Inflammation and atherosclerosis

Question 1

What is the importance of atherosclerosis?

Answer 1

Major component of CVD

Question 2

What are the risk factors of atherosclerosis?

Answer 2

Can control - High LDL/ cholesterol/ BMI/ blood pressure and smoking

Cannot control - Age, gender, postmenopause, genetics

Question 3

Pathology of atherosclerosis

Answer 3

Initiation

Fatty streak

Fibro-fatty streak

Complex lesion

Arterial disease, MI or stroke

Question 4

What are the critical events of atherosclerosis?

Answer 4

Endothelial dysfunction

Inflammation and lipid uptake

Monocyte/ lymphocyte recruitment

Macrophage foam cells

VSMC migration, proliferation and ECM production

Vascular remodelling

Stable or Plaque rupture

Question 5

What is the structure of the normal artery?

Answer 5

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

Question 6

What are the two types of cells important in the atherosclerotic process?

Answer 6

Resident cells

Inflammatory cells

Question 7

Role of the endothelial cells of TI

Answer 7

Selectively permeable barrier for macromolecules

Maintain fluidity under normal conditions

Secrete factors needed for homoeostasis

Question 8

How do the endothelial cells of the TI maintain fluidity?

Answer 8

Release non-thrombotic and non-adhesive factors

Question 9

What factors do endothelial cells release to maintain homeostasis?

Answer 9

Anti and pro-thrombotic factors - tissue factors and von Willebrand

Vasoconstrictors - Endothelin-1

Vasodilators - Nitric Oxide and Prostacyclin

Question 10

Role of the VSMC of the TM

Answer 10

Main part of the arterial wall

Essential for remodelling

Mesenchymal cells - produce ECM proteins like collagen and elastin

Multifunctional - relax, confer strength and elasticity

Question 11

Role of fibroblasts of the TA

Answer 11

Activate to become myofibroblasts during remodelling

Migration, proliferation and ECM deposition

Question 12

What are important inflammatory cells?

Answer 12

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

Question 13

Which macrophages increase inflammation?

Answer 13

M1 cells

Question 14

Which macrophages decrease inflammation and encourage tissue repair?

Answer 14

M2 cells

Question 15

What happens when macrophages engulf lipids?

Answer 15

They become foam cells

Question 16

What are the 4 steps to plaque formation?

Answer 16

Endothelial activation - initiation of inflammation

Monocyte recruitment and macrophage differentiation

Vascular remodelling and fibrous cap formation

Plaque instability and rupture

Question 17

How do endothelial cells become activated?

Answer 17

Activated endothelial cells = dysfuncitonal

Cytokines, hypoxia, turbulent blood flow, free raidcals, bacterial or viral infection

Question 18

What do activated endothelial cells do?

Answer 18

Alter their permeability - compromise the barrier function of blood vessels

Leykocyte adhesion

Pro-coagulant activity

Growth factor/ chemokines

Question 19

ROle of lipoproteins and lipids in blood in atherosclerosis

Answer 19

Modified lipoproteins and lipids in blood stimulate the innate or adaptive immune response

INduce endothelial and smooth muscle to express adhesion molecules and GF

Question 20

What adhesion molecules do activated endothelial cells express?

Answer 20

VCAM-1 = vascular adhesion molecule 1

ICAM-1 = intracellular ahesion molecule

Chemotactic molecules - MCP-1

Growth factors - MCSF

Question 21

How do monocytes differentiate into macrophages?

Answer 21

Adhesion molecules interact with monocytes to adhere, infiltrate and differentiate into macrophages

Monocytes also differentiate upon binding with lipids

Question 22

How do macrophages form foam cells?

Answer 22

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

Question 23

What happens to the VSMC when in contact with foam cells?

Answer 23

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

Question 24

What is a fibrous cap?

Answer 24

Contains the lesion and prevents its contents from causing thrombotic events by the rupture of the plaque

Made of collagen and smooth muscle

Question 25

What causes plaque instability?

Answer 25

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