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| '''Reperfusion injury''', also known as '''ischemia-reperfusion injury''' ('''IRI''') or '''re-oxygenation injury''', is the [[Tissue (biology)|tissue]] [[damage]] which results from the restoration of blood supply to the tissue after a period of [[ischemia]], [[anoxia]] or [[Hypoxia (medical)|hypoxia]] from different [[Pathology|pathologies]]. During the period of absence of [[blood]] to the [[Tissue (biology)|tissues]] a condition is created in which the resulting [[reperfusion]] will result in [[inflammation]] and [[Oxidative|oxidative damage]] through the involvement of various mechanisms mainly involving [[oxidation]], [[Free radical|free radical formation]] and [[Complement|complement activation]] which ultimately leads to [[Programmed cell death|cell death]], rather than restoration of normal function. | | '''Reperfusion injury''', also known as '''ischemia-reperfusion injury''' ('''IRI''') or '''re-oxygenation injury''', is the [[Tissue (biology)|tissue]] [[damage]] which results from the restoration of blood supply to the tissue after a period of [[ischemia]], [[anoxia]] or [[Hypoxia (medical)|hypoxia]] from different [[Pathology|pathologies]]. During the period of absence of [[blood]] to the [[Tissue (biology)|tissues]] a condition is created in which the resulting [[reperfusion]] will result in [[inflammation]] and [[Oxidative|oxidative damage]] through the involvement of various mechanisms mainly involving [[oxidation]], [[Free radical|free radical formation]] and [[Complement|complement activation]] which ultimately leads to [[Programmed cell death|cell death]], rather than restoration of normal function. |
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| Various intracellular or extracellular changes during ischemia leads to increased [[Intracellular calcium-sensing proteins|intracellular calcium]] and [[Adenosine triphosphate|ATP]] depletion that will ultimately land up in the cell death if the ongoing process does not stopped. [[Reperfusion]] forms reactive oxygen species . This leads to Increased [[mitochondrial]] pore permeability, [[Complement|complement activation]] & [[Cytochrome|cytochrome release]], [[inflammation]] and [[edema]] formation, [[Neutrophil]] [[platelet]] adhesion and [[thrombosis]] leading to progressive [[Tissue (biology)|tissue]] death. In [[Heart]] [[reperfusion injury]] is attributed to oxidative stress which in turn leads to [[Cardiac arrhythmia|arrhythmias]], [[Infarction]] and [[Stunned myocardium|Myocardial stunning]]. In case of trauma the resulting restoration of [[blood]] flow to the [[tissue]] after prolonged [[ischemia]] aggravates [[tissue]] damage by either directly causing additional injury or by unmasking the injury sustained during the ischemic period. [[Reperfusion injury]] can occur in any organ of body mainly seen in the [[heart]], [[intestine]], [[kidney]], [[lung]], and [[muscle]], and is due to microvascular damage | | Various intracellular or extracellular changes during ischemia leads to increased [[Intracellular calcium-sensing proteins|intracellular calcium]] and [[Adenosine triphosphate|ATP]] depletion that will ultimately land up in the cell death if the ongoing process does not stopped. [[Reperfusion]] forms reactive oxygen species . This leads to Increased [[mitochondrial]] pore permeability, [[Complement|complement activation]] & [[Cytochrome|cytochrome release]], [[inflammation]] and [[edema]] formation, [[Neutrophil]] [[platelet]] adhesion and [[thrombosis]] leading to progressive [[Tissue (biology)|tissue]] death. In [[Heart]] [[reperfusion injury]] is attributed to oxidative stress which in turn leads to [[Cardiac arrhythmia|arrhythmias]], [[Infarction]] and [[Stunned myocardium|Myocardial stunning]]. In case of trauma the resulting restoration of [[blood]] flow to the [[tissue]] after prolonged [[ischemia]] aggravates [[tissue]] damage by either directly causing additional injury or by unmasking the injury sustained during the ischemic period. [[Reperfusion injury]] can occur in any organ of body mainly seen in the [[heart]], [[intestine]], [[kidney]], [[lung]], and [[muscle]], and is due to microvascular damage. |
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| ==Pathophysiology==
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| === Mainly divided into 2 phases ===
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| 1) [[Ischemia|Ischemi]]<nowiki/>c phase
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| 2) [[Reperfusion|Reperfusio]]<nowiki/>n Phase
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| === Ischemic Phase ===
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| [[File:Reperfusion Injury ( Ischemic Phase).jpg|thumb|465x465px|Reperfusion injury ( Ischemic Phase)]]During this phase mainly the dysregulation of [[Metabolic pathway|metabolic pathways]] occurs and in the [[Reperfusion|reperfusion phase]] there will be generation of [[free radicals]].
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| *[[Ischemia]] when the [[blood]] supply to the [[Tissue (biology)|tissues]] decreases with respect to the demand required to function properly. This results in [[deficiency]] in [[oxygen]], [[glucose]] and various other substrates required for [[cellular metabolism]]. As previously dais the derangement or dysregulation of metabolic function begins in this phase. Due to less [[oxygen]] supply [[cellular metabolism]] shifts to [[anaerobic]] [[glycolysis]] causing the [[glycogen]] to breakdown resulting in the production of 2 ATP and a [[lactic acid]]. This decrease in tissue PH starts further inhibits the [[Adenosine triphosphate|ATP generation]] by negative feed back mechanism. [[Adenosine triphosphate|ATP]] gets broken down into [[Adenosine diphosphate|ADP]], [[Adenosine monophosphate|AMP]] and [[Inosine monophosphate|IMP]]. This finally gets converted to [[adenosine]], [[inosine]], [[hypoxanthine]] and [[xanthine]].
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| * Lack of [[Adenosine triphosphate|ATP]] at the cellular level causes impairment in the function of ionic pumps - [[Na+/K+-ATPase|Na+/K+]] and Ca<sup>2</sup>+ pumps. As a result [[cytosolic]] sodium rises which in turn withdraws water to maintain the [[Osmosis|osmotic]] [[equilibrium]] consequently resulting in the [[cellular]] [[Swelling (medical)|swelling]]. To maintain ionic balance [[Potassium ion channels|potassium ion]] escape from the cell. [[Calcium]] is released from the [[Mitochondrion|mitochondria]] to the cytoplasm and into extracellular spaces resulting in the activation of Mitochondrial calcium- dependent [[Proteases|cytosolic proteases]]. These converts the enzyme [[xanthine dehydrogenase]] to [[xanthine oxidase]]. Phospholipases activated during [[ischemia]] promotes membrane degradation and increases level of [[Fatty acid|free fatty acids]]
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| *[[Ischemia]] also induces expression of a large number of [[genes]] and [[Transcription factor|transcription factors]], which play a major role in the damage to the tissues.
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| **Transcription factors
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| ***[[Activating protein-1]] ([[AP-1 (transcription factor)|AP-1]])
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| ***Hypoxia-inducible factor-1 (HIF-1) which in turn activates transcription of VEGF, [[Erythropoietin]] and [[Glucose transporter|Glucose transporter-1]]
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| ***Nuclear factor-kappa b ([[NF-kB|NF-kb]])
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| ***Activation of NF-kb occurs during both the [[Ischemia|ischemic]] and [[reperfusion]] phases
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| <br />
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| === Reperfusion Phase ===
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| ==== Reactive oxygen species ====
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| The ROS play major role in the tissue damage related to [[ischemia]] [[reperfusion injury]]. Once the ischemic tissue is reperfused the molecular [[oxygen]] catalyzes the conversion of [[hypoxanthine]] to [[uric acid]] and liberating the [[Superoxide|superoxide anion]] (O<sub>2</sub><sup>-</sup>). This superoxide gets further converted to (H<sub>2</sub>O<sub>2</sub>) and the [[hydroxyl radical]] ([[Hydroxyl radical|OH<sup>•</sup>)]]. This OH ion causes the peroxidation [[Lipid|lipids]] in the [[Cell membrane|cell membranes]] resulting in the production and release of proinflammatory [[Eicosanoid|eicosanoids]] and ultimately cell death.
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| [[File:Reperfusion Injury Mech.jpg|thumb|324x324px|Reperfusion Injury]]
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| During the Ischemia reperfusion injury ROS also activate [[Endothelium|endothelial cells]], which further produces numerous [[Cell adhesion molecule|adhesion molecules]]
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| *[[E-selectin]]
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| *[[VCAM-1]] (vascular cell adhesion molecule-1)
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| *[[ICAM-1]] (intercellular adhesion molecule-1)
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| * EMLMl Am -1 ( endothelial-leukocyte adhesion molecule)
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| *[[Plasminogen activator inhibitor-1|PAi-1]] (plasminogen activator inhibitor-1 ), and
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| *[[Interleukin 8|Interleukin-8]] (il-8)
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| ==== Eicosanoids ====
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| ROS causes [[lipid peroxidation]] of cell membranes resulting in release of
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| * ''[[Arachidonic acid]] (substrate for [[Prostaglandin|prostaglandins]])''
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| ** Prostaglandins usually have a [[Vasodilatory|vasodilatory effect]] hat provides protective effect during [[Ischemia]] reperfusion injury. But they have short life so their fast depletion leads to [[vasoconstriction]] ultimately leading to reduced blood flow and exacerbation of [[ischemia]].
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| * ''[[Thromboxane]]''
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| **[[Thromboxane A2|Plasma thromboxane A<sub>2</sub>]] level rises within minutes after reperfusion, resulting in [[vasoconstriction]] and [[platelet aggregation]]. This usually coincide with rapid rise in [[Pulmonary artery hypertension|pulmonary artery pressure]] and a subsequent increase in [[Lung|pulmonary]] [[Microvascular bed|microvascular]] permeability.
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| * ''[[Leukotriene|Leukotrienes]]''
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| ** Leukotrienes are also synthesized from arachidonic acid. [[Leukotriene]]<nowiki/>s acts directly in the [[endothelial cells]], [[smooth muscle]] and indirectly on the [[neutrophils]]. The [[Leukotriene|leukotrienes]] C<sub>4</sub>, D<sub>4,</sub> and E<sub>4</sub> alters the endothelial [[cytoskeleton]], resulting in increased [[vascular]] permeability and [[smooth muscle]] contraction, and finally leading to [[vasoconstriction]].
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| ==== Nitric oxide ====
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| [[L-arginine]] is the substrate for the synthesis of [[Nitric oxide]] with the help of nitric oxide synthase enzyme. The [[nitric oxide synthase]] enzyme is usually of 3 types
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| * CNOS- Constitutive [[Nitric oxide synthase|nitric oxide synthase enzyme]]
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| * INO S- Inducible [[Nitric oxide synthase|nitric oxide synthase enzyme]]
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| * ENO S- [[Endothelial|Endothelia]]<nowiki/>l nitric oxide synthase enzyme
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| In the first 15 minutes of ischemia [[Nitric oxide|NO]] level rises due to transient ENOS activation. As said this elevation is transient so ultimately after few minutes there will be general decline in [[Endothelium|endothelial function]] resulting in fall of NO production. The reduction in ENOS levels during ischemia reperfusion injury are also predispose to vasoconstriction , the response mainly seen in IRI.
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| ==== Endothelin ====
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| These are peptide [[Vasoconstrictor|vasoconstrictors]] mainly produced from the [[endothelium]]. They mainly mediate [[vasoconstriction]] through Ca<sup>2+</sup>-mediated vasoconstriction. [[Endothelin-1|Endothelin -1]] levels increase during [[Ischemia-reperfusion injury|ischemia reperfusion injury]] in both the phases of [[ischemia]] as well as [[reperfusion]], that mainly help in [[capillary]] vasoconstriction. Endothelin - 1 inhibitors are studied widespread regarding their role in inhibiting [[vasoconstriction]] and increasing [[vascular permeability]].
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| ==== Cytokines ====
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| [[Ischemia]] and reperfusion phase of [[ischemia]] [[reperfusion injury]] induces expression of numerous [[Cytokine|cytokines]] mainly:
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| * [[Tumor necrosis factor-alpha|TNF-a]]
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| ** Elevated levels detected during [[cerebral]] and [[skeletal]] IRI. it can also induce generation of ROS and enhance the susceptibility of vascular [[endothelium]] to neutrophil mediated injury by increasing the expression of [[ICAM-1]] which helps in binding of [[Neutrophil|neutrophils]] to the [[endothelium]].
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| **
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| ==References== | | ==References== |
Editors-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editors-In-Chief: Shivam Singla, M.D [2]
Overview
Reperfusion injury, also known as ischemia-reperfusion injury (IRI) or re-oxygenation injury, is the tissue damage which results from the restoration of blood supply to the tissue after a period of ischemia, anoxia or hypoxia from different pathologies. During the period of absence of blood to the tissues a condition is created in which the resulting reperfusion will result in inflammation and oxidative damage through the involvement of various mechanisms mainly involving oxidation, free radical formation and complement activation which ultimately leads to cell death, rather than restoration of normal function.
Various intracellular or extracellular changes during ischemia leads to increased intracellular calcium and ATP depletion that will ultimately land up in the cell death if the ongoing process does not stopped. Reperfusion forms reactive oxygen species . This leads to Increased mitochondrial pore permeability, complement activation & cytochrome release, inflammation and edema formation, Neutrophil platelet adhesion and thrombosis leading to progressive tissue death. In Heart reperfusion injury is attributed to oxidative stress which in turn leads to arrhythmias, Infarction and Myocardial stunning. In case of trauma the resulting restoration of blood flow to the tissue after prolonged ischemia aggravates tissue damage by either directly causing additional injury or by unmasking the injury sustained during the ischemic period. Reperfusion injury can occur in any organ of body mainly seen in the heart, intestine, kidney, lung, and muscle, and is due to microvascular damage.
References