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Latest revision as of 05:12, 20 February 2021

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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+{{Reperfusion injury}}
+{{CMG}} {{AE}} {{Shivam Singla}}
-'''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 [2]]]
 ==Overview==
 '''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.
+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
 ==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 [[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]].
-=== Mainly divided into 2 phases ===
-) [[Ischemia|Ischemi]]<nowiki/>c phase
-) [[Reperfusion|Reperfusio]]<nowiki/>n Phase
-=== Ischemic Phase ===
-[[File:Reperfusion Injury ( Ischemic Phase).jpg|thumb|524x524px|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]].
-*[[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]].
-* 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]]
-*[[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.
-**Transcription factors
-***[[Activating protein-1]] ([[AP-1 (transcription factor)|AP-1]])
-***Hypoxia-inducible factor-1 (HIF-1) which in turn activates transcription of VEGF, [[Erythropoietin]] and [[Glucose transporter|Glucose transporter-1]]
-***Nuclear factor-kappa b ([[NF-kB|NF-kb]])
-***Activation of NF-kb occurs during both the [[Ischemia|ischemic]] and [[reperfusion]] phases
-<br />
-=== Reperfusion Phase ===
-==== Reactive oxygen species ====
-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 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 (OH<sup>•</sup>). This OH ion causes the  peroxidation lipids in the cell membranes resulting in the production and release of proinflammatory eicosanoids and ultimately cell death.
-[[File:Reperfusion Injury Mech.jpg|thumb|325x325px|Reperfusion Injury]]
-During the Ischemia reperfusion injury ROS also activate endothelial cells, which further produces numerous adhesion molecules
-* E-selectin
-* VCAM-1 (vascular cell adhesion molecule-1)
-* ICAM-1 (intercellular adhesion molecule-1)
-* EMLMl Am -1 ( endothelial-leukocyte adhesion molecule)
-* PAi-1 (plasminogen activator inhibitor-1 ), and
-* interleukin-8 (il-8)
-==== Eicosanoids ====
-ROS causes lipid peroxidation of cell membranes resulting in release of
-* ''Arachidonic acid (substrate for prostaglandins)''
-** Prostaglandins usually have a 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.
-* ''Thromboxane''
-** 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 pressure and a subsequent increase in pulmonary microvascular permeability.
-* ''Leukotrienes''
-** Leukotrienes are also synthesized from arachidonic acid. Leukotrienes acts directly in the endothelial cells and smooth muscle and indirectly on the neutrophils. The 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.
-==== Nitric oxide ====
-Nitric oxide (NO) is a signalling molecule synthesised from L-arginine by the nitric oxide synthase enzyme (NOS) of which there are three types, constitutive (CNOS), inducible (INO S) and endothelial (ENO S). An initial surge in NO level in the first 15 minutes of the ischaemic phase is due to transient ENOS activation. This is followed during early reperfusion by a general decline in endothelial function and loss of functional ENOS, so that NO production falls, along with an increased production of reactive oxygen species. ENOS-derived NO is also necessary for the maintenance of vascular tone. The reduction in ENOS levels that occurs in IRI may therefore predispose to vasoconstriction, a common response seen in IRI. The second surge in NO production is largely due to cytokin-emediated up-regulation of INOS after about three hours of reperfusion.
-The pathophysiological role of nitric oxide in reperfusion injury is variable, being dependent on the nature of its generation and appears to be tissue specific. In some instances, NO acts as an anti-oxidant and, in others, combines with the superoxide anion to form the peroxynitrite radical, a potent promoter of lipid peroxidation and hence cellular membrane disruption (Reviewed in<sup>13</sup>). Manipulation of nitric oxide production during IRI, using a range of techniques, has recently provided considerable evidence for a principal role for nitric oxide in the aetiology of IRI. Myocardial IRI has been well studied, with paradoxical results, where low doses of no were found to be protective and high doses harmful. The influence of NO in skeletal muscle IRI has been less well characterized, with some studies suggesting that NO may potentiate cytotoxicity and others suggesting a beneficial role for NO in extremity IRI. In skeletal muscle IRI, NO production may be deleterious and inhibition of NOS activity using a non-specific NOS inhibitor greatly reduced the severity of muscle damage.<sup>14</sup>
-The assessment of experimental data derived from pharmacological NOS inhibition is difficult due to the non-specificity of NOS inhibitors; administration of these inhibitors at differing times during the injury merely adds to the complexity. In essence, augmentation of NO delivery may be beneficial with respect to protection, particularly in the ischaemic and early reperfusion phase. Inhibition of the INOS-induced surge in NO production at later times during reperfusion also mediates defense against IRI-induced tissue damage. However, in the clinical setting, systemic distortion of NO kinetics by administering NOS inhibitors would be likely to induce wide-ranging physiological disturbances. Further investigations will be needed to define a role for NOS inhibition in ameliorating the severity of IRI and local administration of these inhibitors may be required.
-**
 ==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]]
 ==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]].
+[[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==
-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'''
-**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. 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.
-* '''Hydrogen sulfide treatment'''
-**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.
-* '''Cyclosporin'''
-**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.
-**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.
-**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.
-* '''Stem cell therapy'''
-**Recent investigations suggest a possible beneficial effect of mesenchymal stem cells on heart and kidney reperfusion injury
-* '''Superoxide dismutase'''
+* Prevent generation of [[free radicals]]( Oxidative stress) or Increase the [[Tissue (biology)|tissue's]] capacity to trap the [[free radicals]]
-**Superoxide dismutase is an important antioxidant enzyme that transforms superoxide anions to water and hydrogen peroxide. Recent work has demonstrated important therapeutic effects on pre-clinical models of reperfusion damage following an ischemic stroke .
+* Controlling the [[neutrophil]] activation and [[Infiltration (medical)|infiltration]] of [[Ischemic|ischemic tissue]]
+* [[Hypoxic]] [[pre-conditioning]]
-* '''Metformin'''
+[[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]].
-**A series of 2009 studies published in the Journal of Cardiovascular Pharmacology indicate that metformin may prevent injury to cardiac reperfusion by inhibiting Mitochondrial Complex I and opening up MPT pore and in rats.
-* '''Cannabinoids'''
+==Future or Investigational therapies==
-**A research published in 2012 shows that the synthetic analog of phytocannabinoid tetrahydrocannabivarin (THCV), 8-Tetrahydrocannabivarin (THCV) and its 11-OH-8-THCV metabolite prevents hepatic ischemia / reperfusion injury by minimizing oxidative stress and inflammatory reactions through cannabinoid CB2 receptors, thereby lowering tissue damage and protective effects of inflammation. Pretreatment with a CB2 receptor antagonist, whereas a CB1 antagonist appeared to strengthen it, attenuated the defensive effects of somewhere else.
+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]].
-**An earlier study published in 2011 found that cannabidiol (CBD) also protects against hepatic ischemia/reperfusion injury by attenuating inflammatory signals and oxidative and nitrative stress response, resulting in cell death and tissue damage, but is independent of classic CB1 and CB2 receptors. <br />
+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.
-==References==
 [[Category:Physiology]]
 [[Category:Neurotrauma]]