Inflammation And Coronary Artery Disease Flashcards
What diseases can atherosclerosis underly?
Coronary, cerebral and peripheral vascular diseases
What are some constituational risk factors for CAD?
Genetic abnormalities
Family hx
Increasing age
Male
What is an important emerging risk factor for CAD?
High sensitivity c reactive protein (HSCRP)f
What is HSCRP?
An acute phase protein that triggers the oxidation of LDL
Perpetuates CVD
What can cause CHRONIC endothelial injury?
Hyperlipidemia
Hypertnesion
Smoking
What are some exmpales of Endothelial DYSfucntion?
Increased permeability
Leukocyte adhesion
Monocyte adhesion
Emigration
What are the 5 steps that arterial walls will take in response to injury?
- Chronic endothelial injury
- Endothelial dysfunction
- Macrophage activation
- Macrophage and SM. M. Engulf LIPIDS
- Sm. M. Proliferation, Extracellular lipid
Where is atherosclerosis more commonly seen in vessels?
Why here?
At opening of exiting vessels, branch point, posterio abdominal aorta
Bc normally more flow disturbances seen here
What arteries most frequently get atherosclerosis?
- Abdominal aorta
- Coronary
- Popliteal
- Int. Carotid a.
- Circle of willis
What is the surface of endothelial cells?
What does this allow for?
Nonthrombogenic surface - maintains blood in a fluid state
What happens if there a dysfunction occurs in endothelial cells?
Pro-inflamm. And Pro-thrombogenic response
Initiated thrombus formation, atherosclerosis and vascular lesion of HTN
What is the basal state of endothelial cells?
Vs. activated due to injury?
Non-adhesive, non-thrombogenic surface
Active:
- turbulent flow
- hypertension
- cytokine entry
- increased expr. Of PRO-coagulatns and PRO-inflamm. Fxs
What is the role of vascular smooth msucle cells?
Can proliferate and repair
- synthesize collagen, elastin and proteoglycans
- GFs and cytokines
How can lipids initiate endothelial dysfunction?
Lipids in plaques = chol.
Deposition and accumulation of cholesterol in INTIMA
Macrophages take up and oxidize
OxLDL further accumulates in macrophages and sm.M. —> foam cells —> fatty streak
What will be stimulated in reponse to accumulation of toxic LDL?
Inflammatory response - recruitment of leukocytes via IL-1 and TNF 6
What will IL-1 and TNF-6 do for the injured endothelium?
Will increase expression of P and E selectins
=slows down leukocytes so they can bind chemokines
What will leukocytes do once attached to chemokines?
Will flatten and migrate thru endothelium
What is the first leukocyte to respond?
Spec.?
Neutrophils (hours)
LFA1-ICAM1
IL-8/IL-8L
What leukocyte will appear over a matter of days?
Spec.?
Macrophages
VLA4-VCAM1
What will the cytokine and leukocytes due to the injured endohteliuM?
Increase vascularity —> edema
Why is edema good in injured endotheiuM?
Brings plasma proteins into contact w/ damaged area
What are the proteins in the Edema exudate caused by the cytokines and leukocytes?
- Clotting proteins
- Complement proteins
- Kinin cascade
- Fibrinolytic protein
What is the function of the Kinin cascade protein in the inflamm. Exudate?
Vasodilation
-increase permeability of blood vessels and stimulate pain Rs.
What R. Will oxidize lipids?
Scavenger R. CD36
Upon macrophage activation, what will they differentiate into?
To M1 tissue macrophages = pro-inflamm. Response macrophages
What will the M1 macrophages transform into?
Foam cells
What do the cholesterol crystals w/in foam cells promote?
Activation of Inflammasome
What is the inflammasome?
Signaling system for detection of pathogens and stressors
-results in production of IL-1 and IL-18 (both potent inflammatory cytokines)
What does Neutrophils NETosis do?
Creates a scaffolding for platelet/RBC activation, aggregation and thrombosis
What GFs are needed for Smooth muscle cell proliferation?
What will SM. M. Cell proliferation do?
PDGF
Fibroblast GF
Transforming GF = Alpha TGF
Will increase thickness of intima
What will activate macrophages?
IFN-gamma
Why are T cells initially unresponsive to plaques?
Bc of peripheral tolerance
How are T cell clones made reactive to lipids?
Presentation of self-epitopes bc of macrophages
T cells cause inflammation causing atherosclerosis
What is the fatty streak?
Streak of foam cells and extracellular lipid formed in intima when it is expanding (due to sm. M. Cell proliferation)
How does an atherosclerotic plaque form?
Soft fatty streak covered w/ fibrous cap over time
What is the center of the Fatty Streak like?
What will it contain?
Necrotic
-contains lipid, debris, foam cells and thrombus
What is the center of the fatty streak surrounded by?
Surrounded by a zone of inflammatory
And
sm. M. Cells
What is the fibrous cap covering the fatty streak made up of?
Dense collagen fibers
What will accelerate the degradation of the fibrous cap and inhibit its re-synthesis?
Increased inflammation in plaque
How is a thrombosis due to EROSION caused?
What kind of thrombus will this be?
When the fibrous cap is thick and intact
-sessile, non-occlusive thrombus
How is a thrombosis due to RUPTURE caused?
What kind of thrombus will this be?
Thin fibrous cap w/ fissure
-occlusive thrombus
If the atherosclerosis is an inflamm. Response,
How can you tx (non-specifically)?
Steroids
NSAIDs (destabilize plaque)
What is a selective inhibitor that can tx atherosclerosis?
COX2 inhibitor
What did the CANTOS study propose for Atherosclerosis tx?
IL-1Beta inhibitor
