Inflammation and atherosclerosis Flashcards
What is the importance of atherosclerosis?
Major component of CVD
What are the risk factors of atherosclerosis?
Can control - High LDL/ cholesterol/ BMI/ blood pressure and smoking
Cannot control - Age, gender, postmenopause, genetics
Pathology of atherosclerosis
Initiation
Fatty streak
Fibro-fatty streak
Complex lesion
Arterial disease, MI or stroke
What are the critical events of atherosclerosis?
Endothelial dysfunction
Inflammation and lipid uptake
Monocyte/ lymphocyte recruitment
Macrophage foam cells
VSMC migration, proliferation and ECM production
Vascular remodelling
Stable or Plaque rupture
What is the structure of the normal artery?
Tunica adventitia - connective tissue, fibroblasts, supportive and nutrition to T.M
External elastic lamina
Tunica media - VSMC, well ordered and aligned, strength and elasticity
Internal elastic lamina
Tunica intima - endothelium single layer
What are the two types of cells important in the atherosclerotic process?
Resident cells
Inflammatory cells
Role of the endothelial cells of TI
Selectively permeable barrier for macromolecules
Maintain fluidity under normal conditions
Secrete factors needed for homoeostasis
How do the endothelial cells of the TI maintain fluidity?
Release non-thrombotic and non-adhesive factors
What factors do endothelial cells release to maintain homeostasis?
Anti and pro-thrombotic factors - tissue factors and von Willebrand
Vasoconstrictors - Endothelin-1
Vasodilators - Nitric Oxide and Prostacyclin
Role of the VSMC of the TM
Main part of the arterial wall
Essential for remodelling
Mesenchymal cells - produce ECM proteins like collagen and elastin
Multifunctional - relax, confer strength and elasticity
Role of fibroblasts of the TA
Activate to become myofibroblasts during remodelling
Migration, proliferation and ECM deposition
What are important inflammatory cells?
Monocytes - largest WBC, differentiate into macrophages and dendritic cells and respond to inflammatory signals in site of injury/ infection
T cells - activate macrophages and KK cells, stimulate cells to secrete cytokines
Macrophages - phagocytosis, initiate the adaptive defense mechanism by recruitment of cells, increase or decrease inflammation through cytokines
Which macrophages increase inflammation?
M1 cells
Which macrophages decrease inflammation and encourage tissue repair?
M2 cells
What happens when macrophages engulf lipids?
They become foam cells
What are the 4 steps to plaque formation?
Endothelial activation - initiation of inflammation
Monocyte recruitment and macrophage differentiation
Vascular remodelling and fibrous cap formation
Plaque instability and rupture
How do endothelial cells become activated?
Activated endothelial cells = dysfuncitonal
Cytokines, hypoxia, turbulent blood flow, free raidcals, bacterial or viral infection
What do activated endothelial cells do?
Alter their permeability - compromise the barrier function of blood vessels
Leykocyte adhesion
Pro-coagulant activity
Growth factor/ chemokines
ROle of lipoproteins and lipids in blood in atherosclerosis
Modified lipoproteins and lipids in blood stimulate the innate or adaptive immune response
INduce endothelial and smooth muscle to express adhesion molecules and GF
What adhesion molecules do activated endothelial cells express?
VCAM-1 = vascular adhesion molecule 1
ICAM-1 = intracellular ahesion molecule
Chemotactic molecules - MCP-1
Growth factors - MCSF
How do monocytes differentiate into macrophages?
Adhesion molecules interact with monocytes to adhere, infiltrate and differentiate into macrophages
Monocytes also differentiate upon binding with lipids
How do macrophages form foam cells?
Engulf lipids or lipoproteins via scavenger receptors
Protective role - minimise the effect of lipids on endothelial cells
If the inflammatory response does not neutralize the offending agents the process continues and protective response turns destructive
Foam cells in the neointima = form fatty streak
Foam cells eventually die and release their stored lipids
What happens to the VSMC when in contact with foam cells?
VSMC become activated due to the destructive effect of macrophage foam cells
Activation of VSMC causes them to
Proliferate and become more mobile around the lesion
Synthesise ECM proteins - collagen
Form fibrous cap
What is a fibrous cap?
Contains the lesion and prevents its contents from causing thrombotic events by the rupture of the plaque
Made of collagen and smooth muscle
What causes plaque instability?
Inflammatory response continues and there is enlargement of the lesion
Fibrous cap thins as lipids accumulate in the lesion - cellular necrosis leads to necrotic core formation
VSMCs die and lesion may become rigid due to calcification
Plaque ruptures - contents of the lesion spill out of lumen forming thrombus
Thrombus formation can lead to MI
