Inflammation and CAD Flashcards
what contributes to the development of atherosclerosis?
inflammation
what are the big 3 modifiable risk factors for atherosclerosis?
hyperlipidemia, hypertension, and diabetes (all synergistic)
What is the first stage in the development of atherosclerosis?
chronic endothelial injury
what is the second stage in the development of atherosclerosis?
endothelial dysfunction
what is the third stage in the development of atherosclerosis?
macrophage activation and smooth muscle recruitment
what is the fourth stage in the development of atherosclerosis?
macrophages and smooth muscle cells engulf lipid
what is the 5th and final stage of development of atherosclerosis?
smooth muscle proliferation, collagen and other extracellular matrix deposition
what are the most common causes of chronic injury and or dysfunction of endothelium?
hypertension and hyperlipidemia
where do most lesions of atherosclerosis tend to occur at?
openings of exiting vessels, branch points, posterior abdominal aorta
what does chronic endothelial injury lead to?
an acute inflammatory response
what occurs during the endothelial dysfunction phase (stage 2)?
there is increased permeability, leukocyte adhesion, monocyte adhesion, and emigration into the intima
what are some characteristics of endothelial cells in the basal state?
they are non-adhesive and they have a non-thrombogenic surface
what are some characteristics of endothelial cells in the activated state?
they have increased expression of procoagulants, adhesion molecules, and pro-inflammatory factors
what molecules increase expression of P&E selectins on endothelium and ligands on leukocytes?
IL-1 and TNF
what is the long term effects of IL-1 and TNF increasing the expression of P&E selectins on endothelium and ligands on leukocytes?
there will be changes in the hemodynamics in the microenvironment
what do the macrophages begin secreting when they begin phagocytosing debris?
TNF, IL-1, and IL-6
what effect does edema have on the tissue?
it brings plasma proteins into the intimate contact with the damaged area
what are the proteins that are in the inflammatory exudate?
clotting proteins, complement, kinin cascade, and fibrinolytic protein
what does the kinin cascade cause?
vasodilation, increase in permeability of blood vessels
what does fibrinolytic protein cause?
degrades the clot when the wound has healed
what happens once the macrophages start moving into the area that has suffered endothelial dysfunction?
it starts to thicken and increase the amount of cells
what are the lipids in atheromatous plaques?
cholesterol and cholesterol esters
what happens to the cholesterol and cholesterol esters that are deposited in the intima and retained there?
they are phagocytosed by the macrophages and then partially oxidized (aka modification)
what is uptake?
when the modified LDL starts to accumulate within the macrophages and smooth muscle cells
what does the process of retention, modification, and uptake of LDL stimulate?
an inflammatory response
what are the macrophages that being to accumulate the partially oxidized LDL now known as?
foam cells
foam cells collect in lesions known as what?
fatty streaks
what can sense oxidized lipids?
scavenger receptor CD36 on monocytes or TLR-4
what happens when monocytes recognize oxidized lipids through their scavenger receptor CD36?
they differentiate to M1 (classical) tissue macrophages; then produce and release acute phase cytokines, transform to foam cells
what is the inflammasome?
a signaling system for detection of pathogens and stressors
what does the recruitment and assembly of inflammasome proteins result in?
the production of large quantities of both IL-1 and IL-18 which are potent inflammatory cytokines
What effect do cholesterol crystals have on neutrophils?
they cause the neutrophils to deploy their NETs
what is the role of the neutrophil’s NETs?
they provide scaffolding for platelet and RBC activation-; netosis will stimulate the macrophages to have an inflammatory response
several growth factors are implicated in smooth muscle proliferation. What are these growth factors?
PDGF, Fibroblast growth factor, TGF-alpha
What is PDGF released by?
locally adherent platelet macrophages, endothelial cells, and smooth muscle cells
what acts as a smooth muscle chemokine?
TGF-alpha
when does the adaptive immune system start responding?
stage 4
What can the modified LDL lead to?
events leading to APC activation and subsequent loss of tolerance to ApoB of LDL- autoreactive Ts and Bs- they lose their tolerance
What are the mediators of the adaptive immunity?
IFN-gamma, TNF-alpha, and IL-17
what cells are responsible for the adaptive immunity?
Th1, Th17, and b cells
over time a soft fatty streak becomes covered with what?
a fibrous cap
what does the center of the plaque contain?
it is necrotic and it contains lipids, debris, foam cells and thrombus
some plaques are more prone to rupture than others. What plaque type is more likely to rupture?
thin fibrous caps- the red thrombus
which type of plaque is more stable and more likely to erode?
the white thrombus- thick fibrous cap
which plaque more frequently causes STEMI?
the red thrombus
what is the prominent cell type in a red thrombus?
macrophages
what is the prominent cell type in a white thrombus?
smooth muscle cells
what is a major inflammatory marker?
high sensitivity C-reactive protein
what effect do steroids have on CAD?
they increase cardio vascular adverse events and mortality
what effect do NSAIDs have on CAD?
they increase cardio vascular events due to destabilizing the plaque
what effect does the COX2 inhibitor have on CAD?
it increases CVD mortality
what is instrumental in driving atherosclerosis and comes off the inflammasome?
IL-1 beta
what is ACZ885 (canakinumab)?
it was a human mAb, that selectively blocked the IL-1beta inflammatory pathway
