Lecture 28: Inflammation and Coronary Artery Disease Flashcards
What pathologies do atherosclerosis underly?
Coronary, cerebra, and peripheral vascular diseases
What constitutional risk factors for atherosclerosis?
Genetics
Family History
Age
Male
What modifiable risk factors for atherosclerosis?
Hypertension and Hyperlipidemia Smoking Diabetes Vitamin Deficiencies Obesity Sedentary lifestyle Inflammation
What are some inflammatory markers?
Which one is primarily an emerging risk factor for CV disease? Why?
High sensitivity C-reactive protein (HSCRP)
Acute phase interleukins: IL-1, IL-6
Serum amyloid A
-HSCRP, as it promotes inflammatory response
Where do most lesions happen in vasculature?
Where turbulence is more likely to happen
- openings of exiting vessels
- branch points
- posterior abdominal aorta
What interleukins promote expression of P and E selectins on the endothelium?
Expression of these on the endothelium causes….
IL-1
TNF
-phenotypic change in the endothelium > which leads to proinflammatory and prothrombogenic effects
What type of leukocyte does IL-8 attract?
Neutrophils
How do lipids initiate vascular dysfunction?
What receptor on macrophages take up oxidized lipids?
oxidized LDLs are trapped in the mess of macrophages and leukocytes trying to fix the injury > macrophages get overwhelmed with oxidized LDLs and form foam cells > accumulation of foam cells = fatty streak
scavenger receptor CD 36
TLR-4
What factors are important for smooth muscle cell proliferation?
What does smooth muscle cell proliferation result in?
PDGF
Fibroblast growth factor
TGF-α
thicker tunica intima
What adaptive immunity cells play a role in smooth muscle proliferation?
Th1
Th17
B cells
How are fatty streaks formed?
Expansion from foam cells and extracellular lipid
- recruited inflammatory and smooth muscles cells
- increased ECM
How do atherosclerotic plaques form?
Fatty streak is covered with fibrous cap made of collagen
- center is nectroic
- surrounded by zone of inflammatory and smooth muscles cells
What causes plaque instability?
What can be consequence of this?
Fibrous cap remodeling
-physical stresses/weakens can cause plaque to rupture
-Thrombus > erosion
In new studies, what interleukin is being targeted in treating atherosclerosis?
Results/findings?
IL-1β (CANTOS study)
-Unfortunately, canakinumab was not approved due to no significant reduction in mortality rate.
Give an overview on the events that cause atherosclerosis (response to injury model)
Dz like HTN damages endothelial linging > adhesion of immune cells to try and “fix” problem > chronic inflammation, foam cells, fat entrapment > plaque buildup > turbulent flow
How do macrophages make the problem worse?
activated macrophages recruit more leukocytes to area > leukocytes produce inflammatory markers > P selectins bind leukocytes to bind in the endothelium > increased integrin affinity causing penetration into tunica intima
What are inflammatory exudates?
Swelling causes recruitment of clotting proteins (initiate cascade), complement (destroy pathogens), kinins (vasodilator), fibronolytic proteins (degrades clot after healing) to area making it more crowded
How do inflammasomes play a role in the process?
Activated macrophages > foam cells > cholesterol crystals form in foam cells that activate inflammasomes > produce IL-1 and IL-18 (proinflammatory, which increases the inflammatory cascade even more)
How do neutrophils play a role in the process?
Use NETs against cholesterol crystals that serve as scaffold for platelet aggregation on the site
Elastase release > breaks down elasticity of the endothelium, making it stiffer
Describe the reciprocal cycle of inflammatory responses between neutrophils and macrophages
IL-1 activates Neutrophils use NETs which releases DAMPS
Macrophages recognize DAMPs and releases IL-1
What causes lipid reactive T and B cells and what is the consequence of this?
Endothelial lipoproteins have changed phenotype from “self”, so T cells and B cells attack them and become “autoreactive” since these weren’t the proteins they were educated with
