Inflammatory Aspects of Atherosclerosis & Major Blood Vessel Disease (15) Flashcards
What is atherosclerosis?
Cholesterol deposits in the lumen of blood vessels to form plaques which restrict blood flow
How is inflammation involved in atherosclerosis?
The environment becomes pro-inflammatory
Positive feedback loop of inflammation that doesn’t stop:
- Monocyte/macrophage recruitment, retention, proliferation
- Foam cell formation
- Cell death/apoptosis
- Inflammation never resolved
How does monocyte recruitment differ in normal and inflamed cells (in atherosclerosis)?
Normal/Patrolling monocytes crawl along vessel endothelial membranes until recruited by cell surface receptors.
Inflammatory (M1) monocytes are captured by CXCL1 and CCL5 on the endothelial membrane and continue rolling. The cells are ‘arrested’ and extravasated into the vessel wall.
This process is triggered by hypercholesterolemia (LDL enters blood vessel).
How do monocytes differentiate after being recruited into the vessel wall (in atherosclerosis)?
Once in the vessel wall, monocytes can differentiate into M1 macrophages or dendritic cells.
How do macrophages proliferate and form foam cells (in atherosclerosis)?
M1 macrophages take up LDL and oxidised LDL and proliferate, to become foam cells.
Foam cells release retention molecules and pro-inflammatory cytokines and chemokines.
What is the role of differentiated dendritic cells in the vessel wall (in atherosclerosis)?
Dendritic cells will take up LDL and oxidised LDL onto their cell surface.
Pro-inflammatory effects
Describe the cellular changes in foam cells in atherosclerosis.
Lipid-laden macrophages
- Lipoprotein uptake enhanced
- Cholesterol build-up
- Lipid efflux enhanced to try and remove the lipids
- Pro-inflammatory signalling
- ER stress
What is the fate of macrophages after plaque formation?
They can be retained in the plaque.
If the plaque regresses, macrophages can emigrate from the plaque (chemostasis).
Or they will undergo apoptosis. This will result in cell debris; the clearance system (other macrophages) is overwhelmed.
What do foam cell secrete, and how does this affect the internal environment of the plaque?
They secrete pro-inflammatory cytokines and chemokines.
IL-1, IL-6, TNF
CCL2, CCL5, CXCL1
Creates a pro-inflammatory environment inside the plaque.
What is the role of T cells in atherosclerosis?
Different sub-types of T cells have different roles in atherosclerosis.
Pro-atherogenic: TH1, TH9, TFH
Atheroprotective: TH2, TH17, TH22
How does diabetes affect blood vessels?
Hyperglycaemia, FFAs and insulin resistance all contribute to oxidative stress, PKC activation and RAGE activation.
This leads to vasoconstriction, thrombosis and inflammation (in endothelial cells.)
How does the IL-1 family contribute to inflammation?
IL-1 receptors dimerise after exposure to IL-1
This leads to strong pro-inflammatory signalling in cells.
How does inflammation contribute to coagulation and thrombosis?
Inflammation (caused by hyperglycaemia and insulin resistance) recruits and hyperactivates the clotting mechanism.
This can cause endothelial damage
