N E P H RO LO GY – H Y P E RT E N S I O N D I V I S I O N O F I N T E R N A L M E D I C I N E M E D I C A L FAC U LT Y

S E B E L A S M A R E T U N I V E RS I T Y O F S U R A K A RTA

PATOGENESIS INFLAMASI & ATEROSKLEROSIS

Dr.HM.Bambang Purwanto,dr.SpPD-KGH, FINASIM

ATEROSKLEROSIS

MEKANISME PENYEBAB

1. REAKSI INFLAMASI

2. DISFUNGSI ENDOTEL

3. KELAINAN KOAGULASI

SELULAR LARUT

SISTEM IMUN

FISIK

SPESIFIK (ADAPTIF) NON SPESIFIK (INNATE)

SELULAR HUMORAL

- Kulit

- Selaput lendir

- Silia

- Batuk

- Bersin

Biokimia

- Lisozim

- Sekresisebaseus

- Asam lambung

- Laktoferin

- Asam Neuraminik

Humoral

- Komplemen

- APP

- Mediator asal lipid

- Sitokin

- Fagosit

> Mononuklear

> Polimorfonuklear

- Sel NK

- Sel Mast

- Basofil

- Eosinofil

- SD

Sel B

- IgG

- IgA

- IgM

- IgE

- IgD

Sitokin

- Sel T

- Th1

- Th2

- Ts/Tr/Th3

- Tdth

- CTL/Tc

- NKT

- Th17

Gambaran umum sistem imun

Baratawidjaja, 2009; Imunologi Dasar

LPS bp

CD 14

IL 6

TNF -

IL -1

IL 8

APC

CD 4+ TCR

IFN -

SUPER ANTIGEN

IL - 10

IL - 4

IL - 5

IL - 6

Ig

NO ICAM -1

TH - 2 TH - 1 B cell

CD 8+

LPS

IMUNOCOM

SEPSIS

MOD

SHOCK

SEPTIC

IL-2

CSF

Compl.

N

NK

(Guntur, 2006)

C3a, C5a

PGE 2

TLR 4

TLR2

C7a MHC II

PAI-1

Imunopatogenesis

Korikosteroid

MD-2 CD14

LPS bp

TLR4

My D88

TRAF6 IRAK

NF-KB

ENDOTOKSIN

M

NIK/MKK

IKK

Target Genes

- Insulin Treatment

Guntur, 2008;Sepsis Forum

- Metformin

- Low dos Kortikosteroid

- Statin

- ACE Inhibitor

- AG II Blocker

- Anti ROS

- NO

- Bradikinin

- Oestrogen

TNF-

IL-6 IL-12

IL-1

IL-8

TGFβ-1

CYTOKINES

Toll Like Reseptor

Kemampuan Memprediksi HCRP Terhadap Morbiditas dan

Mortalitas Kejadian Kardiovaskuler

↓ eNOS mRNA

HCRP

IL-6

↓ NO

↓ BCL-2

↑ Apoptosis Endothel

NFkβ aktif

↑ ekspresi Sitokin

Sel Hepar

↑ ET-1

↑ ICAM

↑ VCAM

↑ MCP-1

↑ AT-1R

↑ ROS

↑ VSM proliferasi

↑ Restenosis

Disfungsi endothel

(Szmitko PE, 2003)

TNF α Hipotalamus

PG2 + ILI

Aspirin

Panas

(Pirogen Endogen)

Hepatosit

↑ Sintese

Coagulasi ↑

Aktivasi Kuat

Kaheksia

Amiloid Serum

Fibrinogen

CRP

↓ Kontraksi

• Otot Polos Pembuluh Darah

• Jantung

Vasodelatasi

Syok

Sel Lemak

Permeabilitas Eksudasi

Se-Sel Radang

Congesti

↓

Endotel

• ↑ Tissue Faktor

• ↓ Trombo Modulin

• Mengkerut

Protealitik

Gangguan Reseptor Membrane Gangguan Reseptor Eritroporitin

Anemia

• Reseptor Vasopressor

• Proteolitik

(Brata Widjaya, 2009; Purwanto, 2010)

ILI

IL6

KAKHEKTIN ↓ Nafsu Makan KAKHEKTIS (KURUS)

Hipertensi kronis

Stressor endotel

Ekspresi

TNFα IL1β TGFβ1

Apoptosis Plag

Fibrosis Nekrosis

Aterosklerosis

Gagal

ginjal Jantung

koroner

Cerebral - Stroke

- Demensia

- Parkinson

Patogenesis Komplikasi Hipertensi

Robbin, 2005

IL6

HCRP

Angiotensin II plays a central role

in atherosclerosis

Schmieder et al. Lancet 2007;369:1208–19

Angiotensin II

Vascular permeability , leukocyte infiltration

Activation of signalling pathways

Proliferation of vascular

smooth muscle cells (VSMCs)

Matrix deposition

Platelet aggregation Matrix metalloproteinase (MMP) activation

Inflammatory mediators• Adhesion molecules (VCAM-1, ICAM-1...)

• Chemokines (MCP-1, interleukin 8…)• Cytokines (interleukin 1 & 6, TNFα)

• Growth factors

Activation of plasminogen

activator inhibitor type-1 (PAI-1)

NAD(P)H oxidase activity

Reactive oxygen species

Nitric oxide

Vasoconstriction

LDL peroxidation, LOX-1

Oxidative stress Inflammation

Endothelial dysfunction Tissue remodelling

Smooth

Muscle

Cells

FIBROSIS

Monocytes

Makropag

Chemotaxis

Activation

S mad 3

Ang II TGFβ1

Chronics Active

24 Jam

Mekanisme Fibrosis Robin, 2007

Aldosteron Miokardium

Endothelial Dysfunction

oxLDL

Hypertension

Angiotensin II Smoking

Homocysteine

Diabetes

Mod. from Gibbons GH, Clin Cardiol 20 (1997)

- Bradykinin/NO

- Antioxidants (?)

oxidative stress

CV Risk Factors And Endothelial Dysfunction

(Karnen GB, Iris R;2006)