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ischemia/reperfusion injury
CVM II
37
Medical
Graduate
04/18/2010

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Term
what is ischemia?
Definition
the occlusion of blood flow to tissue (loss of O2 and nutrient supply) - resulting in cellular injury
Term
what is reperfusion?
Definition
a restoration of blood flow to a previously ischemic tissue - can result in additional cellular injury (as soon as you reperfuse any organ, endothelial dysfunction is going to be true for many organ beds)
Term
what is the rhyme for reperfusion?
Definition
"keep the blood vessels slick, to the leukocytes don't stick, and if they don't get in - you win"
Term
what is the key to protecting organs from reperfusion injury?
Definition
attenuate organ dysfunction for the forst 300 sec - 5 min (if you can do that, the downstream events are going to be radically attenuated)
Term
what is the time period where cell injury is still reversible?
Definition
20-30 minutes
Term
what is the first and foremost characteristic of I/R injury?
Definition
increased O2-derived free radicals, namely the superoxide anion and hydrogen peroxide
Term
where does the superoxide anion come from? what is the chief source?
Definition
the mitochondria (due to incomplete reduction of O2), oxidases (such as NADPH oxidase in leukocytes/endothelial cells), and eNOS - the chief source (oxidizes BH4->BH2)
Term
*how do the mitochondria and eNOS team up to create superoxide anions?
Definition
due to ischemia, the mitochondria incompletely reduce molecular O2, which then oxidizes BH4->BH2. BH4 is needed as a cofactor for eNOS to make NO, and when BH4 is missing, it starts to make superoxide (eNOS uncoupling)
Term
what part does superoxide dismutase place in I/R injury?
Definition
superoxide dismutase creates hydrogen peroxide from superoxygen anions - and hydrogen peroxide can cause new cell damage, leading to the newly injured cells releasing cytokines - attracting leukocytes that plug up the vasculature (are able to stick to up-regulated adhesion molecule) -> causes "no reflow phenomenon"
Term
when do leukocytes start to stick? when does their accumulation start to become a problem? why do they show up in the first place?
Definition
after about 30 min -> their accumulation starts to become a problem after 2-3 hrs. they are attracted by cytokines released by injured endothelial cells
Term
do antibodies accumulate in ischemic tissues?
Definition
yes, IgM antibodies accumulated in ischemic tissues and activate completment C5a, attracting neutrophils during reperfusion
Term
can activated leukocytes call in more leukocytes? what is this process called?
Definition
yes, activated leukocytes release leukotriene - which attracts additional leukocytes - this is called the "neutrophil amplification rxn"
Term
along with eNOS's problematic production of superoxide anion, what is another problema associated with eNOS in I/R injury?
Definition
there is less NO being produced for proper vasodilation, along with the fact that the superoxide anion (O2-) itself will combine with NO to form the peroxynitrite anion (ONOO-)
Term
can NO repress the attachment of leukocytes? how quickly are various adhesion molecules expressed in the absence of NO?
Definition
yes (as well as vasodilation). w/o NO, P-selectin is expressed in minutes (~10) and ICAM-1 w/in hrs (3-4)
Term
what happens 2-5 min after reperfusion?
Definition
endothelial dysfunction = decreased endothelial derived NO/increased oxidative stress
Term
what happens ~10 min after reperfusion?
Definition
P-selectin expression on the coronary endothelium, promoting PMN rolling on the endothelium
Term
what happens 20 min after reperfusion?
Definition
increased expression of CD11b/CD18 on PMNs and increased expression of ICAM-1 on the coronary endothelium leading to firm adhesion of PMNs on the endothelium
Term
what happens 30 min after reperfusion?
Definition
PMNs transmigrate from the endothelium and begin to accumulate w/in the myocardium, where they can release superoxide - which contributes to cardiac contractile dysfunction
Term
what are clinical situations that can lead to ischemic heart disease?
Definition
MIs, unstable angina pectoris, chronic IHD w/heart failure, coronary angioplasty/bypass, and organ transplantation (most severe)
Term
what is *preconditioning?
Definition
preconditioning is creating intentional ischemic episodes (chemical/mechanical) in a pt before a heart transplant, to prepare them
Term
what causes IHD (ischemic heart disease) in the heart
Definition
atherosclerotic coronary arterial obstructions (CAD) in the LAD, LCX, and/or RCAs in the form of atherosclerotic lesions (containing oxidized LDLs and fibrous caps) that result in occlusions (esp if they rupture) - ultimately resulting in a possible MI
Term
how is blood flow in CAD restored?
Definition
thrombolysis (t-PA, streptokinase), balloon angioplasty, and coronary arterial bypass grafts
Term
what is acute global ischemia?
Definition
sustained acute ischemia followed by reperfusion -> resulting in organ disfunction
Term
what is the application of protein kinase C inhibition in acute global ischemia? what is the common length of time in which this occurs?
Definition
inhibition of protein kinase C during reperfusion is associated with the restoration of postreperfused organ function as it attenuates superoxid release and enhances endothelial-derived NO bioavailability - clinically relevant to MI infarction/transplantation. this usually occurs w/about 20 min of ischemia followed by 45 min of reperfusion.
Term
what is the benefit of preconditioning? what are the 2 kinds?
Definition
*mechanical method: 1-3 min of ischemia, followed by 5 min of reperfusion - repeated 3-4x. *chemical method: pretreat the heart with PKC activators (involving activation of mitochondrial K ATP channels). doing either will prevent more damage if an acute ischemic does occur later.
Term
what can be used to stimulate eNOS?
Definition
PKC epsilon
Term
what can be used to block eNOS from producing NO under normal, nonischemic condition?
Definition
L-NAME, a methyl ester of arginine
Term
can L-NAME be used to block eNOS's production of SO (super oxide) under ischemic conditions?
Definition
no, eNOS will still produce SO
Term
what is the use of exogenous NO (ie nitroglycerin) in treatment of I/R?
Definition
exogenous NO can be used to treat angina pectoris as well as prophylactic attenuation of I/R injury when administered prior to ischemic events
Term
how do statins affect NO levels?
Definition
statins which manage atherosclerosis via inhibition of cholesterol (via inhibition of HMG-CoA reductase) can augment eNOS expression, giving it anti-inflammatory effects
Term
what can help limit reperfusion injury due to superoxide anion release?
Definition
vitamin E - which is an antioxidant
Term
can antibodies to endothelial adhesion molecules, cytokines, and complement activation effective in attenuating I/R injury?
Definition
yes - however most of these are downstream effects
Term
what are 3 mechanisms by which broad-spectrum PKC inhibition can attenuate cardiac contractile dysfunction?
Definition
1) PKC inhibition attenuates SO release from leukocytes/endothelial cells 2) NO bioavailability is augmented via inhibition of SO 3) PKC inhibition attenuates endothelial adhesion molecule expression and subsequent PMN/leukocyte interaction
Term
how will L-NAME affect blood vessels?
Definition
decrease NO (will not decrease SO), and therefore will increase endothelial adhesion molecule expression
Term
how will PKC epsilon inhibition affect hydrogen peroxide levels?
Definition
it will drop them
Term
what does BH2 stand for?
Definition
dihydrobiopterin, which is correlated with SO production
Term
why is NO production lower in ischemic tissue with PKC epsilon activation, when in normal tissue, PKC epsilon stimulates an increase in NO production?
Definition
likely b/c there is more BH2 around, which cannot be used by eNOS, uncoupling it, causing eNOS to start producing SO
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