap yakni:
- fase sensitisasi: waktu yang diperlukan untuk pembentukan IgE hingga
diikatnya oleh reseptor spesifik (Fc R) pada permukaan sel mast dan basofil.
- fase aktivasi: waktu yang diperlukan antara paparan ulang dengan antigen
yang lebih spesifik dan hingga sel mast melepaskan granula-granulanya.
- fase efektor: waktu terjadi respon yang kompleks (anafilaksis) sebagai efek
mediator-mediator yang dilepas oleh sel mast.
Antigen merangsang sel B membentuk IgE dengan bantuan sel Th

IgE diikat oleh sel mast/basofil melalui reseptor Fc

Apabila tubuh terpapar ulang dengan antigen yang sama

Maka antigen diikat oleh IgE yang sudah ada pada permukaan sel mast/basofil

Terbentuk ikatan antigen IgE

Sehingga sel mast/basofil mengalami degranulasi melepas mediator-mediator

Histamin:
Amin vasoaktif
PG leukotrien
mediator lipid:
Bronkokonstriksi
Reaksi(reaksi
hipersensitivitas
fase lamban
cepat
6-24 jam setelah paparan) konstriksi oto
Sekresi mukus
Resistensi salurannafas

Tipe II (Tissue-Spesific Reaction)


Karakter utama tipe ini adalah penghancuran sel target melalui aksi antibodi
dengan antigen pada membran plasma sel. Selain HLAs (histocompatibilty locus
antigens), jaringan-jaringan juga memiliki antigen lainnya yang disebut dengan
tissue-spesific antigen (karena hanya ada pada membran plasma sel-sel tertentu.
Contohnya: platelet memiliki self-antigen sendiri yang tidak dimiliki oleh sel
lainnya. Hipersensitivitas tipe II hanya terbatas pada jaringan atau organ tertentu
yang mengekspresikan antigen khusus.
Pada tipe ini terdapat 2 mekanisme yang memediasi hipersensitivitas tipe II,
yakni: complement mediated lysis dan opsonization.
Terdapat 4 jenis mekanisme umum yang berbeda pada hipersensitivitas tipe II
yang keseluruhannya prosesnya dimulai dari ikatan antibodi dengan tissuespesific antigen. Mekanisme umum tersebut yakni:
1.
antibodi (IgM atau IgG)

beraksi dengan antigen di permukaan membran sel

Aktivasi sistem komplemen

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Terjadi membrane attack complex (C5-9)

Drill trough membrane

Sel lisis
__________________________________________________________________
2. Pada mekanisme ini, penghancuran sel melibatkan makrofag dari sistem fagosit
mononuklear.
Fc R di makrofag mengikat antibodi pada sel yang telah teropsonisasi

Fagositosis sel target


(contohnya di spleen)
__________________________________________________________________
3. Mekanisme ini dibantu oleh antibody-dependent cell-mediated cytotoxicity
(ADCC), salah satu yang berperan adalah sel NK (natural killer).
Fc R di NK + antibodi di sel

NK mengeluarkan substansi toksik

Menghancurkan sel
__________________________________________________________________
4. Mekanisme ini tidak menghancurkan sel, namun hanya menyebabkan
malfungsi.
Sel target + antibodi

Ligan diblok oleh antibodi


(ligan dibutuhkan untuk fungsi normal sel)

Sel malfungsi
Tipe III (Immune Complex-Mediated Injury)
Mekanisme hipersensitivitas tipe ini diakibatkan oleh antigen-antibody/immune
complex yang terbentuk di sirkulasi (dari soluble antigen) kemudian terdeposit di
dinding pembuluh darah atau jaringan ekstravaskular.
Free antigen + free antibody&complement
(complement fragmen=chemotactic neutrophil)

Deposit di jaringan

neutrophil attempt to ingest immune complex

During that, large lysosomal enzymes released to inflammatory site

Attraction of neutrophils + release of lysosomal enzyme

Tissue damage
Sebagian kecil kompleks imun terfiltrasi melalui ginjal tanpa ada konsekwensi
patologis. Sebagian besar sisa terdeposit di jaringan (akan berbahaya apabila rasio
antigen-antibodi = 2:1) severe pathologic. Contohnya: glomerulonephritis,
vasculitis, or arthritis.
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Beberapa keadaan yang sering muncul berkaitan dengan hipersensitivitas tipe III
antara lain:
- Hypocomplementemic: disebabkan karena kompleks imun mengikat banyak
komplemen sehingga terjadi penurunan komplemen. Hal ini tidak terjadi pada
hipersensitivitas tipe lainnya. Selain itu, banyaknya kompleks imun dapat
menimbulkan fenomena remisi/muncul kembali diakibatkan masih tersisanya
kompleks imun yang belum terdeposit pada jaringan.
- Serum sickness: merupakan bentuk sistemik penyakit yang disebabkan
immune complex-mediated yang akan terdeposit di jaringan target sehingga
munculnya inflamasi. Jaringan yang terlibat biasanya: dinding pembuluh
darah, sendi, dan ginjal. Manifestasi lainnya antara lain: demam, pembesaran
nodus limfatikus, memar, dan nyeri pada tempat inflamasi. Lab menunjukkan
adanya peningkatan limfosit, granulosit, dan platelet di sirkulasi.
- Arthus: merupakan bentuk lokal penyakit yang disebabkan immune complexmediated karena paparan ulang terhadap antigen luar yang beraksi dengan
dinding pembuluh darah. Gejalanya dimulai 1 jam setelah terpapar dan
puncaknya pada 6 12 jam. Karakter lesinya adalah adanya inflamasi,
peningkatan permeabilitas, akumulasi netrofil, edema, pendarahan, clotting,
dan kerusakan jaringan.
Tipe IV (Cell-Mediated Tissue Destruction)
Reaksi hipersensitivitas tanpa melibatkan antibodi, dan langsung beraksi dengan sel
limfosit. Hipersensitivitas dibagi menjadi:
1. Delayed type hypersensitivity (DTH) melalui sel CD4+
2. T-cell mediated cytolysis melalui sel CD8+
Delayed type hypersensitivity (DTH)
Respon imun yang merusak tubuh dalam usaha mengucilkan mikroba.
CD4+ Th1

Melepas sitokin
(INF-)
Reaksi inflamasi

makrofag

Menghasilkan produk aktif

enzim hidrolitik,
Oksigen reaktif
intermediate,
Nitric Oxide
Sitokin proinflamasi

Superoksid
Period radikal
Mikroorganisme
hancur

Jaringan rusak

Reaksi khas DTH memiliki 2 fase yakni fase sensitisasi dan fase efektor (7-10 hari)
a. sensitisasi: pematangan limfosit-T, seiap melepaskan limfokin.
Setelah kontak dengan antigen

Sel Th disensitisasi

Berproliferasi

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Diferensiasi menjadi sel DTH


b. fasek efektor/fase elisitasi.
Jika sel DTH terpapar ulang dengan antigen yang sama (sel T memori)

Sitokin

Makrofag aktif
(sebagai sel efektor dalam reaksi hipersensitivitas)

Mengeluarkan enzim litik


T-cell mediated cytolysis
Kerusakan terjadi melalui aktivasi sel CD8+/CTL/Tc.
Penyakit yang ditimbulkan cenderung mengenai beberapa organ saja, biasanya
tidak sistemik (con: hepatitis).
Sel CD8+ yang spesifik untuk antigen/sel autologus dapat membunuh sel
secara langsung.

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Vascular Response
Inflamasi pada vascular tissue : redness, heat, swelling dan pain.
3 karakteristik perubahan pada mikrocirculasi di dekat daerah injury :

Blood vessel dilatasi

Peningkatan vascular permeability dan leakage of fliud out of vessel


WBC adherence ke inner wall of vessel & migrasi melewati dinding
vessel ke tempat injury
- Efek inflamasi pada pembuluh darah dapat terlihat dalam waktu beberapa
detik
- Arteriol yang dekat tempat infeksi atau injury konstriksi, lalu vasodilatasi
kemudian menyebabkan slower blood velocity dan peningkatan local
aliran darah ke tempat injuri. Peningkatan aliran dan capillary permeability
menyebabkan keluarnya plasma dari vessel dan terjadi edema di tempat
injury. Keluarnya plasma dari vessel menyebabkan sisa darah dalam
microcirculation alirannya lambat dan sangat viscous. Peningkatan aliran
dan capillary permeability menyebabkan peningkatan aliran darah dan
peningkatan konsentrasi red cell di tempat inflamasi sehingga
menimbulkan warmth dan redness.
Plasma Protein System
Complement system
Clotting system : Merupakan sekelompok plasma protein yang membentuk
fibrous meshwork pada daerah pertukaran atau daerah inflamasi.
Substansi pada fibrous mesh adalah insoluble protein yang disebut fibrin.
Kinin system
Konversi prekalikrein menjadi kalikrein diinduksi oleh prekallikrein
activator yang identik dengan factor XIIa, kemudian kallikrein mengubah
kininogen menjadi bradikinin. Bradikinin menginduksi kontraksi otot
polos lebih lambat daripada histamine dan bersama dengan PGE series
bertanggung jawab dalam endothelial retraction dan meningkatkan
permeabilitas vascular pada fase selanjutnya dari inflamasi, juga
menginduksi nyeri.
Ketiga plasma protein system ini saling berinteraksi pada respon
inflamasi.
Cellular Mediator of Inflammation
Mast Cell
Sel mast adalah sel yang dalam struktur, fungsi dan proliferasinya serupa
dengan basophil, bedanya adalah sel mast hanya ditemukan dalam jaringan yang
berhubungan dengan pembuluh darah.
Banyak ditemukan di kulit, lapisan GI tract dan respiratory tract.

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Mast Cell Degranulasi

Basophil
Mediator-mediator yang dilepas basofil dan sel mast :
Mediator
Amine : histamin, serotonin.
preformed
Protease netral : triptase, protease, kemotriptik.
Proteoglikan : heparin, kondroitin sulfat.
Hidrolase acid : b-heksosaminidase, bglukuronidase.
Factor kemotaktik
Newly generated Produk asam arachidonat
Leukotrin : LTC4, LTD4, LTE4
Produk siklooksigenase (PGD2)
PAF
Sitokin (factor IL-1, IL-3, IL-4, IL-5, IL-6
pertumbuhan dan Factor inflamasi (TGF-, TNF-)
regulatori)
IFN-
GM-CSF
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A.
1.

Sel Fagosit
Fagosit Mononuclear

Sel Monosit
Fagosit mononuclear berasal dari sel progenitor umum dalam sumsum tulang.
Sesudah berproliferasi dan matang, sel tersebut masuk peredaran darah.
Fungsi :
- bakterisidal/ fagositosis
- aktivasi vascular sel epitel
- aktivitas sebagai respon terhaap infeksi
- modeling dan perbaikan jaringan
- produksi komponen komplemen
- presentasi limfosit
- anti tumor
- antiviral
Monosit tidak hanya menyerang mikroba dan sel kanker dan berperansebagai
APC, tetapi juga memproduksi sitokin dan mengerahkan pertahanan sebagai respon
terhadap infeksi.
2.
Sel Makrofag
Setelah 24 jam dalam peredaran darah, sel monosit akan bermigrasi dari
peredaran darah ke tempat tujuan di berbagai jaringan untuk berdifferensiasi sebagai
makrofag.
Makrofag tersebut bukan bentuk akhir karena sel itu masih dapat membelah diri
membentuk protein dan dapat bertahan hidup berbulan-bulan.
Makrofag yang diaktifkan oleh mikroba dan dapat berdifferensiasi menjadi sel
residen khusus dalam berbagai jaringan. Sel ini namanya berbeda-beda tergantung
tempatnya. Kehadiran makrofag di sepanjang kapiler memungkinkan untuk
menangkap patogen dan antigen yang mudah masuk tubuh. Semuanya mempunyai
kesamaan yaitu dapat mengikat dan memakan partikel antigen dan
mempresntasikannya ke sel T.
Berbagai molekul permukaan penting ditemukan pada permukaan fagosit sebagai
reseptor. Beberapa molekul tersebut berrinteraksi dengan sitokin dan mengaktivkan
fagositosis, yang lainnya meningkatkan adheren dengan permukaan sel lain. Adheren
dan fagositosis antigen oleh monosit dan makrofag dipermudah melalui reseptor
permukaan sel untuk fraksi Fc dari IgG (Fc-R) dan komplemen seperti C3b-R.
Monosit dan makrofag juga mempunyai reseptor untuk IFN, MIF dan MAF.
Makrofag memiliki reseptor yang dapat mengenal molekul non-self. Reseptorreseptor tersebut mengaktifkan respon sellular yang diperlukan pada inflamasi dan
menyingkirkan mikroba.

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Menurut fungsinya, makrofag dibagi menjadi 2 golongan, pertama sebagai fagosit


profesional dan kedua sebgai APC.
3.
a)

Proses Fagositosis
Pencernaan dan pembentukan vakuol
Partikel yang terpajan dengan fagosit akan ditangkap dan ditelan dengan
bantuan reseptor pada membran sel. Bila partikel sudah ditelan, membran
ditutup, partikel digerakkan ke sitoplasma sel dan terbentuk vesikel intrasellular
yang mengandung bakteri atau bahan lainasal ektrasellular yang disebut
fagosom.
Dalam fagosit terdapat kantong yang berisi enzim lisosom. Lisosom
bersatu dengan fagosom dan membentuk fagolisosom yang memungkinkan
terjadinya degradasi semua bahan yang dimakan oleh enzim asal lisosom.
b)
Destruksi intrasellular
Dalam fagolisosom, bahan yang ditelan akan dicerna enzim yang
terkandung dalam granul lisosom. Isi granul lisosom diperlukan untuk
memecah/ mencerna bahan yang ditelan dan membunuh mikroba. Pembunuhan
mikroba terjadi melalui :
i. Penghancuran mikroorganisme yang oksigen independent
Granule neutrofil berisi berbagai enzim hidrolitik, mieloperoksidase, lisozim,
dan arginine-rich basic protein, fosfatase alkali, laktoferin dan lisozim. Isi granul
menghancurkan bahan asing terutama melalui enzimnya seperti henzim hidrolitik.
Enzim-enzim ini dapat mencerna komponen membran sel bakteri.
ii. Penghancuran mikroorganisme yang oksigen dependent
Mikroorganisme dapat dibunuh melalui produk respiratory bursr oleh beberapa
metabolit oksigen mikrobisidal yang dilepas selama fagositosis. Yang disebut
respiratory burst adalah proses yang menghasilkan ROI.
Salah satu enzim, oksidase fagosit, terbentuk atas pengaruh mediator inflamasi
seperti LTB4, PAF dan TNF atau produk bakteri seperti peptida N-formil metionil.
Enzim ini mengubah molekul oksigen menjadi anion superoksid, radikal bebas dan
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H2O2 yang merupakan bahan oksidatif poten untuk mikroba. Bahan tersebut
merupakan ROI yang sangat toksik untuk bakteri dan jaringan, tetapi sangat tidak
stabil, dipecah dengan cepat oleh H2O2 yang akhirnya dipecah katalase (INOS).
INOS merupak katalase dalam konversi arginin menjadi NO yang juga bersifar
bakterisidal. Lalu enzim ketiga adalah protease lisosom yang memecah protein
mikroba.
Semua bahan mikrobisidal tersebut tidak merusak fagosit itu sendiri. Bila reaksi
inflamasi kuat maka enzim yang sama dapat terlepas ke rongga ektrasellular sehingga
jaringan bisa ikut rusak.
c)
Produk yang dilepaskan fagosit
Disamping destruksi partikel asing intrasellular, fagosit juga melepaskan berbagai
komponen biologik aktif.
Makrofag dapat diaktifkan oleh sinyal dari reseptor permukaan. Reseptor untuk
endotoksin (LPS) bakteri yang memberikan sinyal tranduksi melalui reseptor Toll-like
dan reseptor untuk sitokin makrofag terpenting (IFN-). Sinyal dari toll-like
mengaktifkan respon imun nonspesifik, merangsang produksi berbagai protein yang
berperan dalam fungsi pentimg makrofag.
d)
Faktor lain yang meningkatkan fagositosis
Fagosit memiliki reseptor Fc untuk IgG (Fc-R) yang dapat meningkatkan
interaksi antarsel dan opsonisasi. Isotipe IgG (IgG1 dan IgG3) merupakan opsonin
teraktif; IgG2, IgG4 dan IgA juga dapat berupaopsojnin, tetapi kurang efisien.
e)
Fagosit frustasi
Bila fagosit menempel pada suatu bahantertentu (membran basal) yang tidak
dapat dimakan, sel sel akan melepas enzim lisosomnya keluar sel (eksositosis).
Proses ini dapat menimbulkan kerusakan seperti terjadi pada penyakit kompleks
imun.
B.
Fagosit Polimorfonuclear
Fagosit polimorfonuclear dibentuk dala sumsum tulang denga kecepatan 8
juta/menit dan hidup selama 2-3 hari. Granulosit merupakan 60-70% dari seluruh
sel darah putih, tetapi dapat ditemukan juga diluar pembuluh darah oleh karena
dapat keluar dari pembuluh darah.
1.
Neutrofil
Butir-butir azurofilik primer (lisosom)
mengandung hidrolase asam,
mieloperoksidase dan neutromidase (lisozim), sedangkan butir-butir sekunder atau
spesifik mengandung laktoferin dan lisozim. Neutrofil mempunyai reseptor untuk
IgG dan komplemen.
2.
Eosinofil
Berfungsi sebagai fagosit. Eosinofil dapat pula dirangsang untuk degranulasi
seperti halnya sel mast dan melepas mediator, diantara mediatornya : arilsulfatase
dan histaminase yang dapat mengaktifkan histamin sehingga eosinofil pernah
dianggap sebagai sel peredam alergi.
Eosinofil mengandung berbagai granul
seperti MBP, ECP, EDN dan EPO yang bersufat toksik dan bila dilepas dapat
menghancurkan sel sasaran. Eosinofil juga berperan pada imunitas parasi.
Eosinofil memilki berbagai reseptor antara lain IgE dengan afinitas kuat.
Null Cell, Sel K dan Sel NK
Sel null disebut juga sel K atau sel populasi ketiga yang merupkan 37%
limfosit dalam sumsum tulang adalah sel yang menunjukkan morfologi sebagai
limfosit, tetapi tidak memiliki petanda sel B atau sel T atau immunoglobulin
permukaan. Sekitar 15-24% dari limfosit perifer adalah sel null yang berperan
dalam ADCC dan pada ALL.
Ada 3 tipe sel null yaitu :
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1) Stem cell yang tidak berdifferensiasi dan dapat menjadi matang sebagai
limfosit T dan B
2) Sel dengan IgG labil dan afinitas kuat terhadap Fc-R yang resisten
terhadap tripsin.
3) LGL yang terdiri atas sel NK dan sel K yang merupakan sekitar 3,5%
limfosit dalam sumsum tulang.
Sel NK merupakan bagian dari sel null atau sel populasi ketiga atau non-TnonB.
70-80-% dari sel tersebut berupa LGL, mengandung banyak sitoplasma dengan granul
azurofilik. Sel dikenal karena memiliki petanda permukaan CD56 dan CD16 tetapi
tidak CD3. Sel NK berperan pada imunitas keganasan dan sel terinfeksi yangtidak
mengekspresikan MHC-I.
Sel NK mengandung perforin atau sitolisin, sejenis C9 yang dapat membuat
lobang-lobang kecil pada membran sel sasaran. Perforin dilepaskan setelah terjadi
kontak.
Sel NK mengandung granul-granul yang berisi TNF- dan protease serin yang
disebut granrim, contohnya fragmentin yang merupakan protein sitotoksik yang
dilepaskan bila terjadi degranulasi sel NK.
Membran sel NK mengandung protein yang mengkat perforin, mencegah insersi
dan bpolimerasi dalam membran sehingga sel NK sendiri tehindar dari efek perforin.

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SISTEM IMUN SPESIFIK


Sel limfosit merupakan sel yang berperan utama dalam system imun spesifik, sel T pada
imunitas selular dan sel B pada imunitas humoral. Pada imunitas humoral, sel CD4+ T berinteraksi
dengan sel B dan merangsang proliferasi dan differensiasi sel B. Pada imunitas sellular, sel CD4+
mengaktifkan makrofag untuk menghancurkan mikroba interaselular yang menginfeksi sel.
Baik pada fase induksi maupun fase efektor, respon sel T dipacu oleh pengenalan spesifik
antigen. Sel T akan mengenal fragmen peptida dari antigen yang diikat molekul permukaan yang
disandi gen MHC.
I.
SEL DENDRITIK
Sel dendritik adalah sel fagosit mononuklear, merupakan sel terpoten dari semua jenis APC,
yaitu sel yang menyajikan antigen ke sel T. SD berasal dari sel asal dalam sumsum tulang atau dari
prekursor monosit dalam darah atau dari monosit sendiri. Alternatif prekursor SD adalah dalam timus
yang dapat menjadi SD, sel T dan sel NK.
Molekul permukaan mempunyai peranan penting dalam fungsi sel dengan
melibatkan molekul MHC-II yang diperlukan untuk presentasi antigen; CD80 (B7-1) dan CD86
(B7-2), berperan sebagai molekul kostimulatori dalam aktivitas sel T dan beberapa molekul adhesi.
II.
PEMATANGAN LIMFOSIT, SELEKSI POSITIF DAN NEGATIF
Sel B dan sel T berasal dari sel prekursor yang sama, diproduksi dalam sumsum tulang,
termasuk pembentukan TCR. Sel B menjadi matang dalam sumsum tulang, sedang progenitor sel T
bermigrasi ke dan menjadi matang di timus. Masing-masing sel berproliferasi atas pengaruh sitokin
terutama IL-12 yang meningkatkan jumlah sel imatur.

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III.

PETANDA PERMUKAAN DAN FUNGSIONAL


A. Petanda Permukaan
Kemampuan limfosit untuk mengenal benda asing dimungkinkan oleh adanya TCR pada
permukaan sel. TCR terdiri atas heterodimer yang mengikat antigen/MHC dan kompleks polipeptide
yang disebut kompleks CD3 yang diperlukan untuk mencetuskan aktivitas sel T selanjutnya.
Pada permukaan sel T dan sel B di temukan berbagai reseptor antara lain untuk fraksi Fc
antibodi IgG (Fc-R) yang berperan dalam mengatur respona limfosit.
B. Petanda Fungsional
Mitogen dan lektin merupakan aktivator poliklonal yang dapat mengaktifkan banyak klon
limfosit. Glikoprotein (lektin) asal tanaman yaitu konkanavalin A (con-A) dan PHA merupakan
mitogen penting untuk sel T. Contoh-contoh aktivator poliklonak adalah anti-IgM untuk sel B, antiCD3, super-antigen bakteri atau LPS yang diperoleh dari dinding sel bakteri negatif-Gram dan PHA
untuk sel T.

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Pokeweed merupakan mitogen baik untuk sel B maupun sel T. Superantigen dapat
mengaktifkan sejumlah besar sel T.
IV.
SEL T
A. Fungsi sel T
Sel T umumnya berperan pada inflamasi, aktivasi dan proliferasi sel B dalam produksi
antibodi. Sel T juga berperan dalam pengenalan dan penghancuran sel yang terinfeksi virus. Imunitas
humoral (sel B) melepas antibodi yang berperan dalam eliminasi mikroba ekstraselular. Sel T, terdiri
atas sel Th yang mengaktifkan makrofag untuk membunuh mikroba dan sel CTL/Tc yang membunuh
sel terinfeksi mikroba dan mengeliminasi reservoir infeksi.

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B. Subset sel T
Sel T terdiri atas sel CD4+, CD8+ dan sel NK.
1. Sel T Naif (virgin)
Sel limfosit naif adalah sel limfosit matang yang meninggalkan timus dan belum
berdifferensiasi, belum pernah terpajan dengan antigen dan menunjukkan molekul permukaan
CD45RA. Sel ditemukan dalam organ limfoid perifer. Sel naif yang terpajan dengan antigen akan
berkembang menjadi sel Th0 yang selanjutnya dapat berkembang menjadi sel efektor ThI dan Th2
yang dapat dibedakan atas dasar jenis-jenis sitokin yang diproduksinya. Sel Th0 memproduksi sitokin
dari ke 2 jenis sel tersebut seperti IL-2, IFN dan IL-4.
Homing sel T naif ke kelenjar getah bening terjadi atas pengaruh L-selektin yang berikatan
dengan ligannya di HEV dalam kelenjar getah bening. Sel T yang diaktifkan bermigrasi yang dibantu
selektin-E, selektin-P dan integrin, berbagai kemokin yang diproduksi kelenjar getah bening di tempat
infeksi.
Antigen yang dibawa sel dendritik ke KGB akan dikenal sel T naif. Sel T naif yang
diaktifkan, berdifferensiasi menjadi sel effektor dan sel memori yang dapat menetap di organ limfoid
atau bermigrasi ke kelenjar nonlimfoid.

2. Sel T CD4+
Sel T naif CD4+ mengenal antigen yang dipresentasikan bersama MHC-II oleh APC dan
berkembang menjadi subset sel Th1 atau sel Tdth atau Th2 yang tergantung dari sitokin lingkungan.
Dalam kondisi yang berbeda dapat dibentuk dua subset sel T yang berlawanan.
3. Sel T dan T
Ada 2 jalur diferensiasi sel T yang dapat dibedakan dari ekspresi reseptor sel T yang berlainan
yaitu yang merupakan populasi minor yang terutama ditemukan di kulit dan mukosa jaringan
saluran cerna. Sel T terbanyak mengekspresikan reseptor T .
Sel T yang mengekspresikan reseptor antigen, defisien dalam rantai polipeptide dan . Sel T
berperan dalam pertahanan terdepan untyuk mengenl mikroba yang masuk kulit dan mukosa
saluran cerna. Sel tersebut melepas sitokin yang mengawali respon inflamasi, menolong sel B,
mengaktifkan makrofag dan menghancurkan sel terinfeksi virus. Fungsional hal itu sama dengan sel T
. Sel T dapat mengenal antigen nonpeptide seperti fosfolipid dinding bakteri tanpa memerlukan
presentasi dan proses terlebih dahulu oleh APC.

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4. Sel T CD8+ (cytotoxic T lymphocyte/ CTL/ T cytolytic/ Tc)
CD8+ mengenal antigen yang dipresentasikan bersama molekul MHC-1. Fungsi:
menyingkirkan sel terinfeksi virus, menhancurkan sel ganas dan sel histoinkompatible yang
menimbulkan penolakan pada transplantasi, menghancurkan sel yang terinfeksi bakteri intraselular.
5. Sel Ts atau sel Tr
Sel Ts berperan menekan aktivitas sel efektor T yang lain dan sel B. Menurut fungsinya, sel
Ts dapat dibagi menjadi sel Ts spesifik untuk antigen tertentu dan sel Ts nonspesifik.
V.
SEL B
Aktivasi sel B di awali dengan pengenalan spesifik oleh reseptor permukaan. Antigen dan
perangsang lain termasuk Th merangsang proliferasi dan differensiasi klon sel b spesifik. Sel B mulamula memproduksi IgM atau isotipe yang lain (spt, IgG), menjadi matang atau menetap sebagai sel
memori.

A. Ig permukaan
Sel B termuda sudah ditemukan dalam hati janin dan sumsum tulang, belum mempunyai Ig
atau petanda permukaan. Mula-mula dibentuk IgM dalam sitoplasma sel yang dapat digunakan
sebagai ciri dari sel pre-B. IgM bergerak ke arah membran sel dan kemudian dijadikan reseptor
monomerik permukaan IgM (sel dapat mengenal antigen untuk pertama kali). Kontak antara antigen
dan seL B muda ini tidak menimbulkan ekspansi dan differensiasi. Selanjutnya, dibentuk IgD yang
kemudian juga bergerak ke arah membran sel. Sel yang sudah memiliki IgM dan IgD sebagai reseptor
dianggap matang.

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Atas pengaruh antigen dan sel T, sel B berproliferasi dan berdifferensiasi menjadi sel plasma
yang mampu membentuk dan melepas Ig dengan spesifisitas yang sama seperti reseptor yang ada
pada permukaan sel prekursornya. Sebagian sel matang akan kembali ke dalam fase istirahat, dan
sebagian sel B memori yang dapat memberikan respon imun dengan lebih cepat pada pajanan ulang
dengan antigen yang sama.
Atas rangsangan antigen pertama, sel B memproduksi IgM dan atas rangsangan antigen yang
sama, selanjutnya terjadi pengalihan untuk memproduksi IgG, atau IgA atau IgE. Semua sel B hanya
dapat memilki satu jenis molekul Ig saja pada permukaannya, hanya IgM, IgG dsb.

B. Reseptor
1. Reseptor Fc.
Semua sel B memiliki reseptor untuk fraksi Fc dari IgG (Fc-R).
2. Reseptor C3
Sel B memiliki reseptor untuk komponen komplemen yang diaktifkan C3b.
3. Reseptor EBV
EBV dapat diikat sel B melalui reseptor spesifik (RC3d), infeksi EBV sering menimbulkan
replikasi sel B yang stabil dan terus menerus.
4. Perbedaan sel B dan sel T
Semua sel T memilki reseptor yang diperlukan untuk aktivasi dan juga sebagai petanda. Sel B
menggunakan antibodi sebagai reseptor antigen.

ANTIGEN DAN ANTIBODI


I. ANTIGEN
Istilah antigen mengandung dua arti. Pertama untuk menggambarkan molekul yang memacu
respons imun (juga disebut imunogen) dan kedua untuk menunjukkan molekul yang dapat bereaksi
dengan antibodi atau sel T yang sudah disensitasi. Secara fungsional antigen dibagi menjadi
imunogen dan hapten. Bahan kimia ukuran kecil seperti dinitrofenol dapat diikat antibodi, tetapi
bahan tersebut sendiri tidak dapat mengaktifkan sel B (tidak imunogenik). Untuk memacu respons
antibodi, bahan kecil tersebut perlu diikat oleh molekul besar. Kompleks yang terdiri atas molekul
kecil (disebut hapten) dan molekul besar (disebut molekul pembawa) dapat berperan sebagai
imunogen. Contoh hapten ialah berbagai golongan antibiotik dan obat lainnya dengan berat molekul
kecil. Hapten biasanya dikenal oleh sel B, sedangkan molekul pembawa oleh sel T. Molekul
pembawa sering digabung dengan hapten dalam usaha memperbaiki imunisasi. Hapten membentuk
epitop pada molekul pembawa yang dikenal sistem imun dan merangsang pembentukan antibodi.
Respons sel B terhadap hapten memrlukan protein pembawa untuk dapat dipresentasikan ke sel Th.

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Epitop atau determinan antigen adalah bagian dari antigen yang dapat membuat kontak fisik
dengan reseptor antibodi, menginduksi pembentukan antibodi yang dapat diikat dengan spesifik oleh
bagian dari antibodi atau oleh reseptor antibodi. Makromolekul dapat dapat memiliki berbagai epitop
yang masing-masing merangsang produksi antibodi spesifik yang berbeda. Paratop ialah bagian dari
antibodi yang mengikat epitop. Respons imun dapat terjadi terhadap semua golongan bahan kimia
seperti hidrat arang, protein dan asam nukleat.
II. SUPERANTIGEN
Superantigen adalah molekul yang merupakan pemacu respons imun poten yang dapat
mengaktifkan 5%-30% sel T, memiliki tempat-tempat untuk mengikat reseptor sel dari dua sistem
imun yaitu rantai dari TCR dan rantai atau dari molekul MHC-II, tidak memerlukan proses
interselular melalui APC dan tidak terbatas pada alel MHC-II khusus.
Superantigen merupakan molekul protein kecil, biasanya 22-30 kd yang diproduksi berbagai
patogen untuk manusia seperti Stafilokok aureus (enterotoksin dan toksin eksofoliatif), Stafilokok
piogenes (eksotoksin), negatif-Gram (toksin Yersinia enterokolitika, Yersinis pseudotuberkulosis),
virus (EBV, CMV, HIV, rabies) dan parasit (Toksoplasma gondi). Mungkin lebih baik bila disebut
supermitogen, oleh karena dapat memacu mitosis sel CD4 tanpa bantuan APC.
Sifat umum superantigen
Efek superantigen terhadap sel T terlihat setelah diikat TCR melalui kompleks peptida MHC.
Namun kualitas respons sel T lebih cepat dan besar berup produksi sitokin seperti IL-2, TNF-, IFN, ekspresi reseptor sitokin dan proliferasi yang dapat menimbulkan ekspansi masif sel T reaktif
spesifik. Sebagai ajuvan dalam imunisasi, superantigen dapat meningkatkan respons imun terhadap
antigen tersebut. Superantigen adalah molekul yang sangat poten terhadap mitogen sel T, berikatan
dengan berbagai regio dari rantai reseptor sel T. Ikatan tersebut merupakan sinyal poten untuk
mitosis dan dapat mengaktifkan sejumlah besar populasi sel T. Sampai 20% dari semua sel T dalam
darah dapat diaktifkan oleh satu molekul superantigen.
Contoh superantigen adalah anterotoksin dan toksin yang menimbulkan sindrom syok toksin
yang diproduksi stafilokok aureus. Molekul tersebuut dapat memacu penglepasan sejumlah besar
sitokin seperti IL-1 dan TNF dari sel T yang berperan dalam patologi jaringan lokal pada syok
anafilaktik oleh stafilokok. Melalui MHC-I dan TCR sel T, superantigen mengarahkan sel Th untuk
memberikan sinyal ke sel B, makrofag, sel dendritik dan sel sasaran lain dari molekul MHC-II. Hal
tersebut akan mengaktifkan sel sasaran.
III. ANTIBODI

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COMPLEMENT SYSTEM
System complement merupakan system pertahanan yang terdiri dari plasma protein yang
menyerang dan menghancurkan mikroba. System ini dapat teraktivasi dengan 2 pathway ( classical
dan alternative ), keduanya merupakasn suatu aliran / cascade dari reaksi imun. Keduanya
menyebabkan kejadian yang sama : inflamasi, memperkuat fagositosis, dan membunuh mikroba.
System komplemen terdiri atas lebih dari 30 jenis protein berbeda dalam plasma darah dan
dalam membrane plasma. Meliputi protein yang disebut C1 sampai C9 ( C singkatan untuk
complement ) dan protein yang dinamakan factor B, D, dan P ( properdin ).
Classical pathway, berawal ketika terjadi ikatan antara antigen dan antibody. Antigen disini
bisa jadi merupakan bakteri atau sel asing lainnya. Kompleks antara antigen-antibody ini
mengaktivasi complement protein C1 dengan cara C1 berikatan pada region di antibody. Kemudian
terjadilah cascade reaksi enzimatik, di mana protein komplemen yang inaktif akan dipecah menjadi
fragmen aktif seperti C2a, C2b, dan begitu juga dengan C4.
Alternative pathway tidak melibatkan antibody. Ia berawal dari interaksi langsung dengan
polisakarida pada permukaan mikroba dan factor B, D, dan P. Interaksi ini mengaktivasi complement
protein C3 dan terjadilah cascade.
Proses terjadinya classical dan alternative pathway meliputi :
1. Aktivasi inflamasi
Beberapa protein komplemen ( C3a, C4a, dan C5a ) berkontribusi dalam pembentukan
inflamasi seperti berpengaruh pada dilatasi arteriol sehingga meningkatkan aliran darah ke
area yang terinfeksi, selain itu juga menyebabkan release histamine dari mast cell, basophil,
dan platelet. Karena histamine meningkatkan permeabilitas kapiler darah, maka sel darah
putih dapat bergerak lebih mudah ke jaringan untuk melawan infeksi atau alergi. Protein
komplemen lain berperan sebagai agen chemotactic yang menarik phagocyte ke area invasi.
2. Opsonisasi
Fragmen komplemen C3b berikatan dengan permukaan mikroba lalu berinteraksi dengan
reseptornya di fagosit yang berperan dalam fagositosis. Membuat mikroba agar lebih
mudah untuk di-fagositosis disebut dengan opsonisasi.
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3. Cytolysis
Beberapa protein komplemen ( C5b, C6, C7, C8, dan C9 ) bersama-sama membentuk
membrane attack complement (MAC) yang disisipkan ke membrane plasma mikroba
sehingga membuat lubang besar. Lubang ini mengakibatkan fluid yang ada di luar sel
mengalir ke interior sel mikroba, sehingga menyebabkan mikroba membengkak (swelling)
dan pecah (cytolysis).

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1. MEDIATOR YANG DI LEPAS KOMPLEMEN

II. AKTIVASI KOMPLEMEN


Sistem komplemen dapat diaktifkan melalui 3 jalur: lektin; klasik; dan alternatif. Jalur klasik
diaktifkan oleh kompleks imun sedang jalur alternatif dan jalur lektin tidak.

A. Aktivasi Komplemen melalui Jalur Lektin


MBL (Mannan Binding Lectin) adalah kolektin yang dapat diikat melalui bagian lektin hidrat
arang kuman. Setelah MBL diikat kuman melalui lektin tsb, MBL segera mengaktifkan C3.

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B. Aktivasi Komplemen melalui Jalur Klasik
Meskipun reaksi melalui jalur klasik terjadi sesudah reaksi jalur lainnya. Aktivasi jalur klasik
dimulai dengan C1 yang di cetuskan oleh kompleks imun antibodi dan antigen.
IgM yang memilki sebanyak lima Fc mudah diikat oleh C1. meskipun C1 tidak mempunyai
sifat enzim, namun setelah berikatan dengan Fc, dapat mengaktifkan C2 dan C4 yang selanjutnya
mengaktifkan C3.
IgM dan IgG1, IgG2, IgG3 (IgM lebih kuat dibanding dengan IgG) yang membentuk
kompleks imun dengan antigen, dapat mengaktifkan komplemen melalui jalur klasik. Jalur klasik
melibatkan 9 komplemen protein utama yaitu C1-C9. selama aktivasi, protein-protein tersebut di
katifkan secara berurutan. Produk yang dihasilkan menjadi katalisator dalam reaksi berikutnya. Lipid
A dari endotoksin, protease, kristal urat, polinukleotide, membran virus tertentu dan CRP dapat
mengaktifkan komplemen melalui jalur klasik.
C. Aktivasi Komplemen melalui jalur alternatif
Dimulai dari C3 yang merupakan molekul yang tidak stabil dan terus menerus ada dalam
aktivasi spontan derajat rendah dan klinis yang tidak berarti. Aktivasi spontan C3 diduga terjadi pada
permukaan sel, meskipun sel normal mengekspresikan inhibitor permukaan yang mencegah aktivasi
C3.
Permukaan patogen tidak memiliki inhibitor komplemen. Setiap sel yang tidak dilindungi
oleh inhibitor komplemen akan diserang oleh komplemen. Aktivasi komplemen yang berlebihan tidak
diinginkan oleh karena menimbulkan inflamasi dan kematian sel yang luas. Untuk mencegah hal itu
diperlukan inhibitor komplemen.
Jalur alternatif terjadi tanpa melalui tiga reaksi pertama yang terdapat pada jalur klasik (C1,
C4 dan C2). Bakteri (endotoksin), jamur, virus, parasit, kontras (pada pemeriksaan radiologi), agregat
IgA (IgA1, IgA2), IgG4, dan faktor nefritik dapat mengaktifkan komplemen melalui jalur alternatif.
Protein tertentu dan lipopolisakaride dapat mengktifkan komplemen melalui jalur klasik dan
alternatif.
Aktivasi sistem komplemen dapat mengawali 3 jalur yang berbeda. Semua jalur berakhir
dalam produksi C3b (fase awal). C3b menimbulkan fase lambat aktivasi komplemen yaiitu produksi
peptida yang merangsang inflamasi (C5a) dan polimerasi C9 merupakan MAC karena menimbulkan
lubang-lubang di membran plasma.

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IV. FUNGSI KOMPLEMEN


A. Inflamasi
Dalam proses inflamasi ada 3 hal yang terjadi:
1. Peningkatan pasokan darah ke tempat benda asing dan mikroorganisme atau jaringan yang
rusak
2. Peningkatan permeabilitas kapiler yang ditimbulkan oleh pengerutan sel endotel yang
memungkinkan molekul yang sangat besar seperti antibodi dan fagosit bergerak keluar
pembuluh darah menuju ke tempat benda asing (diapedesis), mikroorganisme atau jaringan
yang rusak.
3. Selanjutnya leukosit, terutama fagosit polimorfonuklear dan monosit dikerahkan dari sirkulasi
dan bergerak menuju tempat benda asing, mikroorganisme atau jaringan yang rusak.
B. Kemokin

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o Kemokin adalah molekul yang dapat menarik dan mengerahkan sel-sel fagosit.
o C3a, C5a dan C5-6-7 merupakan kemokin.
o C5a adalah kemoatraktan untuk neutrofil yang juga merupakn anafilatoksin.
C. Fagositosis - Opsonin
o C3b dan C4b mempunyai sifat opsonin.
o Opsonin adalah molekul yang dapt diikat disatu pihak oleh partikel (kuman) dan di lain pihak
oleh reseptornya sehingga memudahkan fagositosis bakteri atau sel lain.
D. Adherens Imun
o Adherens imun merupakan fenomena dari partikel antigen yang melekat pada berbagai
permukaan (mis: Vessel), kemudian dilapisi antibodi dan mengaktifkan komplemen mudah
di fagositosis.
o C3b berfungsi dalam adherens imun.
E. Eliminasi kompleks Imun
o C3a atau iC3b dapat diendapkan di permukaan kompleks imun dan merangsang eliminasi
kompleks imun.
F. Lisis osmotik bakteri
o Aktivasi komplemen yang terjadi di permukaan sel bakteri akan membnetuk MAC dan
akhirnya menimbulkan lisis osmotik sel atau bakteri.
G. Aktivitas sitolitik
o Eosinofil dan sel PMN mempunyai reseptor untuk C3b dan IgG sehingga C3b dapat
meningkatkan sitotoksisitas sel effektor ADCC yang kerjanya bergantung pada IgG.
H. Imunitas nonspesifik dan spesifik
Makrofag atau neutrofil dapat diaktifkan C5a secara langsung atau oleh toksin bakteri seperti
LPS melalui reseptor TCR atu melalui fagositosis dengan bantuan C3b sebagai opsonin.
Makrofag yang diaktifkan melepas berbagai mediator larut seperti IL-1, TNF yang
meningkatkan respon inflamasi, expresi molekul adhesi untuk neutrofil di permukaan sel endotel,
meningkatkan permeabilitas, kemotaksis dan aktivitas sel PMN sendiri.
Juga sitotoksisitas sel NK yang memiliki untuk komplemen dapat ditingkatkan. Komplemen
juga berperan dalam imunitas spesifik karena aktivasi makrofag menimbulkan peningkatan jumlah sel
APC yang mempresentasikan antigen ke sel T.

MAJOR HISTOCOMPATIBILITY COMPLEX


Major Histocompatibility Complex (MHC) merupakan genomic region yang besar atau
gene family yang ditemukan di seluruh vertebrata dan mempunyai peranan yang penting dalam
system imun, autoimunitas dan proses reproduksi, pada manusia disebut sebagai HLA ( Human
leucocyte antigen ) karena molekul tersebut ditemukan di leukosit. Yang termasuk : HLA-A, HLA-B,
HLA-C, HLA-DPA1, HLA-DPB1, HLA-DQA1, HLA-DQB1, HLA-DRA, dan HLA-DRB1.
Terdiri dari 3 kelas :
Nama
Fungsi
Expression
Semua sel bernukleat. Protein MHC kelas I
Mengkode heterodimeric peptide-binding berisi sebuah rantai & 2-micro-globulin
MHC
proteins, disebut juga antigen-processing chain. Mereka mempresentasikan bagian
class I
molecules seperti TAP dan Tapasin.
antigen ke cytotoxic T-cells cells dan akan
berikatan dengan CD8 pada cytotoxic T-cells.
Mengkode heterodimeric peptide-binding
Pada antigen-presenting cells protein MHC
proteins dan proteins yang memodulasi
kelas II berisi rantai & dan mereka
MHC
pengangkatan peptide ke protein MHC
mempresentasikan bagian antigen ke Tclass II kelas II di dalam kompartemen lysosomal
helper cells dengan berikatan pada reseptor
seperti MHC II DM, MHC II DQ, MHC
CD4 pada T-helper cells.
II DR, dan MHC II DP.
MHC
Mengkode component untuk imun
class III lainnya, seperti complement components

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region

(e.g., C2, C4, factor B) dan beberapa


mengkode juga cytokines (e.g., TNF-)
dan juga hsp.

THE IMMUNE RESPONSE


Setiap respon imun merupakan sesuatu yang kompleks dan rumit karena melibatkan beberapa
tipe sel. Respon ini terangsang apabila terdapat antigen yang masuk ke dalam tubuh manusia dan
mengakibatkan keluarnya sel khusus yang bernama Antigen Presenting Cells ( APC ) . Kemudian
APC akan mengambil sedikit bagian dari antigen yang masuk kemudian menampakannya dalam
bentuk yang dapat dikenali oleh antigen-specific helper T lymphocytes. T helper cells menjadi aktif
dan nantinya akan mengaktifkan limfosit lain seperti B Cells atau Cytotoxic T Cells. Yang nantinya
setiap limfosit yang aktif akan berproliferasi dan mengeluarkan fungsi asalnya yaitu meng-inaktivasi
atau menghancurkan antigen. Pada setiap tahap di proses ini, limfosit dan APC akan berhubungan
antara satu sama lain dan juga dengan sel lain melalui kopntak langsung ataupun melalui sekresi
cytokines.pada saat berhubungan dengan sel lain secara simultan atau dengan komplemen seperti
kinin atau fibrinolytic systems, yang mengakibatkan pengaktifan sistem fagosit, pembekuan darah dan
permulaan dari proses penyembuhan luka. Dan pada akhirnya proses ini akan berakhir setelah antigen
telah di-eliminasi.
Figure 4-2 menggambarkan proses respon imun secara skematis dengan penjelasan seperti
dibawah ini :

Immunogens & Antigens


Immunologists biasanya menggunakan kata antigen yang bermakna suatu agen yang
merangsang respon imun. Dengan kata lain molekul mempunyai kemampuan untuk dapat
dikenali oleh immunoglobulin or T-cell receptor yang nantinya akan menjadi target respon.
Terdapat juga immunogen yang bermakna molekul atau sekumpulan molekul yang dapat
mengakibatkan respon imunpada inangnya. jenis-jenis immunogen termasuk eathogenic
microorganisme (eg. viruses.bacteria, or parasites), foreign tissue grafts, atau substansi yang
terdapat di lingkungan sekitar seperti serbuk sari, rerumputan atau bisa juga makanan.
Protein secara umum merupakan immunogen yang potensial. Molekul jenis lain seperti
lipids, carbohydrates, or nucleic acids umumnya menjadi target dari respon imun setelah
mereka berikatan dengan immunogenic protein ( seperti pada lipoproteins. glycoproteins, or
nucleoprotein complexes).
ANTIGEN PROCESSING & PRESENTATION
Respon pada proteinaceous immunogens dapat dimulai hanya apabila immunogen telah
ditangkap, diproses, dan dipresentasikan oleh APC. Alasan kenapa harus melalui proses diatas
karena T Cells hanya mengenali immunogen yang telah berikatan dengan protein Major
Histocompatibility Complex (MHC) yang terdapat di permukaan sel. Dimana terdapat 2 kelas
berbeda dari MHC. Diantaranya Class 1 MHC protein yang terdapat di seluruh bagian sel
somatis tubuh dan digunakan untuk mem-presentasikan sustansi ke Cells T CD8, yang
kebanyakan merupakan Cytotoxic. Class 2 MHC protein hanya terdapat di macrophages dan
sedikit tipe sal lainnya yang digunakan untuk mempresentasikan kepada Cells T CD4, yang
kebanyakan Helper Cells. Disebut juga APC Profesional yang meliputi dendritic cells,
Macrophages, dan limfosit B.
APC yang dipresentasikan pada 4-2 adalah dendritic and yang memulai proses dalam
respon imun. Dendritik sel terdapat pada semua jaringan, termasuk permukaan epitel dan oran
limfoid yang kaya akan T sel, yang dapat mengijinkan mereka untuk mengawasi kulit,
gastrointestinal dan jalur respirasi, darah dan limfe untuk mendeteksi adanya benda asing.
Sitoplasma dari dendritik sel meluas keluar yang disebut strukturnya yaitu veils dan apabila
memanjang disebut dendrites yang menyediakan area permukaan yang luas untuk berinteraksi
dengan immunogen. Mereka juga memperlihatkan adanya beberapa reseptor permukaan seperti
reseptor untuk mannose atau untuk bacterial lipopolysaccharide (LPS). Yang juga dapat
mengenali dan mengikat pathogen. Dendritik sel dapat menangkap bagian dari immunogen
melalui fagositosis dan juga dapat menangkap immunogen yang lebih kecil melalui
pinositosis atau endositosis yang dimediasi oleh reseptor ( Figure 2-6 ). Ketiga pathway diatas
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digunkana juga oleh makrofag. B limfosit merupakan fagosit yang buruk, tetapi dapat melakukan
endositosis secara efisien antigen yang mengkiat pada immunoglobulin permukaan mereka atau
reseptor lainnya. Sebagai suatu kelompok, APC dapat menangkap immunogen dari berbagai jenis
untuk memastikan tidak ada immmunogen potensial yang lolos.
Immunogen yang telah ditangkap oleh APC akan diselubungi oleh membrane-lined vesicles
pada sitiplasmanyadan kemudian akan melakukan suatu proses yang dinamakan antigen
processing untuk proteinaceous immunogen, akan dilanjutkan dengan denaturasi dan partial
proteolytic digestion lalu immunogen akan membelah menjadi short peptide. Sejumlah kecil
dari peptide tersebut akan berhubungan secara non kovalen dengan Class III MHC protein
dan akan dikirimkan ke permukaan dari APC yang kemudian dapat dideteksi oleh helper T
Cells, proses ini dinamakan antigen presentation. CD4 helper T limfosit akan datang yang
secara langsung akan berinteraksi dengan APC yang kemudian akan aktif.

Pengaktifan Helper T Limfosit


Helper T (T H) sel berperan sebagai principal orchestrators pada respon imun karena
mereka membutuhkan pengaktifan dari kedua jenis sel limfoid efektor: cytotoxic T (T c) cells
dan antibody-secreting plasma cell. Pengaktifan sel TH terjadi lebih awal pada respon imun dan
membutuhkan sekurangnya 2 sinyal. 1 sinyal disediakan dari pengikatan dari kompleks pada
permukaan APC dan ditransmisikan melewati CD3 protein complex. Sinyal kedua, yaitu disebut
sinyal sostimulatory juga membutuhkan hubungan yang dekat antara APC dan permukaan sel TH
dan ini biasanya dikirimkan oleh protein sel TH yang disebut dengan CD28 ketika ini berikatan
dengan satu bagian lainnya pada protein B7 di permukaan APC
Bersama-sama, kedua sinyal diatas mempengaruhi helper T cell untuk mensekresikan
cytokine yang disebut interleukin2 (IL-2) dan juga mulai untuk memperlihatkan afinitas tinggi yang
spesifik pada reseptor interleukin2 (IL-2) di permukaanya. interleukin2 (IL-2) adalah faktor
mitogenik yang sangat potensial untuk lifosit T dan sangat penting sebagai respon proliferasi dari T
sel yang teraktifasi.
Protein IL-2 mempunyai masa hidup sangat pendek di luar sel dan beraksi hanya dengan jarak
yangat cepat. Pada kenyataanya, IL-2 mempunyai efek yang sangat besar pada sel dimana dia
disekresikan, fenomena yang dikenal sebagai efek autocrine. Walaupun Sel T medapatkan kedua
sinyal aktivasi dari kontak dengan APC, ini tidak akan mulai untuk berproliferasi apabila tidak ada
aktifitas dari IP-2 atau permukaanya terdapat bloker reseptor IL-2. IL-2 disekresikan oleh sel TH yang
teraktifasi dan juga dapat beraksi dengan cepat, yang disebut dengan efek paracrine, ini merupakan
hal yang penting untuk mengaktifasi sel TH, yang umumnya tidak memproduksi cukup IL-2 untuk
merangsang proliferasi mereka. Kemudian dengan tambahan IL-2, sel TH yang teraktifasi akan
mensekresikan cytokine laiinya yang akan meningkatkan pertumbuhan, proliferasi, dan fungsi dari sel
B, makrofag, dan tipe sel lainnya

Activation of B Cells & Cytotoxic T Cells


Ketika sel T mulai aktif lebih awal, beberapa sel B ju a telah bersatu dengan immunogen
melalui reseptor entigen mereka. Yang mereka sekresikan dari membrannya. Tidak seperti T cell, Sel
b mengenali immunogen denghan bebas dan tidak melalui proses tertentu . ikatan antigen spesifik
memberikan satu dari 2 sinyal yang dibutuhkajn untuk aktivasi sel B. sinyal yang kedua berasal dari
aktivasi sel TH, yang akan menyediakan protein yang akan membantu aktivasi Sel B yung disebut Tcell help. Kombinasi dari antigen binding dan heper faktor bagaimanapun juga akan menciptakan
sinya mitogenik yang sangat kuat. Beberapa salinan dari setiap yang terakticasi akan berdiferesiasi
menuju sel plasma yang akan mensekresikan antibodi spesifik untuk setiap immunogen
Fungsi limfosit T untuk mengeluarkan sel yang terlihat sebagai antigen benda asing pada
permukaan merek, seperti virus dan lainnya. Kebanyakan T sel mengeluarkan CD8 daripada CD4 dan
akan mengenali antigen yang berikatan dengan Class 1 daripada Class 2 MHC protein. Ketika sel
somatis terinfeksi oleh virus, beberapa immunogenis viral protein akan melakukan proses di dalam
sel, dan mengakibatkan peptide akan terlihat di permukaan kompleks dengan molekul class 1 MHC.
Kompleks ini akan dikenali oleh reseptor T-sel yang akan menciptakan salah satu sinyal dari aktivasi

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ENDOCRINE N METABOLISM
Relationships Between the Pituitary Gland and Hypothalamus
Hypothalamus is a master of pituitary, dimana hypothalamus mensekresi hormone-hormon
yang mempengaruhi sekresi hormone dari pituitary.
Hypothalamus mensekresi 9 hormon dan pituitary mensekresi 7 hormon : hormone-hormon
tersebut bersama-sama memegang peranan penting dalam regulasi segala aspek pertumbuhan,
perkembangan, dan homeostasis
HYPOPHYSEAL GLAND
Di hypophyseal fossa dari sella turcica di sphenoid bone & terikat pada hypothalamus oleh
infundibulum.
Structures, hormones, and Functions of the Anterior and Posterior Pituitary
Anterior Pituitary (adenohypophysis)
- Mensekresi hormone yg mengatur aktifitas tubuh dari pertumbuhan hingga
reproduksi
- Pengeluaran hormone : yg distimulus oleh releasing hormone dan dihambat o/
inhibiting hormones yg dihasilkan hypothalamus.
Hypophysyseal Portal System : aliran darah dari kapiler-kapiler hypothalamus ke vena porta
untuk mengangkut darah ke kapiler anterior pituitary
superior hypopyseal artery (sbg cabang dari internal carotid artery)
membawa darah ke hypothalamus.

primary plexus of the hypophyseal portal system


(Di pemisahaan antara hypothalamus & infundibulum)

Hypophyseal portal veins (Turun keluar infundibulum)

Secondary plexus of the hypophyseal portal system (di anterior pituitary)


Types of Anterior Cells
Somototrophs : human growth hormone/somatotropin (u/menstimulus insulin like growth
factor untuk stimulate general body growth & aspect of metabolism)
Thyrotrophs : thyroid stimulating hormone /thyropin
Fungsi u/ control sekresi & akivitas lain dari kelenjar tyroid
Gonodotrophs : Follicle stimulating hormone (FSH) & Luteinizing hormone (LH)
Fungsi:
- untuk stimulate sekresi estrogen & progesterone
- pematangan oosit
- Stimulate sekresi testosterone & produksi sperma
Lactotrophs : prolactin produksi ASI
Corticotrophs : Adenocorticotropic hormone (ACTH) / corticotropin
Fungsi : stimulate adrenal cortex untuk sekresi glucocorticoids
* beberapa corticotrophs jg mensekrese melanocyte stimalting hormone.
Posterior Pituitary (Neurohypophysis)

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* Tidak mensitesis tapi menyimpan & mengeluarkan 2 hormones


* terdiri dari pituicytes & axon terminal dari hypothalamic neurosecretory cells
Paraventricular : oxytocin
Fungsi :
- menstimulus kontraksi otot uterus selama melahirkan
- menstimulus kontraksi myoepithel di mamary gland untuk ejeksi susu
Supraoptic : ADH (vasopressin)
Fungsi :
- mengurangi volume urine
- mengurangi hilangnya air saat perspirasi
- meningkatkan tekan darah dengan konstriksi arterioles
Vaskularisasi posterior pituitary
Internal carotid arteries

Inferior hypophyseal arteries

Capillary plexus of the infundibular


(menerima secreted oxytocin & ADH process)

Posterior hypophyseal veins


THYROID GLAND
- Terletak di inferior dari larynx
- Bentuk menyerupai kupu-kupu
- Terdiri dari right & left lateral lobe dihubungkan oleh isthmus (anterior trachea)
- Mengandung tyroid follicles (seperti bola)
- Thyroid follicles dikelilingi basement membrane
- Thyroid follicles mengandung follicular cells memanjang kedalam lumen (dalam
dindingnya)
Jika follicular sel tidak ektif : cuboidal squamous
Jika follicular sel aktif (dipengaruhi TSH) : cuboidal columnar silindris.
- Follicular sel memproduksi 2 macam hormone :
Thyroxine / tetraiodothyronine/T4 : mengandung 4 atom iodine
Triiodothyronine/T3 : mengandung 3 atom iodine
- Diantara follicle ada parafollicular cells/ C cells : mensekrete calcitonin (u/ regulasi Ca
homeostasis)
Synthesis & Secresi T3 & T4
1. Penangkapan lodide
Follicular sel menangkap iodide dr darah ke sitosol (transport aktif)
2. Sintesis thyroglobulin (TGB glikoprotein)
Thyroglobulin dibuat di RE.& dimodifikasi di komplek golgi
3. Oksidasi iodide
2I- I2 agar I bisa bereaksi dg tyrosin yang ada di TGB
4. Iodination of tyrosine I2 + tyrosin 1st : monoiodotyrosine (T1)
2nd : diiodotyrosine (T2)
TGB + I2 : disimpan di lumen tyroid follicle
5. Coupling T1 & T2
T2 + T2 = T4 atau T1 + T2 = T3
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6. Pinocytosis & digestion of colloid


Droplet colloid masuk ke follicular sel (pinositosis) & bergabung dg lysosom
kemudian lisosom mencerna TGB sisa T3 & T4.
7. Sekresi thyroid hormone
karena T3 + T4 tipid soluble maka berdifusi dg membrane plasma ke cairan interstitial
lalu ke darah.
Cat : biasanya T4 lebih banyak disekresi namun T3 lebih potensial sehingga setelah T4
keluar biasanya dikonversi menjadi T3 dg membuang 1 atom I2.
8. Transport in the blood
T3 & T4 + transport protein = Thyroxine Binding Globuline (TBG)
Fungsi Thyroid Hormon :
1) Meningkatkan basal metabolic rate : BMR , metabolisme CA, lipid, protein
2) Menstimulasi sintesis penambahan sodium-potassium pumps (Na +/K-/aTPase)
3) Meningkatkan suhu tubuh (calorigenik effect)
4) Menstimulasi sintesis protein
5) Meningkatkan penggunaan glukosa dan asam lemak untuk memproduksi ATP
6) Menstimulasi lipolisis
7) Meningkatkan kerja catecholamines (norepinephrine & epinephrine) regulasi
reseptor
8) Mengatur perkembangan dan pertumbuhan jaringan saraf dan tulang
Control dr Sekresi hormone thyroid
1. Kadar T3 & T4 dalam darah yang rendah menstimulus hypothalamus mensekresi
TRH (thyroid releasing hormone)
2. TRH masuk ke hypopyseal portal vein & msk ke anterior pituitary menstimulasi
thyrotroph mensekresi TSH (Thyroid Stimulating Hormones)
3. TSH menstimulasi aktifitas dari follicular sel
4. Follicular sel mensekresi T3 & T4
5. Kenaikan kadar T3 & T4 dalam darah menghambat TRH & TSH

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