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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-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.

Pathophysiology

The component playing a major role in the pathophysiology of Ischemia-reperfusion injury is Reactive oxygen species (ROS) causing damage to cellular and biological membranes. Neutrophils also play an important role in initiating and propagating much of the damage involved in the process of Ischemia-reperfusion injury. Ischemia is the phase that precedes the restoration of blood flow to that organ or tissue, resulting in the built-up of xanthine oxidase and hypoxanthine that upon the restoration of blood flow leads to the formation of ROS. Neutrophils also potentiate the effect of Ischemia-reperfusion injury through microvascular injury by releasing various proteolytic enzymes and ROS. Most of the experimental studies carried out in helping understand the mechanism of Ischemia reperfusion injury are mainly on the cat, dog, and horses.

Risk Factors

Ischemia reperfusion injury is a complex disorder associated with various cardiovascular and other risk factors mainly including Hypertension, hyperlipidemia, Diabetes, Insulin resistance, aging, and defects with coronary artery circulation. Although the exact mechanism about how these causes injuries are still not clear but studies have done so far best explains their role in mediating oxidative stress and endothelial cell dysfunctions, the two most important pathophysiological processes involved in the mediation of injury.

Natural History, Complications and Prognosis

Reperfusion injury mechanism is mostly studied by scientists in cats and dogs with the first experimental study done in 1955 by Sewell and later different studies were done to understand more about the reperfusion injury mechanisms. Most of the complications associated with reperfusion injury are mainly due to the formation of reactive oxygen species and neutrophil activation ultimately resulting in tissue damage-causing Ischemia, Infarction, Haemorrhage, and edema. Prognosis, in general, is poor with Ischemia-reperfusion injury resulting in tissue injury and damage. The most important determinant of prognosis is the time taken to reperfuse the ischemic tissue. More the delay in time to reperfusion, worse the prognosis is.

Medical Therapy

The most common myth about the ischemia-reperfusion injury is itself related to blood flow. One can easily think like if everything is happening due to ischemia and with the restoration of blood flow, the injury should heal. Here is the trick, reperfusion in turn further exacerbates the injury mainly due to the formation of free radicals. There are few approaches that are studied widely and do play a major role in controlling the injury related to ischemia-reperfusion injury

Prevent generation of free radicals( Oxidative stress) or Increase the tissue's capacity to trap the free radicals
Controlling the neutrophil activation and infiltration of ischemic tissue
Hypoxic pre-conditioning

Hyperbaric oxygen therapy is also studied widely and best suited when used within 6 hrs of hypoxia as it helps in the reduction of local and systemic hypoxia and in turn, increases the survival of affected tissue.

Future or Investigational therapies

A lot of studies done in the past three decades helped a lot in understanding the molecular mechanisms associated with Ischemia-reperfusion injury. Also, these studies helped in evaluating various strategies to decrease the incidence and severity associated with Ischemia-reperfusion injury. Existing therapies for Ischemia-reperfusion injury can be divided into Pharmacological and non-pharmacological interventions. A lot of promising studies and clinical trials are still under the pipeline. Till the date, the most encouraging results are associated with ischemic preconditioning and postconditioning, adenosine, and exenatide. A lot of studies have demonstrated the combined effect of pharmacological and nonpharmacological approach as together to be used as a multifactorial approach to improve the clinical outcomes.

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 __NOTOC__
+{{Reperfusion injury}}
-'''Editors-In-Chief:''' [[C. Michael Gibson]], M.S., M.D. [mailto:Mgibson@perfuse.org]; '''Associate Editors-In-Chief: '''[[User:Kashish Goel|Shivam Singla, M.D]]
+{{CMG}} {{AE}} {{Shivam Singla}}
 ==Overview==
-[[File:Reperfusion Injuryyyy.jpg|thumb|351x351px|[[Reperfusion]] Injury Mechanisms]]
+'''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.
-The introduction and wide application of [[reperfusion]] strategies in patients with [[STEMI]] has significantly reduced the mortality rate over last decade. Despite this, the rate of 30-day mortality remains high and approximately 25% of surviving patients develop [[heart failure]]. One of the mechanisms responsible for these adverse outcomes is '''[[Reperfusion injury]]'''.  Reperfusion injury refers to myocardial cell death secondary to restoration of blood flow to the [[ischemia|ischemic]] myocardium. The absence of [[oxygen]] and [[nutrient]]s from blood creates a condition in which the restoration of [[circulatory system|circulation]] results in [[inflammation]] and [[oxidation|oxidative]] damage through the induction of [[oxidative stress]] rather than restoration of normal function.
+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.
-[[Ischemia-reperfusion injury]] creates the base line for tissue damage and [[Cellular apoptosis susceptibility protein|cellular apoptosis]]. The tissue damage follows a natural progression of cellular and metabolic events initiated by an [[Ischemia|ischemic]] episode. Ischemia induces various intracellular or extracellular changes leading ton increased calcium intracellularly and [[Adenosine triphosphate|ATP]] depletion that will end up in the cell death if the ongoing process does not stopped. [[Reperfusion]] is considered as a stopper for this and leads to flushing of tissues with toxic metabolites , primarily reactive oxygen species . This leads to Increased mitochondrial pore permeability <math>\longrightarrow</math>[[Complement|complement activation]] & [[Cytochrome|cytochrome release]] <math>\longrightarrow</math>Inflammation and edema <math>\longrightarrow</math>Neutrophil platelet adhesion and [[thrombosis]] leading to progressive tissue death.
 ==Pathophysiology==
-Pathophysiological Mechanism is as follows:
+The component playing a major role in the [[pathophysiology]] of [[Ischemia-reperfusion injury]] is Reactive [[oxygen]] species (ROS) causing damage to [[cellular]] and [[biological membranes]]. [[Neutrophils]] also play an important role in initiating and propagating much of the damage involved in the process of [[Ischemia-reperfusion injury]]. [[Ischemia]] is the phase that precedes the restoration of [[blood]] flow to that organ or [[tissue]], resulting in the built-up of [[xanthine oxidase]] and [[hypoxanthine]] that upon the restoration of [[blood]] flow leads to the formation of [[Reactive oxygen species|ROS]]. [[Neutrophils]] also potentiate the effect of [[Ischemia-reperfusion injury]] through [[microvascular injury]] by releasing various [[Proteolytic enzyme|proteolytic enzymes]] and [[Reactive oxygen species|ROS]]. Most of the experimental studies carried out in helping understand the mechanism of [[Ischemia-reperfusion injury|Ischemia reperfusion injury]] are mainly on the [[cat]], [[dog]], and [[horses]].
-* The pathophysiologic mechanisms underlying reperfusion injury includes various steps starting from  infarction, inflammation, generation of free radicals, an increase in intracellular calcium, development of edema, mitochondrial damage and finally leading to activation of coagulation.
-*'''[[Reperfusion]]''' damage occurs after myocardial reperfusion after a period of decreased [[oxygen]] supply. The damage from reperfusion injury is partially due to the affected tissue's inflammatory response. [[White blood cells]] transported to the region by fresh blood release a host of inflammatory factors such as [[Interleukin|interleukins]] and free radicals in response to tissue injury. Blood flow restored reintroduces oxygen inside cells that damages cellular proteins, DNA, and plasma membrane. Damage to the membrane of the cell will in effect cause further free radicals to be released. These reactive species can also act indirectly to turn on apoptosis through redox signaling. Also, leukocytes may build up in small capillaries, block them and cause more ischemia
-[[File:Mechanism of Reperfusion injury.jpg|border|397x397px|Mechanism Of Reperfusion injury|right]]
-* Mitochondrial dysfunction plays a significant role in reperfusion injury. Although the mitochondrial membrane is normally impermeable to ions and metabolites, ischemia changes permeability by elevating concentrations of intro-mitochondrial calcium, reducing concentrations of adenine nucleotides, and inducing oxidative stress. It gives primacy to the mitochondrial transfer pore permeability (MPTP), which opens when reperfusion occurs. This contributes to increased osmotic load in the mitochondrial body causing swelling and breakup, releasing proteins that induce apoptosis from mitochondria. Mitochondrial activity is impaired, and ATP is hydrolyzed, allowing degrading enzymes to activate. Finally, excessive activation of the Poly ADP ribose polymerase-1 (PARP-1) impairs the work of other organelles and speeds up the development of reactive oxygen species.
-* Hypoxanthine is produced as breakdown product of the ATP metabolism in prolonged ischemia (60 minutes or more). As a consequence of higher oxygen availability the enzyme xanthine dehydrogenase is converted to xanthine oxidase. This oxidation contributes to the conversion of molecular oxygen into highly reactive superoxide and hydroxyl radicals. Xanthine oxidase also produces uric acid, which can act both as a pro-oxidant and as a reactive species scavenger such as per-oxinitrite. To produce the potent reactive species per-oxinitrite, too much nitric oxide formed during reperfusion reacts with superoxide. These radicals and reactive oxygen species attack lipids , proteins, and glycosaminoglycan from the cell membrane, causing further damage. Specific biological processes may also be initiated by redox signaling.
-<br />
 ==Risk Factors==
-Risk factors for reperfusion injury include
+[[Ischemia reperfusion injury]] is a complex disorder associated with various [[cardiovascular]] and other risk factors mainly including [[Hypertension]], [[hyperlipidemia]], [[Diabetes]], [[Insulin resistance]], [[aging]], and defects with [[coronary artery]] [[circulation]]. Although the exact mechanism about how these causes injuries are still not clear but studies have done so far best explains their role in mediating [[oxidative stress]] and [[endothelial cell]] dysfunctions, the two most important pathophysiological processes involved in the mediation of [[injury]].
-* [[Hypertension]] with [[left ventricular hypertrophy]],
-* [[Congestive heart failure]],
-* Increased age,
-* [[Diabetes]], and
-* [[Hyperlipidemia]]
-<br />
 ==Natural History, Complications and Prognosis==
-[[Reperfusion injury]] may be responsible for about 50% of the total infarct size after an acute [[myocardial infarction]] as well as [[myocardial stunning]], [[congestive heart failure]] and [[reperfusion arrhythmias]] such as [[ventricular arrhythmias]].<ref name="pmid17855673">{{cite journal |author=Yellon DM, Hausenloy DJ |title=Myocardial reperfusion injury |journal=N. Engl. J. Med. |volume=357 |issue=11 |pages=1121–35 |year=2007 |month=September |pmid=17855673 |doi=10.1056/NEJMra071667 |url=}}</ref>
+[[Reperfusion injury]] mechanism is mostly studied by scientists in [[cats]] and [[dogs]] with the first experimental study done in 1955 by Sewell and later different studies were done to understand more about the [[reperfusion injury]] mechanisms. Most of the [[complications]] associated with [[reperfusion injury]] are mainly due to the formation of [[reactive oxygen species]] and [[neutrophil]] activation ultimately resulting in [[tissue]] damage-causing [[Ischemia]], [[Infarction]], [[Haemorrhage]], and [[edema]]. Prognosis, in general, is poor with Ischemia-reperfusion injury resulting in tissue injury and damage. The most important determinant of prognosis is the time taken to reperfuse the [[ischemic tissue]]. More the delay in time to [[reperfusion]], worse the prognosis is.
-<br />
 ==Medical Therapy==
-Various proposed medical managements studied are:
+The most common myth about the [[Ischemia-reperfusion injury|ischemia-reperfusion]] injury is itself related to [[blood]] flow. One can easily think like if everything is happening due to [[ischemia]] and with the restoration of [[blood flow]], the injury should [[Healing|heal]]. Here is the trick, [[reperfusion]] in turn further exacerbates the injury mainly due to the formation of [[free radicals]]. There are few approaches that are studied widely and do play a major role in controlling the [[injury]] related to [[ischemia-reperfusion injury]]
-* '''Therapeutic hypothermia'''
+* Prevent generation of [[free radicals]]( Oxidative stress) or Increase the [[Tissue (biology)|tissue's]] capacity to trap the [[free radicals]]
+* Controlling the [[neutrophil]] activation and [[Infiltration (medical)|infiltration]] of [[Ischemic|ischemic tissue]]
+* [[Hypoxic]] [[pre-conditioning]]
-It has been shown in rats that neurons sometimes die completely 24 hours after the blood flow returns. Some claim that this delayed reaction is the result of the multiple inflammatory immune responses that occur during reperfusion.<ref name="urlReperfusion injury - Wikipedia">{{cite web |url=https://en.wikipedia.org/wiki/Reperfusion_injury#cite_note-Newsweek-7 |title=Reperfusion injury - Wikipedia |format= |work= |accessdate=}}</ref> Such inflammatory reactions cause intracranial pressure, a pressure that leads to cell damage and cell death in some cases. Hypothermia has been shown to help reduce intracranial pressure and thus decrease the adverse effects of inflammatory immune responses during reperfusion. Besides that, reperfusion also increases free radical development. Hypothermia has also been shown to decrease the patient's development of deadly free radicals during reperfusion.<ref name="pmid13800633">{{cite journal |vauthors=BIGELOW WC |title=Methods for inducing hypothermia and rewarming |journal=Ann. N. Y. Acad. Sci. |volume=80 |issue= |pages=522–32 |date=September 1959 |pmid=13800633 |doi=10.1111/j.1749-6632.1959.tb49229.x |url=}}</ref>
+[[Hyperbaric oxygen]] therapy is also studied widely and best suited when used within 6 hrs of [[hypoxia]] as it helps in the reduction of local and [[Hypoxemia|systemic hypoxia]] and in turn, increases the [[Survival rate|survival]] of affected [[tissue]].
-* '''Hydrogen sulfide treatment'''
+==Future or Investigational therapies==
+A lot of studies done in the past three decades helped a lot in understanding the [[molecular]] mechanisms associated with [[Ischemia-reperfusion injury]]. Also, these studies helped in evaluating various strategies to decrease the [[incidence]] and severity associated with [[Ischemia-reperfusion injury]].
-There are several preliminary studies in mice that seem to show that treatment with hydrogen sulfide ( H2S) could have a protective effect against reperfusion injury.<ref name="urlThe Cardioprotective Actions of Hydrogen Sulfide in Acute Myocardial Infarction and Heart Failure">{{cite web |url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4090472/ |title=The Cardioprotective Actions of Hydrogen Sulfide in Acute Myocardial Infarction and Heart Failure |format= |work= |accessdate=}}</ref>
+Existing therapies for [[Ischemia-reperfusion injury]] can be divided into [[Pharmacological]] and [[non-pharmacological]] interventions. A lot of promising studies and [[clinical trials]] are still under the pipeline. Till the date, the most encouraging results are associated with [[ischemic]] preconditioning and postconditioning, [[adenosine]], and [[exenatide]]. A lot of studies have demonstrated the combined effect of [[pharmacological]] and [[nonpharmacological]] approach as together to be used as a multifactorial approach to improve the [[clinical]] outcomes.
-* '''Cyclosporine'''
-In addition to its well-known immunosuppressive capabilities, the one-time administration of cyclosporine at the time of percutaneous coronary intervention (PCI) has been found to deliver a 40 percent reduction in infarct size in a small group proof of concept study of human patients with reperfusion injury published in The New England Journal of Medicine in 2008.<ref name="pmid26321103">{{cite journal |vauthors=Cung TT, Morel O, Cayla G, Rioufol G, Garcia-Dorado D, Angoulvant D, Bonnefoy-Cudraz E, Guérin P, Elbaz M, Delarche N, Coste P, Vanzetto G, Metge M, Aupetit JF, Jouve B, Motreff P, Tron C, Labeque JN, Steg PG, Cottin Y, Range G, Clerc J, Claeys MJ, Coussement P, Prunier F, Moulin F, Roth O, Belle L, Dubois P, Barragan P, Gilard M, Piot C, Colin P, De Poli F, Morice MC, Ider O, Dubois-Randé JL, Unterseeh T, Le Breton H, Béard T, Blanchard D, Grollier G, Malquarti V, Staat P, Sudre A, Elmer E, Hansson MJ, Bergerot C, Boussaha I, Jossan C, Derumeaux G, Mewton N, Ovize M |title=Cyclosporine before PCI in Patients with Acute Myocardial Infarction |journal=N. Engl. J. Med. |volume=373 |issue=11 |pages=1021–31 |date=September 2015 |pmid=26321103 |doi=10.1056/NEJMoa1505489 |url=}}</ref>
-Cyclosporine has been confirmed in studies to inhibit the actions of cyclophilin D, a protein which is induced by excessive intracellular calcium flow to interact with other pore components and help open the MPT pore. Inhibiting cyclophilin D has been shown to prevent the opening of the MPT pore and protect the mitochondria and cellular energy production from excessive calcium inflows.<ref name="pmid26735999">{{cite journal |vauthors=Mewton N, Bergerot C, Ovize M |title=Cyclosporine before PCI in Acute Myocardial Infarction |journal=N. Engl. J. Med. |volume=374 |issue=1 |pages=90 |date=January 2016 |pmid=26735999 |doi=10.1056/NEJMc1514192 |url=}}</ref>
-Reperfusion leads to biochemical imbalances within the cell that lead to cell death and increased infarct size. More specifically, calcium overload and excessive production of reactive oxygen species in the first few minutes after reperfusion set off a cascade of biochemical changes that result in the opening of the so-called mitochondrial permeability transition pore (MPT pore) in the mitochondrial membrane of cardiac cells.
-The opening of the MPT pore leads to the inrush of water into the mitochondria, resulting in mitochondrial dysfunction and collapse. Upon collapse, the calcium is then released to overwhelm the next mitochondria in a cascading series of events that cause mitochondrial energy production supporting the cell to be reduced or stopped completely. The cessation of energy production results in cellular death. Protecting mitochondria is a viable cardio protective strategy.
-Cyclosporine is currently in a phase II/III (adaptive) clinical study in Europe to determine its ability to ameliorate neuronal cellular damage in traumatic brain injury.
-* '''TRO40303'''
-TRO40303 is a new cardio protective compound that was shown to inhibit the MPT pore and reduce infarct size after ischemia-reperfusion. It was developed by Trophos company and currently is in Phase I clinical trial.<ref name="urlTranslation of TRO40303 from myocardial infarction models to demonstration of safety and tolerance in a randomized Phase I trial">{{cite web |url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3923730/ |title=Translation of TRO40303 from myocardial infarction models to demonstration of safety and tolerance in a randomized Phase I trial |format= |work= |accessdate=}}</ref>
-* '''Stem cell therapy'''
-Recent investigations suggest a possible beneficial effect of mesenchymal stem cells on heart and kidney reperfusion injury.<ref name="pmid21498423">{{cite journal |vauthors=van der Spoel TI, Jansen of Lorkeers SJ, Agostoni P, van Belle E, Gyöngyösi M, Sluijter JP, Cramer MJ, Doevendans PA, Chamuleau SA |title=Human relevance of pre-clinical studies in stem cell therapy: systematic review and meta-analysis of large animal models of ischaemic heart disease |journal=Cardiovasc. Res. |volume=91 |issue=4 |pages=649–58 |date=September 2011 |pmid=21498423 |doi=10.1093/cvr/cvr113 |url=}}</ref><ref name="urlProtection of mesenchymal stem cells on acute kidney injury - PubMed">{{cite web |url=https://pubmed.ncbi.nlm.nih.gov/24220681/ |title=Protection of mesenchymal stem cells on acute kidney injury - PubMed |format= |work= |accessdate=}}</ref>
-* '''Superoxide dismutase'''
-Superoxide dismutase is an effective anti-oxidant enzyme which converts superoxide anions to water and hydrogen peroxide. Recent researches have shown significant therapeutic effects on pre-clinical models of reperfusion injury after ischemic stroke.
-* '''Metformin'''
-A series of 2009 studies published in the Journal of Cardiovascular Pharmacology suggest that Metformin may prevent cardiac reperfusion injury by inhibition of Mitochondrial Complex I and the opening of MPT pore and  in rats.
-* '''Cannabinoids'''
-A study published in 2012 show that the synthetic analogue of the phytocannabinoid Tetrahydrocannabivarin (THCV), Δ<sup>8</sup>-Tetrahydrocannabivarin (Δ<sup>8</sup>-THCV) and its metabolite 11-OH-Δ<sup>8</sup>-THCV, prevent hepatic ischaemia/reperfusion injury by decreasing oxidative stress and inflammatory responses through cannabinoid CB2 receptors and thereby decrease tissue injury and inflammation with a protective effect against liver damage. Pretreatment with a CB2 receptor antagonist attenuated the protective effects of Δ<sup>8</sup>-THCV, while a CB1 antagonist tended to enhance it.
-An earlier study published in 2011 found, that Cannabidiol (CBD) also protects against hepatic ischemia/reperfusion injury by attenuating inflammatory signaling and response of oxidative and nitrative stress, and thereby cell death and tissue injury, but independent from classical CB1 and CB2 receptors.
-<br />
-==References==
-{{reflist|2}}
-{{Reperfusion injury}}
 [[Category:Physiology]]