Term
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Definition
| the occlusion of blood flow to tissue (loss of O2 and nutrient supply) - resulting in cellular injury |
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Term
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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) |
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Term
| what is the rhyme for reperfusion? |
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Definition
| "keep the blood vessels slick, to the leukocytes don't stick, and if they don't get in - you win" |
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Term
| what is the key to protecting organs from reperfusion injury? |
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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) |
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Term
| what is the time period where cell injury is still reversible? |
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Definition
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Term
| what is the first and foremost characteristic of I/R injury? |
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Definition
| increased O2-derived free radicals, namely the superoxide anion and hydrogen peroxide |
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Term
| where does the superoxide anion come from? what is the chief source? |
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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) |
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Term
| *how do the mitochondria and eNOS team up to create superoxide anions? |
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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) |
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Term
| what part does superoxide dismutase place in I/R injury? |
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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" |
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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? |
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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 |
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Term
| do antibodies accumulate in ischemic tissues? |
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Definition
| yes, IgM antibodies accumulated in ischemic tissues and activate completment C5a, attracting neutrophils during reperfusion |
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Term
| can activated leukocytes call in more leukocytes? what is this process called? |
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Definition
| yes, activated leukocytes release leukotriene - which attracts additional leukocytes - this is called the "neutrophil amplification rxn" |
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Term
| along with eNOS's problematic production of superoxide anion, what is another problema associated with eNOS in I/R injury? |
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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-) |
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Term
| can NO repress the attachment of leukocytes? how quickly are various adhesion molecules expressed in the absence of NO? |
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Definition
| yes (as well as vasodilation). w/o NO, P-selectin is expressed in minutes (~10) and ICAM-1 w/in hrs (3-4) |
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Term
| what happens 2-5 min after reperfusion? |
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Definition
| endothelial dysfunction = decreased endothelial derived NO/increased oxidative stress |
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Term
| what happens ~10 min after reperfusion? |
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Definition
| P-selectin expression on the coronary endothelium, promoting PMN rolling on the endothelium |
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Term
| what happens 20 min after reperfusion? |
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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 |
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Term
| what happens 30 min after reperfusion? |
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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 |
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Term
| what are clinical situations that can lead to ischemic heart disease? |
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Definition
| MIs, unstable angina pectoris, chronic IHD w/heart failure, coronary angioplasty/bypass, and organ transplantation (most severe) |
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Term
| what is *preconditioning? |
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Definition
| preconditioning is creating intentional ischemic episodes (chemical/mechanical) in a pt before a heart transplant, to prepare them |
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Term
| what causes IHD (ischemic heart disease) in the heart |
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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 |
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Term
| how is blood flow in CAD restored? |
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Definition
| thrombolysis (t-PA, streptokinase), balloon angioplasty, and coronary arterial bypass grafts |
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Term
| what is acute global ischemia? |
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Definition
| sustained acute ischemia followed by reperfusion -> resulting in organ disfunction |
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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? |
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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. |
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Term
| what is the benefit of preconditioning? what are the 2 kinds? |
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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. |
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Term
| what can be used to stimulate eNOS? |
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Definition
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Term
| what can be used to block eNOS from producing NO under normal, nonischemic condition? |
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Definition
| L-NAME, a methyl ester of arginine |
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Term
| can L-NAME be used to block eNOS's production of SO (super oxide) under ischemic conditions? |
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Definition
| no, eNOS will still produce SO |
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Term
| what is the use of exogenous NO (ie nitroglycerin) in treatment of I/R? |
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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 |
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Term
| how do statins affect NO levels? |
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Definition
| statins which manage atherosclerosis via inhibition of cholesterol (via inhibition of HMG-CoA reductase) can augment eNOS expression, giving it anti-inflammatory effects |
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Term
| what can help limit reperfusion injury due to superoxide anion release? |
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Definition
| vitamin E - which is an antioxidant |
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Term
| can antibodies to endothelial adhesion molecules, cytokines, and complement activation effective in attenuating I/R injury? |
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Definition
| yes - however most of these are downstream effects |
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Term
| what are 3 mechanisms by which broad-spectrum PKC inhibition can attenuate cardiac contractile dysfunction? |
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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 |
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Term
| how will L-NAME affect blood vessels? |
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Definition
| decrease NO (will not decrease SO), and therefore will increase endothelial adhesion molecule expression |
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Term
| how will PKC epsilon inhibition affect hydrogen peroxide levels? |
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Definition
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Term
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Definition
| dihydrobiopterin, which is correlated with SO production |
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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? |
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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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