ENDOTEL dan INFLAMASI (

ERYATI DARWIN
FAKULTAS KEDOKTERAN
UNIVERSITAS ANDALAS
 ENDOTEL
FUNGSI :
BARIER FISIK
SEKRESI MEDIATOR
MENJAGA HOMEOSTASIS: RESPON FISIOLOGIS PADA CEDERA VASKULER
PROSES PENYEMBUHAN LUKA
REGULASI ALIRAN DARAH DAN TONUS PEMBULUH DARAH
INFLAMASI
(1) Peran endotel:

kontrol hemostasis
koagulasi darah dan fibrinolisis
Interaksi trombosit dan leukosit dengan dinding pembuluh
regulasi tonus pembuluh darah, dan tekanan darah.
Produksi senyawa vasoaktif endogen kontrol fungsi sel-sel
otot polos pembuluh darah dan sirkulasi sel darah
keseimbangan tonus vaskuler
Gangguan disfungsi endotel
(2) Disfungsi endotel :
konsentrasi faktor vasodilatasi dan faktor vasokonstriksi tidak
seimbang (NO , AT II).
angiotensin-converting enzyme (ACE) aktivitas AT II NO
akut : kontraksi otot polos diameter lumen vasokonstriksi
kronis : - pertumbuhan, proliferasi dan diferensiasi sel-sel
otot polos - penurunan anti-proliferasi oleh NO
- penurunan fibinolysis
- peningkatan trombosit
 AT II:
- regulasi tekanan darah
- inflamasi
- permeabilitas aterosklerosis risiko
kardiovaskular.
- remodeling sel-sel otot polos
- stres oksidatif

ACE inhibitor atau angiotensin receptor blocker (ARB)

mengembalikan aktivitas fisiologis sel endotel
 Faktor-faktor yang mempengaruhi
DE
Hipertensi
DM
Rokok
LDL
Homosistein
Defisiensi estrogen

Endotel
Otot polos

Apoptosis
Adesi leukosit
Deposisi lipid
Vasokonstruksi
Proliverasi otot polos
trombosis
 MEDIATOR TONUS VASKULER/ANTIKOAGULAN

Prostacyclin
Relaksasi vaskuler
Inhibisi aktivasi dan adesi trombosit
Nitric oxide
relaksasi vaskuler
Inhibisi aktivasi trombositprotein C dan antitrombin supresi produksi trombin
Endothelium-derived hyperpolarizing factor
Induksi realksasi vaskuler
Endothelin-1
Induksi vasokonstriksi
Tissue Plasminogen activator
Activasi fibrinolysis
Ectoenzyme adenosine-diphosphatase
Degradation ADP
Tissue Factor Pathway Inhibitor
Inhibisi Tissue Factor/Factor VIIa complex
dll
 MEDIATOR PROKOAGULAN
Tissue Factor
Released following endothelial
injury, possibly by activated
endothelium
Von Willebrand Factor
Forms bridges for platelet adhesion
and aggregation
Plasminogen Activator
 MEDIATOR PENYEMBUHAN
Platelet-derived growth factor (PDGF)
Mitogenesis of smooth muscle and fibroblasts
Fibroblast growth factor (FGF)
Fibroblast proliferation
Transforming growth factor (TGF-)
Modulation of vascular repair (cell
proliferation inhibition)
Epidermal growth factor (EGF)
Endothelial cell growth factor (ECGF)
 MEDIATOR HEMOSTASIS
MENGINDUKSI RELAKSASI VASKULER DAN ANTI-CLOTTING:
Nitric oxide
- Relaksasi otot vasodilatasi
- Inhibisi adesi dan agregasi trombosit
- Inhibisi adesi leukosit dan kemotaksis
- antimikroba
Prostacyclin
- relaksasi dan vasodilatasi
- Inhibisi adesi dan agregasi trombosit
Endothelium-derived hyperpolarizing factor
 Cedera endotel
Inflamasi
- Infekious (Bakteri, virus)
- Non-infeksius (Immune-mediated)
Nekrosis
- Toxins
- Agen Infeksius (virus)
Degenerasi Endotel
- Endotoxin
Trauma
Invasi
- neoplasia
 Proses hemostasis
1. Primer perubahan vaskuler
- Aktivasi endotel
- Kontraksi otot polos--> vasokonstriksi
- Aktivasi trombosit
- Adesi trombosit pada endotel
- Agregasi trombosit
- Sekresi Thromboxane dan Platelet Factor 3
- Kontraksi trombosit damn fibrinolosis inisiasi penyembuhan

2.Sekunder
- Koagulasi intrinsik
- Koagulasi ekstrinsik
AktivasiAdesiagregasi sekresi kloting
ENDOTEL

INFLAMASI
Endotel dan inflamasi
 INFLAMASI

MERUPAKAN RESPON YANG TERJADI UNTUK

MELINDUNGI TUBUH DARI PENYEBAB
KERUSAKAN SEL (MIKROBA, TOKSIN), TRAUMA
DAN KONSEKUENSI DARI KERUSAKAN SEL
(NEKROSIS)

ISTILAH INFLAMASI : DESKRIPSI DARI DOLOR,

RUBOR, CALOR, TUMOR

PERUBAHAN-PERUBAHAN TERJADI KARENA:

1. VASODILATASI PEMBULUH DARAH
2. PENINGKATAN PERMEABILITAS KAPILER
3. INFILTRASI SELULER :
KHEMOTAKSIS
KEMOKINESIS
 RESPON INFLAMASI

TERJADI PADA JARINGAN YANG MEPUNYAI PEMBULUH

DARAH
MELIBATKAN:
- PEMBULUH DARAH
- PLASMA
- SEL-SEL DALAM SIRKULASI
- MATRIKS EKSTRASELULER
- PROTEIN SERAT (KOLAGEN, ELASTIN)
- GLIKOPROTEIN ADHESIF (FIBRONEKKTIN,
LAMININ)
- PROTEOGLIKAN
 AKTIVASI SEL PADA RESPON INFLAMASI

MELALUI FASE-FASE;
1. SIGNALING
2. AKTIVASI
3. MIGRASI

MIGRASI SEL MELIBATKAN:

1. MOLEKUL ADHESI (VASCULAR ADRESIN)
2. RESEPTOR
3. LIGAND
4. KEMOTAKSIS
 MOLEKUL ADESI PADA PROSES MIGRASI SEL

ENDOTEL MEMPUNYAI MOLEKUL ADESI UNTUK

LEUKOSIT:

1. SELEKTIN
SELEKTIN-L HOMING RECEPTOR
SELEKTIN-E ENDOTEL
SELEKTIN-P PLATELET
2. INTEGRIN LEUCOCYTE INTEGRIN
3. IMUNOGLOBULIN SUPERFAMILY (ICAM-1, VCAM-1)
4. MUCIN-LIKE MOLECULE
5. CD 44
 MEDIATOR PADA RESPON INFLAMASI

MOLEKUL SOLUBEL/ DIFUSIBEL

IL-1
IL-6
TNF-,
IFN-, ,
PRODUK BAKTERI
EKSOGEN (ENDOTOKSIN, LPS)
ENDOGEN (ALAMIAH, ADAPTIF)
 TAHAP-TAHAP MIGRASI SEL

1. INDUKSI OLEH TNF-EKSPRESI SELEKTIN-P DAN E OLEH

ENDOTEL IKATAN LEUKOSIT DG ENDOTEL

2. ROLING

3. INTERAKSI INTEGRIN (LFA-1) DG ICAM-1IKATAN KUAT

LEUKOSIT DG ENDOTEL

4. INTERAKSI LFA-1, MAC-1 DAN PECAM LEUKOSIT DENGAN

SELEKTIN L , E DAN ICAM-1DIAPEDESIS
Hipotesis patogenesis inflamasi-aterosklerosis
Endotel pada sepsis
Intravasasi dan ekstravasasi metastasis
Interaksi sel tumor dan
endotel
 Sitokin dan inflamasi
Komunikasi antar sel sitokin
Masenger kimia
Td: IL, IFN, GF
Td: limfokin, monokin
sitokin u/chemoatraktan chemokin
sitokin
 Common Cytokine Imbalances
Th1/Th2 cytokine imbalance with a relative
excess of Th1. This type of imbalance is
often seen in acute inflammation.
The uncontrolled and excessive Th1
cytokines may often destroy tissues
throughout the body and precipitate
autoimmune disease in susceptible
individuals.

Th1/Th2 cytokine imbalance with a relative

excess of Th2. This type of imbalance is
often seen in acute inflammation.
An excess of Th2 cytokines may overly
suppress microbicidal actions of Th1
cytokines. Allergies may result from
excessive Th2 activity, and can often result
in atopic conditions in susceptible
individuals.
 Sitokin pada alergi
Lymphokines: IL-2, IL-3, IL-4, IL-5, IL-13, IL-15, IL-16,
IL-17.
Pro-inflammatory cytokines: IL-1, TNF, IL-6, IL-11,
GM-CSF, SCF.
Anti-inflammatory cytokines: IL-10, IL-1ra, IFN-, IL-
12, IL-18.
Chemotactic cytokines (chemokines): Regulated on
Activation, Normal T cell Expressed, and Secreted
(RANTES),Monocyte chemoattractant protein (MCP-
1), MCP-2, MCP-3, MCP-4, MCP-5, Macrophage
inflammatory protein (MIP-1), eotaxin, IL-8.
Growth factors: PDGF, TGF-, FGF, EGF, IGF.
 chemokin (chemotactic
cytokines)
Fungsi:
Hemostatik: migrasi leukosit
CCL14, CCL19, CCL20, CCL21, CCL25, CCL27,
CXCL12 and CXCL13. This classification is not
strict, for example CCL20 can act also as pro-
inflammatory chemokine.
Inflamasi: patologistimulus IL-1,
TNF,LPS,Virus
CXCL-8, CCL2, CCL3, CCL4, CCL5, CCL11,
CXCL10.
Cytokines released from airway epithelial cells following various stimuli and other
cytokines released from other cells such as macrophages. Cytokines from airway
epithelial cells have effects on other cell types such as eosinophils, lymphocytes,
airway smooth muscle cells, and fibroblasts.
Interactions between resident and inflammatory cells and cytokines in the
airways. For abbreviations
 Kanker dan inflamasi

The Multifaceted Role of Inflammation in Cancer:

- Inflammation acts at all stages of tumorigenesis. It may contribute
to tumor initiation through mutations, genomic instability, and
epigenetic modifications.
- Inflammation activates tissue repair responses, induces
proliferation of
premalignant cells, and enhances their survival. Inflammation also
stimulates angiogenesis, causes localized immunosuppression,
and promotes the formation of a hospitable microenvironment in
which premalignant cells can survive, expand, and accumulate
additional mutations and epigenetic changes. Eventually,
- inflammation also promotes metastatic spread. Mutated cells are
marked with X. Yellow, stromal cells; brown, malignant cells;
red, blood
vessels; blue, immune and inflammatory cells. EMT, epithelial-
mesenchymal transition; ROS, reactive oxygen species; RNI,
reactive nitrogen intermediates
 Role of Inflammation in Tumor Initiation and Promotion
(A) Tumor initiation. Reactive oxygen species (ROS) and reactive nitrogen
intermediates (RNI) produced by inflammatory cells may cause mutations in
neighboring epithelial cells. Also, cytokines produced by inflammatory cells
can elevate intracellular ROS and RNI in premalignant cells. In addition,
inflammation
can result in epigenetic changes that favor tumor initiation. Tumorassociated
inflammation contributes to further ROS, RNI, and cytokine
production.
(B) Tumor promotion. Cytokines produced by tumor-infiltrating immune cells
activate key transcription factors, such as NF-kB or STAT3, in premalignant
cells to control numerous protumorigenic processes, including survival,
proliferation,
growth, angiogenesis, and invasion. As parts of positive feed-forward
loops, NF-kB and STAT3 induce production of chemokines that attract additional
immune/inflammatory cells to sustain tumor-associated inflammation
 Immunosurveillance, Tumor-Promoting
Inflammation, and Therapy-Induced Inflammation

a. Balance between immunosurveillance and tumor-

promoting inflammation in the tumor microenvironment.
Tumor-promoting cytokines act on immune and malignant
cells to tilt the balance toward tumor promotion.
Tumorpromoting immunity dampens immunosurveillance,
which otherwise inhibits tumor growth.
b. Therapy-induced inflammation. Various forms of therapy
induce death (necrosis) of malignant cells resulting in the
release of necrotic products and DAMPs that activate
cytokine-producing inflammatory cells. These cytokines
activate prosurvival genes in residual cancer cells,
rendering them resistant to subsequent rounds of therapy.
However, in some cases, therapy-induced inflammation
augments the presentation of tumor antigens and
stimulates an antitumor immune response that improves
the therapeutic outcome.
 .Cartoon illustrating tumor-induced endothelial cell activation. Growth factors secreted by
tumor cells bind to receptor-tyrosine kinases, which lead to induction of intracellular
signaling. As a consequence, endothelial cells become polarized and start to transmigrate
through the basal membrane into the surrounding matrix. Endothelial cells express integrin
adhesion molecules in newly formed focal adhesions as well as the proteolytic enzymes at the
leading edge as a prerequisite for efficient cell motility. RTK: receptor tyrosine kinase; uPAR:
urokinase-type plasminogen activator receptor; ECM: extracellular matrix; MMP: matrix
metalloproteinases; TAF: tumorassociated fibroblasts
 Fig 5
Extravasation of cancer cells is a multi-step process. The first step consists in the
transient adhesion of cancer cells to the endothelium. It involves endothelial
adhesion molecules such as E-selectin and P-selectin and their counter-receptors
present on cancer cells. This step is associated with the rolling of the cancer cells
on the endothelium (1). The second step consists in a firmer adhesion of cancer
cells to endothelial cells (2). It is mediated through chemoattractants and cell
adhesion molecules on the endothelium and integrins on the cancer cells. The third
step is characterized by the extravasation of cancer cells through endothelial cell
cell junctions (3). EC Endothelial cells, TC tumour cell (adapted from [107]