CELLULAR

ADAPTATIONS
CELL INJURY &
CELL DEATH
ADAPTASI SEL , JEJAS SEL & KEMATIAN SEL.
 pd saat mengalami stres fisiologis/rangsang
patologis → sel melakukan adaptasi → utk mencapai kondisi
baru & mempertahankan kelangsungan hidup

 bila stimulus patologik diperbesar hingga melampaui adaptasi

sel thd stimulus → timbul jejas (cell injury) yg bersifat
sementara (reversibel)

 apabila stimulus menetap atau bertambah besar →sel

mengalami jejas yg menetap (irreversibel) → berakibat sel
mengalami nekrosis atau apoptosis
ADAPTASI SEL
 Adaptations

Change in size
Change in number of
cells
Change into another
type of cell
ATROFI:
penyusutan (peng-keriputan) ukuran sel dgn jalan hilangnya substansi sel.
Merupakan bentuk respons adaptasi & dpt bertumpuk tumpuk s/d
kematian sel.

 Atrofi bisa fisiologik atau patologik.

 Atrofi fisiologik :
1. Masa pertumbuhan embionik awal : Duktus tiroglosus; notochord.
2. Uterus : Mengecil stlh partus.
Atrofi patologik
 Tergantung penyebabnya, bisa lokal atau general (umum).

Penyebab atrofi pada umumnya adalah :

1. Beban kerja yg menurun ---- Disuse atrophy.
2. Hilangnya invervasi saraf ---- Denervation atrophy
3. Berkurangnya supply darah
4. Nutrisi yg tidak cukup (inadequat)
5. Hilangnya Stimulasi endokrin.
6. Penuaan ( senile atrophy).
7. Penekanan (tissue compression).
 Figure 1-5 A, Atrophy of the brain in an 82-year-old male with atherosclerotic disease. Atrophy of the brain is due to aging and reduced blood supply. The meninges have
been stripped. B, Normal brain of a 36-year-old male. Note that loss of brain substance narrows the gyri and widens the sulci.

8
Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 15 February 2005 03:27 AM)
© 2005 Elsevier
 Mekanisme terjadinya atrofi
9

 1. Peningkatan degradasi protein a.l. oleh hormon

(glucocorticoid & hormon tiroid)
 2. Juga oleh cytokines (TNF dapat meningkatkan
proteolisis otot)
Hypertrophy
 Increased size &
functional capacity
 Due to
 hormonal stimulation
 increased functional
demand
11

HYPERTROPHY refers to an increase in the size of cells,

resulting in an increase in the size of the organ.

Hipertrofi dapat fisiologi atau patologik.

 Otot jantung & otot skeletal mampu hipertrofi hebat .

Stimuli-nya : beban kerja yg meningkat.

 Pertumbuhan otot uterus selama kehamilan merupakan

contoh bagus pengaruh hormonal pada peningkatan
besarnya organ sbg hasil hipertrofi dan hiperplasia.
12
 Hipertrofi otot uterus (kiri) & BPH (kanan)
13
Hyperplasia
 Increase in
number of cells
 Due to
 hormonal
stimulation
 increased
functional demand
 chronic stress or
injury
15

 HYPERPLASIA : peningkatan jumlah sel didalam

organ/jaringan,
biasanya menghasilkan peningkatan volume dari organ/jaringan tsb.

 Dirangsang oleh stimuli external : mis. pertumbuhan

uterus karena pengaruh hormonal peningkatan
jumlah sel otot polos & sel epitel & juga pembesaran
sel tsb.
 PHYSIOLOGIC
HYPERPLASIA.
16

1. HORMONAL HYPERPLASIA
Proliferasi epitel kelenjar mammae perempuan saat pubertas &
kehamilan. Juga hiperplasia fisiologik pada uterus waktu hamil.

2. COMPENSATORY HYPERPLASIA
Proliferasi & regenerasi sel hepar setelah hepatektomi
partial.

MECHANISMS OF HYPERPLASIA.
1. Increased local production of growth factors.
2. Increased levels of growth factors on the responding cells
3. Activation of particular intracellular signaling pathways
 Pathologic Hyperplasia
17

terutama disebabkan oleh stimulasi hormonal atau growth

factor (faktor pertumbuhan) yg berlebihan
 Hiperplasia endometrium estrogen meningkat
 BPH androgen meningkat

 Pathologic hyperplasia, constitues a fertile soil in which

cancerous proliferation may eventually arise.

 Hiperplasia juga merupakan respons penting pada jaringan

ikat sewaktu penyembuhan luka; dimana terjadi proliferasi
fibroblast & pembuluh darah pada saat reparasi jaringan.
(Growth factors berperan disini).
 Kel. Endometrium normal (kiri) vs Kel.
Endometrium hiperplastik (kanan)
kusumowardoj
o - FK Unair,
Surabaya

18
Dysplasia
 Disorderly overgrowth
of cells
 Premalignant
Metaplasia
 One cell type to another
 Reversible
 Metaplasia,
21
merupakan perubahan reversibel suatu tipe sel dewasa diganti
oleh tipe sel dewasa lainnya. (epitelial maupun mesenkimal)
 Figure 1-6 Metaplasia. A, Schematic diagram of columnar to squamous metaplasia. B, Metaplastic transformation of esophageal stratified squamous epithelium (left) to
mature columnar epithelium (so-called Barrett metaplasia).

22
Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 15 February 2005 03:27 AM)
© 2005 Elsevier
 Metaplasia.
Figure 1-6

B, Metaplastic
transformation
of esophageal
stratified
squamous
epithelium (left)
to mature
columnar
epithelium (so-
called Barrett
metaplasia).

23
Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 15 February 2005 03:27 AM)
© 2005 Elsevier
JEJAS SEL
 All disease occurs
because of cell injury
 Either because of the
injury itself or the repair
process that follows
Causes of Cell Injury
 Hypoxia
 Hypoxia
 Inadequate oxygenation
 Most common cause of cell
injury
 Usually due to ischemia
 Causes chemical & acid-
base imbalances
 Reversible if O2 restored or
death if not
Causes of Cell Injury
 Hypoxia
 Direct physical action
 Direct Physical Action
Major problems are
hemorrhage &
ischemia
Causes of Cell Injury
 Hypoxia
 Direct physical action
 Ionizing radiation
Ionizing Radiation
 Ionizes H2O into H+ &
OH-
 OH- attaches to DNA
& prevents cell
reproduction
 DNA mutations
Causes of Cell Injury
 Hypoxia
 Direct physical action
 Ionizing radiation
 Toxic molecular injury
Toxic Molecular Injury

Dose related
Causes of Cell Injury
 Hypoxia
 Direct physical action
 Ionizing radiation
 Toxic molecular injury
 Microbes
Microbes
 Toxins can
interfere with
protein synthesis
or utilization of O2
Causes of Cell Injury
 Hypoxia
 Direct physical action
 Ionizing radiation
 Toxic molecular injury
 Microbes
 Inflammatory & immune reactions
 Inflammatory & Immune Reactions
 Due to cell injury &
then in turn causes
injury
Causes of Cell Injury
 Hypoxia
 Direct physical action
 Ionizing radiation
 Toxic molecular injury
 Microbes
 Inflammatory & immune reactions
 Nutritional imbalances
 Genetic defects
 Aging
Mekanisme jejas sel

1. Respon sel terhadap rangsangan yang mencederai

tergantung pada jenis cedera, durasinya serta
keparahannya
2. Konsekuensi cedera sel tergantung pada
jenis,keadaan dan kemampuan adaptasi sel yang
mengalami cedera
3. Cedera sel terjadi akibat kelainan fungsional dan
biokimiawi dari satu atau lebih komponen esensial
 Figure 1-10 Cellular and biochemical sites of damage in cell injury.

40
Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 15 February 2005 03:48 AM)
© 2005 Elsevier
 a.Depletion of ATP
= Kekurangan ATP
41

 Kekurangan ATP atau sintesa ATP yg menurun

sering berhubungan dgn jejas hypoxic & jejas toxic
 Figure 1-11 Functional and morphologic consequences of decreased intracellular ATP during cell injury.

42
Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 15 February 2005 03:48 AM)
© 2005 Elsevier
 b.Mitochondria
dysfunction in
cell injury.

43 kusumowardojo - FK Unair, Surabaya

Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 15 February 2005 03:48 AM)
© 2005 Elsevier
 c.Free Radicals = radikal bebas
44

Radikal bebas = bahan kimia yg mempunya satu elektron

tanpa pasangan di orbit luarnya,  sangat reaktif & bereaksi
dgn molekul sekitarnya: protein, lipids, & karbohidrat

 Radikal bebas  ditimbulkan oleh berbagai cara:

 Energi radiasi: sinar ultraviolet, x-ray
 Bhn kimia exogenous atau obat2 ( CCl4)
 Reaksi oksidasi-reduksi (pada proses metabolisme normal)
 Bhn metal : besi, tembaga
 Nitric oxide (NO)
 d. Defek pada permeabilitas membran

Figure 1-15 Mechanisms of membrane damage in cell injury. Decreased O2 and

increased cytosolic Ca2+ are seen in ischemia but may accompany other forms of cell injury.
45 Reactive oxygen species, which typically are often produced on reperfusion of ischemic tissues,
also cause membrane damage (not shown).
Downloaded © 2005
from: Robbins & Cotran Pathologic Basis of Disease (on 15Elsevier
February 2005 03:48 AM)
 Morphology of reversible injury
46

1.Pembengkakan sel :  degenerasi hidropik atau

degenerasi vakuolar

 Mikroskopik sinar : vakuole kecil2 yg

jernih (pucat) tampak dlm sitoplasma.
 Degenerasi hidropik

47
48

2.Perlemakan (fatty change)

 Fatty change terjadi pd jejas hipoksia, berbagai

jejas toksik atau metabolik.

 Mikroskopik sinar: vakuole lemak besar & kecil

di dlm sitoplasma sel.
 Fatty liver

49
Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 15 February 2005 04:51 AM)
© 2005 Elsevier
Intracellular Accumulations
 Some due to
phagocytosis or other
normal physiologic
mechanisms
 Intracellular Accumulations
51

 Salah satu manifestasi kelainan metabolik sel adalah

akumulasi (penimbunan) berbagai zat abnormal.
 Akumulasi berlebihan dari bahan sel normal,a.l. air,
lipids, protein & karbohidrat
 Akumulasi berlebihan bhn abnormal, exogen (bhn
mineral, produk agen infeksiosa,) atau endogen (hasil
sintesis atau metabolisme abnormal)
 Pigmen.
Fat
 Fatty Change ( Steatosis )
= Perlemakan
 Adalah akumulasi abnormal dari triglycerides di
dalam parenkim sel.
 Fatty change sering didapatkan di hepar, tetapi
dapat juga terjadi di jantung, otot & ginjal.
 Penyebab :
Toxin, malnutrisi protein, diabetes melitus,
obesitas, anoxia & alcohol abuse
Cholesterol
 Most extensive &
damaging accumulation
 Atherosclerosis
Protein
Glycogen
Pigments

Hemosiderin granules in liver cells. A, H&E

section showing golden-brown, finely granular
pigment. B, Prussian blue reaction, specific for
iron.
NEKROSIS & APOPTOSIS
 NEKROSIS & APOPTOSIS
61

Nekrosis selalu proses patologik

Apoptosis dapat merupakan fungsi normal &

tidak harus berhubungan dgn jejas sel.
64 kusumowardojo - FK Unair, Surabaya
Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 15 February 2005 03:47 AM)
Figure 1-8 © 2005 Elsevier
 Necrosis
65

perubahan2 morfologik yg mengikuti kematian sel di dalam

jaringan hidup, terutama dihasilkan oleh aksi degradasi progresif
oleh enzim2 pada jejas lethal.

 Mikroskopik sinar : sel tampak lebih kemerah2an

(eosinophilia)
 Inti :
Kariolisis
Piknosis
Kario-reksis
 Sel normal (kiri) & Piknosis (kanan)
kusumowardoj
o - FK Unair,
Surabaya

66
 Kario-reksis (kiri) & Kariolisis (kanan)
kusumowardoj
o - FK Unair,
Surabaya

67
 Beberapa bentuk Nekrosis
68

 Nekrosis koagulativa  denaturasi (Dead cells form a gel-

like consistency, Infarction most common cause)
 Nekrosis liquifaktif  enzimatik (Dead tissue dissolves
into liquid)
 Gangrenous necrosis

 Nekrosis kaseosa  koagulatif khusus (fokus

granulomatosa)

 Nekrosis lain: Fat necrosis (May due to trauma Lipase

pankreas  Triglycerides digested & free fatty acids precipitate as calcium
salts
 Myocardium
Figure 1-18 Ischemic necrosis of the myocardium. A, Normal myocardium. B,
with coagulation necrosis (upper two thirds of figure), showing strongly
eosinophilic anucleate myocardial fibers. Leukocytes in the interstitium are an early
kusumowardojo
69reaction to necrotic muscle. Compare with A-and
FK Unair, Surabaya
with normal fibers in the lower part of the figure.
Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 15 February 2005 03:56 AM)
© 2005 Elsevier
 Figure 1-19 Coagulative and liquefactive necrosis. A, Kidney infarct
exhibiting coagulative necrosis, with loss of nuclei and clumping of cytoplasm but with
preservation of basic outlines of glomerular and tubular architecture. B, A focus of liquefactive
70 necrosis in the kidney caused by fungal infection.
kusumowardojo - FK Unair,The focus is filled with white cells and
Surabaya
cellular debris, creating a renal abscess that obliterates the normal architecture.
 Gangrenous necrosis
71
Caseous Necrosis
 TB
 “cheesy”
 Cellular detail gone
APOPTOSIS
 KEMATIAN SEL YG TERPROGRAM
SECARA INTRASELULER SECARA
KETAT

* Enzim diaktifkan untuk menghancurkan DNA

inti selnya sendiri & protein inti maupun
sitoplasmanya.
Membran plasma sel tetap intak, tetapi struktur
selnya rusak, shg sel apoptotik menjadi target
fagositosis secara cepat =
sebelum terjadinya inflamasi
 Figure 1-9 The sequential ultrastructural
changes seen in necrosis (left) and apoptosis
(right). In apoptosis, the initial changes
consist of nuclear chromatin condensation
and fragmentation, followed by cytoplasmic
budding and phagocytosis of the extruded
apoptotic bodies

74
Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 15 February 2005 03:47 AM)
© 2005 Elsevier
 Figure 1-26 A, Apoptosis of epidermal cells in an immune-mediated reaction. The apoptotic cells are visible in the epidermis
with intensely eosinophilic cytoplasm and small, dense nuclei. H&E stain. (Courtesy of Dr. Scott Granter, Brigham and
Women's Hospital, Boston, MA.) B, High power of apoptotic cell in liver in immune-mediated hepatic cell injury. (Courtesy of
Dr. Dhanpat Jain, Yale University, New Haven, CT.)
75
Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 15 February 2005 04:15 AM)
© 2005 Elsevier
 Figure 1-25 Ultrastructural features of apoptosis. Some nuclear fragments show peripheral crescents of compacted
chromatin, whereas others are uniformly dense. (From Kerr JFR, Harmon BV: Definition and incidence of apoptosis: a
historical perspective. In Tomei LD, Cope FO (eds): Apoptosis: The Molecular Basis of Cell Death. Cold Spring Harbor, NY, Cold
Spring Harbor Laboratory Press, 1991, pp 5-29.)

76
Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 15 February 2005 04:15 AM)
© 2005 Elsevier
 Apoptosis dlm situasi fisiologik
77

 Destruksi sel terprogram selama embriogenesis:

implantasi, organogenesis, involusi perkembangan,
& metamorfosis.
 Involusi tergantung-hormonal (Hormonal-
dependent involution) pada dewasa.
 Apoptosis dlm situasi fisiologik
78

 Pengurangan/penghapusan sel pada populasi sel yg

proliferatif (epitel kripte usus).
 Kematian sel tubuh yg sdh bekerja untuk hal yg
berguna, i.e. neutrofil dlm respons inflamasi &
limfosit dlm respons imun.
 Eliminasi thd limfosit yg potensial bisa bereaksi
merugikan diri-sendiri.
 Kematian sel oleh sel limfosit-T (sel yg terinfeksi
virus & tumor).
 APOPTOSIS pada kondisi Patologik
79

 Kematian sel oleh berbagai stimuli jejas (injurious

stimuli)
 Jejas sel pada peny. Virus tertentu.
 Atrofi patologik di dalam parenkhim organ setelah
obstruksi saluran. (pankreas, parotis, ginjal)
 Kematian sel pada tumor.
 Morfologi Apoptosis  Pengkerutan sel (Cell
shrinkage)
80  Kondensasi khromatin
 Pembentukan “blebs”
sitoplasmik &
“apoptotic bodies”
 Fagositosis oleh
makrofag terhadap sel
yg mengalami
apoptosis atau”cell
bodies”
Mekanisme apoptosis
1.fase inisiasi  2. fase eksekusi
Kaspase menjadi aktif  Enzim bekerja
secara katalitik menimbulkan kematian
sel
 Memecah matriks
nukleus dan sitoskeleton
 Pembersihan sel yang
mati : faktor rekrutment
fagosit
 Mechanisms of Apoptosis

82

kusumowardojo - FK Unair, Surabaya

The extrinsic (death receptor-
initiated) pathway of apoptosis
 terimakasih
85