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{{short description|Tissue damage after return of blood supply following ischemia or hypoxia}}
{{Short description|Tissue damage after return of blood supply following ischemia or hypoxia}}
{{Infobox medical condition (new)
{{Infobox medical condition (new)
| name = Reperfusion injury
| name = Reperfusion injury
| synonyms = '''Reperfusion insult'''
| synonyms = '''Reperfusion insult'''
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| image = Ischemic preconditioning of the heart.png
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| caption = Native records of contractile activity of the left ventricle of isolated rat heart perfused under [[Langendorff heart|Langendorff technique]]. Curve A - contractile function of the heart is greatly depressed after [[ischemia]]-reperfusion. Curve B - a set of short ischemic episodes ([[ischemic preconditioning]]) before prolonged ischemia provides functional recovery of contractile activity of the heart at reperfusion.
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'''Reperfusion injury''', sometimes called '''ischemia-reperfusion injury''' ('''IRI''') or '''reoxygenation injury''', is the [[tissue (biology)|tissue]] damage caused when [[blood]] supply returns to tissue (''[[wikt:re-#Prefix|re-]]'' + ''[[perfusion]]'') after a period of [[ischemia]] or lack of oxygen (anoxia or [[hypoxia (medical)|hypoxia]]). The absence of [[oxygen]] and [[nutrient]]s from blood during the ischemic period 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 (or along with) restoration of normal function.
'''Reperfusion injury''', sometimes called '''ischemia-reperfusion injury''' ('''IRI''') or '''reoxygenation injury''', is the [[tissue (biology)|tissue]] damage caused when [[blood]] supply returns to tissue (''[[wikt:re-#Prefix|re-]]'' + ''[[perfusion]]'') after a period of [[ischemia]] or lack of oxygen (anoxia or [[hypoxia (medical)|hypoxia]]). The absence of [[oxygen]] and [[nutrient]]s from blood during the ischemic period 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 (or along with) restoration of normal function.

Reperfusion injury is distinct from [[cerebral hyperperfusion syndrome]] (sometimes called "Reperfusion syndrome"), a state of abnormal cerebral vasodilation.


==Mechanisms==
==Mechanisms==
Reperfusion of ischemic tissues is often associated with microvascular injury, particularly due to increased permeability of capillaries and arterioles that lead to an increase of diffusion and fluid filtration across the tissues. Activated endothelial cells produce more [[reactive oxygen species]] but less [[nitric oxide]] following reperfusion, and the imbalance results in a subsequent inflammatory response.<ref>{{cite journal|last=Carden|first=DL|author2=Granger, DN |title=Pathophysiology of ischaemia-reperfusion injury.|journal=The Journal of Pathology|date=Feb 2000|volume=190|issue=3|pages=255–66|pmid=10685060|doi=10.1002/(SICI)1096-9896(200002)190:3<255::AID-PATH526>3.0.CO;2-6}}</ref>
Reperfusion of ischemic tissues is often associated with microvascular injury, particularly due to increased permeability of capillaries and arterioles that lead to an increase of diffusion and fluid filtration across the tissues. Activated endothelial cells produce more [[reactive oxygen species]] but less [[nitric oxide]] following reperfusion, and the imbalance results in a subsequent inflammatory response.<ref>{{cite journal |last1=Carden |first1=Donna L. |last2=Granger |first2=D. Neil |title=Pathophysiology of ischaemia-reperfusion injury |journal=The Journal of Pathology |date=February 2000 |volume=190 |issue=3 |pages=255–266 |doi=10.1002/(SICI)1096-9896(200002)190:3<255::AID-PATH526>3.0.CO;2-6 |pmid=10685060 |s2cid=37383438 |doi-access=free }}</ref>
The [[inflammatory response]] is partially responsible for the damage of reperfusion injury. [[White blood cell]]s, carried to the area by the newly returning blood, release a host of [[cytokine|inflammatory factors]] such as [[interleukin]]s as well as [[reactive oxygen species|free radicals]] in response to tissue damage.<ref name="WMClark">{{cite web | last = Clark | first = Wayne M. | title = Reperfusion Injury in Stroke | work = eMedicine | publisher = WebMD | date = January 5, 2005 | url = http://www.emedicine.com/neuro/topic602.htm | accessdate = 2006-08-09 }}</ref> The restored blood flow reintroduces oxygen within [[cell (biology)|cell]]s that damages cellular [[protein]]s, [[DNA]], and the [[plasma membrane]]. Damage to the cell's membrane may in turn cause the release of more free radicals. Such reactive species may also act indirectly in [[redox signaling]] to turn on [[apoptosis]]. White blood cells may also bind to the [[endothelium]] of small [[capillary|capillaries]], obstructing them and leading to more ischemia.<ref name="WMClark" />
The [[inflammatory response]] is partially responsible for the damage of reperfusion injury. [[White blood cell]]s, carried to the area by the newly returning blood, release a host of [[cytokine|inflammatory factors]] such as [[interleukin]]s as well as [[reactive oxygen species|free radicals]] in response to tissue damage.<ref name="WMClark">{{EMedicine|article|1162437|Reperfusion Injury in Stroke}}</ref> The restored blood flow reintroduces oxygen within [[cell (biology)|cell]]s that damages cellular [[protein]]s, [[DNA]], and the [[plasma membrane]]. Damage to the cell's membrane may in turn cause the release of more free radicals. Such reactive species may also act indirectly in [[redox signaling]] to turn on [[apoptosis]]. White blood cells may also bind to the [[endothelium]] of small [[capillary|capillaries]], obstructing them and leading to more ischemia.<ref name="WMClark" />
Another hypothesis would be that normally, tissues contain free radical scavengers to avoid damage by oxidizing species normally contained in the blood. Ischemic tissue would have decreased function of these scavengers because of cell injury. Once blood flow is reestablished, oxygen species contained in the blood will damage the ischemic tissue because the function of the scavengers is decreased.


Reperfusion injury plays a major part in the biochemistry of [[ischemic cascade|hypoxic brain injury in stroke]]. Similar failure processes are involved in brain failure following reversal of [[cardiac arrest]];<ref>{{cite web| last = Crippen| first = David| title = Brain Failure and Brain Death: Introduction| work = Scientific American Surgery, Critical Care, April 2005| url= http://www.sciamsurgery.com/sciamsurgery/institutional/payPerAdd.action?chapterId=part08_ch10| accessdate = 2007-01-09}}</ref> control of these processes is the subject of ongoing research. Repeated bouts of ischemia and reperfusion injury also are thought to be a factor leading to the formation and failure to [[wound healing|heal]] of [[chronic wound]]s such as [[pressure sore]]s and [[diabetic foot ulcer]].<ref name="TMustoe">{{cite journal | author=Mustoe T. | title=Understanding chronic wounds: a unifying hypothesis on their pathogenesis and implications for therapy | journal=American Journal of Surgery | volume=187 | issue=5A | year=2004 | pages=65S–70S | pmid=15147994 | doi=10.1016/S0002-9610(03)00306-4}}</ref> Continuous pressure limits blood supply and causes ischemia, and the inflammation occurs during reperfusion. As this process is repeated, it eventually damages tissue enough to cause a [[wound]].<ref name="TMustoe" />
Reperfusion injury plays a major part in the biochemistry of [[ischemic cascade|hypoxic brain injury in stroke]]. Similar failure processes are involved in brain failure following reversal of [[cardiac arrest]];<ref>{{cite book |last1=Hendry |first1=Robert |last2=Crippen |first2=David |chapter=Brain failure and brain death |pages=1609–1612 |editor1-last=Fink |editor1-first=Mitchell P. |editor2-last=Jurkovic |editor2-first=Gregory J. |title=ACS Surgery: Principles and Practice |date=2007 |publisher=B C Decker |isbn=978-1-55009-399-5 }}</ref> control of these processes is the subject of ongoing research. Repeated bouts of ischemia and reperfusion injury also are thought to be a factor leading to the formation and failure to [[wound healing|heal]] of [[chronic wound]]s such as [[pressure sore]]s and [[diabetic foot ulcer]].<ref name="TMustoe">{{cite journal |last1=Mustoe |first1=Thomas |title=Understanding chronic wounds: a unifying hypothesis on their pathogenesis and implications for therapy |journal=The American Journal of Surgery |date=May 2004 |volume=187 |issue=5 |pages=S65–S70 |doi=10.1016/S0002-9610(03)00306-4 |pmid=15147994 }}</ref> Continuous pressure limits blood supply and causes ischemia, and the inflammation occurs during reperfusion. As this process is repeated, it eventually damages tissue enough to cause a [[wound]].<ref name="TMustoe" />


The main reason for the acute phase of ischemia-reperfusion injury is oxygen deprivation and, therefore, arrest of generation of [[Adenosine triphosphate|ATP]] (cellular energy currency) by mitochondria [[oxidative phosphorylation]]. Tissue damage due to the general energy deficit during ischemia is followed by reperfusion (increase of oxygen level) when the injury is enhanced. [[Mitochondrial complex I]] is thought to be the most vulnerable enzyme to tissue ischemia/reperfusion but the mechanism of damage is different in different tissues. For example brain ischemia/reperfusion injury is mediated via complex I redox-dependent inactivation.<ref>{{cite journal |last1=Galkin |first1=A |title=Brain Ischemia/Reperfusion Injury and Mitochondrial Complex I Damage. |journal=Biochemistry. Biokhimiia |date=November 2019 |volume=84 |issue=11 |pages=1411–1423 |doi=10.1134/S0006297919110154 |pmid=31760927 |s2cid=207990089 }}</ref> It was found that lack of oxygen leads to conditions in which mitochondrial complex I loses its natural cofactor, [[flavin mononucleotide]] (FMN) and become inactive.<ref name="Stepanova Sosunov Niatsetskaya et al 2019">{{cite journal |last1=Stepanova |first1=Anna |last2=Sosunov |first2=Sergey |last3=Niatsetskaya |first3=Zoya |last4=Konrad |first4=Csaba |last5=Starkov |first5=Anatoly A. |last6=Manfredi |first6=Giovanni |last7=Wittig |first7=Ilka |last8=Ten |first8=Vadim |last9=Galkin |first9=Alexander |title=Redox-Dependent Loss of Flavin by Mitochondrial Complex I in Brain Ischemia/Reperfusion Injury |journal=Antioxidants & Redox Signaling |date=20 September 2019 |volume=31 |issue=9 |pages=608–622 |doi=10.1089/ars.2018.7693 |pmid=31037949 |pmc=6657304 }}</ref> When oxygen is present the enzyme catalyzes a physiological reaction of [[Nicotinamide adenine dinucleotide|NADH]] oxidation by [[Coenzyme Q10|ubiquinone]], supplying electrons downstream of the [[Electron transport chain|respiratory chain]] (complexes III and IV). Ischemia leads to dramatic increase of [[Succinic acid|succinate]] level.<ref>{{cite journal |last1=Sahni |first1=Prateek V |last2=Zhang |first2=Jimmy |last3=Sosunov |first3=Sergey |last4=Galkin |first4=Alexander |last5=Niatsetskaya |first5=Zoya |last6=Starkov |first6=Anatoly |last7=Brookes |first7=Paul S |last8=Ten |first8=Vadim S |title=Krebs cycle metabolites and preferential succinate oxidation following neonatal hypoxic-ischemic brain injury in mice |journal=Pediatric Research |date=February 2018 |volume=83 |issue=2 |pages=491–497 |doi=10.1038/pr.2017.277 |pmid=29211056 |pmc=5866163 }}</ref> In the presence of succinate mitochondria catalyze reverse electron [[Reverse electron flow|transfer]] so that fraction of electrons from succinate is directed upstream to FMN of complex I.<ref name="Stepanova Kahl Konrad et al 2017">{{cite journal |last1=Stepanova |first1=Anna |last2=Kahl |first2=Anja |last3=Konrad |first3=Csaba |last4=Ten |first4=Vadim |last5=Starkov |first5=Anatoly S |last6=Galkin |first6=Alexander |title=Reverse electron transfer results in a loss of flavin from mitochondrial complex I: Potential mechanism for brain ischemia reperfusion injury |journal=Journal of Cerebral Blood Flow & Metabolism |date=December 2017 |volume=37 |issue=12 |pages=3649–3658 |doi=10.1177/0271678X17730242 |pmid=28914132 |pmc=5718331 }}</ref> Reverse electron transfer results in a reduction of complex I FMN, increased generation of ROS, followed by a loss of the reduced cofactor (FMNH<sub>2</sub>) and impairment of mitochondria energy production.<ref name="Stepanova Kahl Konrad et al 2017"/> The FMN loss by complex I and I/R injury can be alleviated by the administration of FMN precursor, riboflavin.<ref name="Stepanova Sosunov Niatsetskaya et al 2019"/>
In prolonged ischemia (60 minutes or more), [[hypoxanthine]] is formed as a breakdown product of [[Adenosine triphosphate|ATP]] metabolism. The enzyme ''[[xanthine dehydrogenase]]'' acts in reverse, that is as a ''[[xanthine oxidase]]'' as a result of the higher availability of oxygen. This oxidation results in molecular oxygen being converted into highly reactive [[superoxide]] and [[hydroxyl]] [[Radical (chemistry)|radicals]]. Xanthine oxidase also produces [[uric acid]], which may act as both a prooxidant and as a scavenger of reactive species such as peroxynitrite. Excessive [[nitric oxide]] produced during reperfusion reacts with [[superoxide]] to produce the potent reactive species [[peroxynitrite]]. Such radicals and reactive oxygen species attack cell membrane lipids, proteins, and glycosaminoglycans, causing further damage. They may also initiate specific biological processes by [[redox signaling]].


Reperfusion can cause [[hyperkalemia]].<ref name="Atlee2007">{{cite book|author=John L. Atlee|title=Complications in anesthesia|url=https://books.google.com/books?id=qVdr5MVok1YC&pg=PA55|accessdate=25 July 2010|year=2007|publisher=Elsevier Health Sciences|isbn=978-1-4160-2215-2|pages=55–}}</ref>
Reperfusion can cause [[hyperkalemia]].<ref name="Atlee2007">{{cite book |last1=Atlee |first1=John L. |title=Complications in Anesthesia |date=2007 |publisher=Elsevier Health Sciences |isbn=978-1-4160-2215-2 |pages=55– |url=https://books.google.com/books?id=qVdr5MVok1YC&pg=PA55 }}</ref>


Reperfusion injury is a primary concern in [[liver transplantation]] surgery.<ref name="Lemasters1997">{{cite journal | author=Lemasters JJ. | title=Reperfusion injury after liver preservation for transplantation | journal= Annual Review of Pharmacology and Toxicology | pmid=9131256 | doi=10.1146/annurev.pharmtox.37.1.327 | volume=37 | year=1997 | pages=327–38}}</ref>
Reperfusion injury is a primary concern in [[liver transplantation]] surgery.<ref name="Lemasters1997">{{cite journal |last1=Lemasters and |first1=John J. |last2=Thurman |first2=Ronald G. |title=Reperfusion injury after liver preservation for transplantation |journal=Annual Review of Pharmacology and Toxicology |date=April 1997 |volume=37 |issue=1 |pages=327–338 |doi=10.1146/annurev.pharmtox.37.1.327 |pmid=9131256 }}</ref>


==Treatment==
==Treatment==
{{Main|Reperfusion therapy}}
{{Main|Reperfusion therapy}}
⚫
[[File:Ischemic preconditioning of the heart.png|thumb|300px| Native records of contractile activity of the left ventricle of isolated rat heart perfused under [[Langendorff heart|Langendorff technique]]. Curve A - contractile function of the heart is greatly depressed after [[ischemia]]-reperfusion. Curve B - a set of short ischemic episodes ([[ischemic preconditioning]]) before prolonged ischemia provides functional recovery of contractile activity of the heart at reperfusion.]]

A study of [[aortic cross-clamping]], a common procedure in [[cardiac surgery]], demonstrated a strong potential benefit with further research ongoing.{{Citation needed|date=June 2008}}


===Therapeutic hypothermia===
===Therapeutic hypothermia===
{{See also|Hypothermia therapy for neonatal encephalopathy}}
An intriguing area of research demonstrates the ability of a reduction in body temperature to limit ischemic injuries. This procedure is called [[therapeutic hypothermia]], and it has been shown by a number of large, high-quality randomised trials to significantly improve survival and reduce brain damage after birth asphyxia in newborn infants, almost doubling the chance of normal survival. For a full review see [[Hypothermia therapy for neonatal encephalopathy]].


However, the therapeutic effect of hypothermia does not confine itself to metabolism and membrane stability. Another school of thought focuses on hypothermia's ability to prevent the injuries that occur after circulation returns to the brain, or what is termed [[wikt:reperfusion|reperfusion]] injuries. In fact an individual suffering from an ischemic insult continues suffering injuries well after circulation is restored. In rats it has been shown that neurons often die a full 24 hours after blood flow returns. Some theorize that this delayed reaction derives from the various inflammatory immune responses that occur during reperfusion.<ref name="Newsweek">Adler, Jerry. "Back From the Dead." Newsweek. July 23, 2007.</ref> These inflammatory responses cause intracranial pressure, pressure which leads to cell injury and in some situations cell death. Hypothermia has been shown to help moderate intracranial pressure and therefore to minimize the harmful effect of a patient's inflammatory immune responses during reperfusion. Beyond this, reperfusion also increases free radical production. Hypothermia too has been shown to minimize a patient's production of deadly [[free radicals]] during reperfusion. Many now suspect it is because hypothermia reduces both intracranial pressure and free radical production that hypothermia improves patient outcome following a blockage of blood flow to the brain.<ref name="pmid14767591">{{cite journal |vauthors = Polderman KH |title = Application of therapeutic hypothermia in the ICU: opportunities and pitfalls of a promising treatment modality. Part 1: Indications and evidence |journal = Intensive Care Med |volume = 30 |issue = 4 |pages = 556–75 |year = 2004 |pmid = 14767591 |doi = 10.1007/s00134-003-2152-x }}</ref>
However,{{clarify|reason=Did something get chopped off here?|date=October 2022}} the therapeutic effect of hypothermia does not confine itself to metabolism and membrane stability. Another school of thought focuses on hypothermia's ability to prevent the injuries that occur after circulation returns to the brain, or what is termed [[wikt:reperfusion|reperfusion]] injuries. In fact an individual suffering from an ischemic insult continues suffering injuries well after circulation is restored. In rats it has been shown that neurons often die a full 24 hours after blood flow returns. Some theorize that this delayed reaction derives from the various inflammatory immune responses that occur during reperfusion.<ref name="Newsweek">{{cite news |title=Back to Life: The Science of Reviving the Dead |url=https://www.newsweek.com/back-life-science-reviving-dead-104449 |work=Newsweek |date=22 July 2007 }}</ref> These inflammatory responses cause intracranial pressure, pressure which leads to cell injury and in some situations cell death. Hypothermia has been shown to help moderate intracranial pressure and therefore to minimize the harmful effect of a patient's inflammatory immune responses during reperfusion. Beyond this, reperfusion also increases free radical production. Hypothermia too has been shown to minimize a patient's production of deadly [[free radicals]] during reperfusion. Many now suspect it is because hypothermia reduces both intracranial pressure and free radical production that hypothermia improves patient outcome following a blockage of blood flow to the brain.<ref name="pmid14767591">{{cite journal |last1=Polderman |first1=Kees H. |title=Application of therapeutic hypothermia in the ICU: opportunities and pitfalls of a promising treatment modality. Part 1: Indications and evidence |journal=Intensive Care Medicine |date=1 April 2004 |volume=30 |issue=4 |pages=556–575 |doi=10.1007/s00134-003-2152-x |pmid=14767591 |s2cid=5733761 }}</ref>


===Hydrogen sulfide treatment===
===Hydrogen sulfide treatment===
There are some preliminary studies in mice that seem to indicate that treatment with [[hydrogen sulfide]] (H<sub>2</sub>S) can have a protective effect against reperfusion injury.<ref>Elrod J.W., J.W. Calvert, M.R. Duranski, D.J. Lefer. "Hydrogen sulfide donor protects against acute myocardial ischemia-reperfusion injury." ''Circulation'' 114(18):II172, 2006.</ref>
There are some preliminary studies in mice that seem to indicate that treatment with [[hydrogen sulfide]] (H<sub>2</sub>S) can have a protective effect against reperfusion injury.<ref>{{cite journal |last1=Elrod |first1=John W |last2=Calvert |first2=John W |last3=Duranski |first3=Mark R |last4=Lefer |first4=David J |title=Abstract 947: Hydrogen Sulfide Donor Protects Against Acute Myocardial Ischemia-Reperfusion Injury |journal=Circulation |date=31 October 2006 |volume=114 |issue=suppl_18 |pages=II_172 |doi=10.1161/circ.114.suppl_18.II_172-a |doi-broken-date=31 January 2024 |url=https://www.ahajournals.org/doi/abs/10.1161/circ.114.suppl_18.II_172-a }}</ref>


===Cyclosporin===
===Cyclosporin===
In addition to its well-known immunosuppressive capabilities, the one-time administration of [[cyclosporin]] 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>{{cite journal |author1=Piot C. |author2=Croiselle P. |author3=Staat P. | year = 2008 | title = Effect of Cyclosporine on Reperfusion Injury in Acute Myocardial Infaction | url = https://semanticscholar.org/paper/ffcd2bf6ad8763956fc1015dd4610124bf213732| journal = New England Journal of Medicine| volume = 359 | issue = 5| pages = 473–481 | doi=10.1056/nejmoa071142|pmid=18669426 |display-authors=etal}}</ref>
In addition to its well-known immunosuppressive capabilities, the one-time administration of [[cyclosporin]] 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>{{cite journal |last1=Piot |first1=Christophe |last2=Croisille |first2=Pierre |last3=Staat |first3=Patrick |last4=Thibault |first4=Hélène |last5=Rioufol |first5=Gilles |last6=Mewton |first6=Nathan |last7=Elbelghiti |first7=Rachid |last8=Cung |first8=Thien Tri |last9=Bonnefoy |first9=Eric |last10=Angoulvant |first10=Denis |last11=Macia |first11=Christophe |last12=Raczka |first12=Franck |last13=Sportouch |first13=Catherine |last14=Gahide |first14=Gerald |last15=Finet |first15=Gérard |last16=André-Fouët |first16=Xavier |last17=Revel |first17=Didier |last18=Kirkorian |first18=Gilbert |last19=Monassier |first19=Jean-Pierre |last20=Derumeaux |first20=Geneviève |last21=Ovize |first21=Michel |title=Effect of Cyclosporine on Reperfusion Injury in Acute Myocardial Infarction |journal=New England Journal of Medicine |date=31 July 2008 |volume=359 |issue=5 |pages=473–481 |doi=10.1056/NEJMoa071142 |pmid=18669426 |doi-access=free }}</ref>


Cyclosporin 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="Javadov S. 2007" />
Cyclosporin 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="Javadov S. 2007" />


However, the studies CIRCUS and CYCLE (published in September 2015 and February 2016 respectively) looked at the use of cyclosporin as a one time IV dose given right before perfusion therapy (PCI). Both studies found there is no statistical difference in outcome with cyclosporin administration.<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 |display-authors = 6|title = Cyclosporine before PCI in Patients with Acute Myocardial Infarction |journal = New England Journal of Medicine|volume = 373 |issue = 11 |pages = 1021–31 |year = 2015 |pmid = 26321103 |doi = 10.1056/NEJMoa1505489|hdl = 10044/1/41761|url = http://spiral.imperial.ac.uk/bitstream/10044/1/41761/2/nejmoa1505489.pdf }}</ref><ref name="pmid26821623">{{cite journal |vauthors = Ottani F, Latini R, Staszewsky L, La Vecchia L, Locuratolo N, Sicuro M, Masson S, Barlera S, Milani V, Lombardi M, Costalunga A, Mollichelli N, Santarelli A, De Cesare N, Sganzerla P, Boi A, Maggioni AP, Limbruno U |title = Cyclosporine A in Reperfused Myocardial Infarction: The Multicenter, Controlled, Open-Label CYCLE Trial |journal = J. Am. Coll. Cardiol. |volume = 67 |issue = 4 |pages = 365–374 |year = 2016 |pmid = 26821623 |doi = 10.1016/j.jacc.2015.10.081 |doi-access = free }}</ref> Research is ongoing.
However, the studies CIRCUS and CYCLE (published in September 2015 and February 2016 respectively) looked at the use of cyclosporin as a one time IV dose given right before perfusion therapy (PCI). Both studies found there is no statistical difference in outcome with cyclosporin administration.<ref name="pmid26321103">{{cite journal |last1=Cung |first1=Thien-Tri |last2=Morel |first2=Olivier |last3=Cayla |first3=Guillaume |last4=Rioufol |first4=Gilles |last5=Garcia-Dorado |first5=David |last6=Angoulvant |first6=Denis |last7=Bonnefoy-Cudraz |first7=Eric |last8=Guérin |first8=Patrice |last9=Elbaz |first9=Meier |last10=Delarche |first10=Nicolas |last11=Coste |first11=Pierre |last12=Vanzetto |first12=Gerald |last13=Metge |first13=Marc |last14=Aupetit |first14=Jean-François |last15=Jouve |first15=Bernard |last16=Motreff |first16=Pascal |last17=Tron |first17=Christophe |last18=Labeque |first18=Jean-Noel |last19=Steg |first19=Philippe Gabriel |last20=Cottin |first20=Yves |last21=Range |first21=Grégoire |last22=Clerc |first22=Jérome |last23=Claeys |first23=Marc J. |last24=Coussement |first24=Patrick |last25=Prunier |first25=Fabrice |last26=Moulin |first26=Frédéric |last27=Roth |first27=Olivier |last28=Belle |first28=Loïc |last29=Dubois |first29=Philippe |last30=Barragan |first30=Paul |last31=Gilard |first31=Martine |last32=Piot |first32=Christophe |last33=Colin |first33=Patrice |last34=De Poli |first34=Fabien |last35=Morice |first35=Marie-Claude |last36=Ider |first36=Omar |last37=Dubois-Randé |first37=Jean-Luc |last38=Unterseeh |first38=Thierry |last39=Le Breton |first39=Hervé |last40=Béard |first40=Thierry |last41=Blanchard |first41=Didier |last42=Grollier |first42=Gilles |last43=Malquarti |first43=Vincent |last44=Staat |first44=Patrick |last45=Sudre |first45=Arnaud |last46=Elmer |first46=Eskil |last47=Hansson |first47=Magnus J. |last48=Bergerot |first48=Cyrille |last49=Boussaha |first49=Inesse |last50=Jossan |first50=Claire |last51=Derumeaux |first51=Geneviève |last52=Mewton |first52=Nathan |last53=Ovize |first53=Michel |title=Cyclosporine before PCI in Patients with Acute Myocardial Infarction |journal=New England Journal of Medicine |date=10 September 2015 |volume=373 |issue=11 |pages=1021–1031 |doi=10.1056/NEJMoa1505489 |pmid=26321103 |hdl=10044/1/41761 |doi-access=free |hdl-access=free }}</ref><ref name="pmid26821623">{{cite journal |last1=Ottani |first1=Filippo |last2=Latini |first2=Roberto |last3=Staszewsky |first3=Lidia |last4=La Vecchia |first4=Luigi |last5=Locuratolo |first5=Nicola |last6=Sicuro |first6=Marco |last7=Masson |first7=Serge |last8=Barlera |first8=Simona |last9=Milani |first9=Valentina |last10=Lombardi |first10=Mario |last11=Costalunga |first11=Alessandra |last12=Mollichelli |first12=Nadia |last13=Santarelli |first13=Andrea |last14=De Cesare |first14=Nicoletta |last15=Sganzerla |first15=Paolo |last16=Boi |first16=Alberto |last17=Maggioni |first17=Aldo Pietro |last18=Limbruno |first18=Ugo |title=Cyclosporine A in Reperfused Myocardial Infarction |journal=Journal of the American College of Cardiology |date=February 2016 |volume=67 |issue=4 |pages=365–374 |doi=10.1016/j.jacc.2015.10.081 |pmid=26821623 |s2cid=205575155 |doi-access=free }}</ref>


Reperfusion leads to biochemical imbalances within the cell that lead to [[cellular death|cell death]] and increased infarct size. More specifically, [[Hypercalcaemia|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.<ref name="Javadov S. 2007">{{cite journal |author1=Javadov S. |author2=Karmazyn M. | year = 2007 | title = Mitochondrial Permeability Transition Pore Opening as an Endpoint to Initiate Cell Death and as a Putative Target for Cardioprotection | url = | journal = Cell Physiol Biochem | volume = 20 | issue = 1–4| pages = 1–22 | doi=10.1159/000103747|pmid=17595511 | doi-access = free }}</ref>
Reperfusion leads to biochemical imbalances within the cell that lead to [[cellular death|cell death]] and increased infarct size. More specifically, [[Hypercalcaemia|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.<ref name="Javadov S. 2007">{{cite journal |last1=Javadov |first1=Sabzali |last2=Karmazyn |first2=Morris |title=Mitochondrial Permeability Transition Pore Opening as an Endpoint to Initiate Cell Death and as a Putative Target for Cardioprotection |journal=Cellular Physiology and Biochemistry |date=2007 |volume=20 |issue=1–4 |pages=1–22 |doi=10.1159/000103747 |pmid=17595511 |s2cid=1949575 |doi-access=free }}</ref>


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 cardioprotective strategy.<ref name="Hausenloy D 2008">{{cite journal |author1=Hausenloy D. |author2=Yellon D.|author2-link=Derek M. Yellon | year = 2008 | title = Time to take myocardial reperfusion injury seriously | url = https://semanticscholar.org/paper/6a3d7e679f06ac369e9885f61228798e663f27cb| journal = New England Journal of Medicine| volume = 359 | issue = 5| pages = 518–520 | doi=10.1056/nejme0803746|pmid=18669431 }}</ref>
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 cardioprotective strategy.<ref name="Hausenloy D 2008">{{cite journal |last1=Hausenloy |first1=Derek J. |last2=Yellon |first2=Derek M. |title=Time to Take Myocardial Reperfusion Injury Seriously |journal=New England Journal of Medicine |date=31 July 2008 |volume=359 |issue=5 |pages=518–520 |doi=10.1056/NEJMe0803746 |pmid=18669431 }}</ref>


In 2008, an editorial in the New England Journal of Medicine called for more studies to determine if cyclosporin can become a treatment to ameliorate reperfusion injury by protecting mitochondria.<ref name="Hausenloy D 2008" /> To that end, in 2011 the researchers involved in the original 2008 NEJM study initiated a phase III clinical study of reperfusion injury in 1000 myocardial infarction patients in centers throughout Europe. Results of that study were announced in 2015 and indicated that "intravenous ciclosporin did not result in better clinical outcomes than those with placebo and did not prevent adverse left ventricular remodeling at 1 year".<ref name="pmid26321103"/>
In 2008, an editorial in the New England Journal of Medicine called for more studies to determine if cyclosporin can become a treatment to ameliorate reperfusion injury by protecting mitochondria.<ref name="Hausenloy D 2008" /> To that end, in 2011 the researchers involved in the original 2008 NEJM study initiated a phase III clinical study of reperfusion injury in 1000 myocardial infarction patients in centers throughout Europe. Results of that study were announced in 2015 and indicated that "intravenous cyclosporine did not result in better clinical outcomes than those with placebo and did not prevent adverse left ventricular remodeling at 1 year."<ref name="pmid26321103"/>
This same process of mitochondrial destruction through the opening of the MPT pore is implicated in making [[traumatic brain injuries]] much worse.<ref name="pmid21142667">{{cite journal |vauthors = Sullivan PG, Sebastian AH, Hall ED |title = Therapeutic window analysis of the neuroprotective effects of cyclosporine A after traumatic brain injury |journal=J. Neurotrauma |volume = 28 |issue = 2 |pages = 311–8 |year = 2011 |pmid = 21142667 |pmc = 3037811 |doi = 10.1089/neu.2010.1646 }}</ref> Ciclosporin 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.
This same process of mitochondrial destruction through the opening of the MPT pore is implicated in making [[traumatic brain injuries]] much worse.<ref name="pmid21142667">{{cite journal |last1=Sullivan |first1=Patrick G. |last2=Sebastian |first2=Andrea H. |last3=Hall |first3=Edward D. |title=Therapeutic Window Analysis of the Neuroprotective Effects of Cyclosporine A after Traumatic Brain Injury |journal=Journal of Neurotrauma |date=February 2011 |volume=28 |issue=2 |pages=311–318 |doi=10.1089/neu.2010.1646 |pmid=21142667 |pmc=3037811 }}</ref>


===TRO40303===
===TRO40303===


TRO40303 is a new cardioprotective 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=" pmid = 24507657 ">{{cite journal | author = Le Lamer S | title = Translation of TRO40303 from myocardial infarction models to demonstration of safety and tolerance in a randomized Phase I trial. | journal = J Transl Med | volume = 12 | issue = |date=Feb 2014 | pmid = 24507657 | doi = 10.1186/1479-5876-12-38 | pmc=3923730 | pages=38}}</ref>
TRO40303 is a new cardioprotective 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>{{cite journal |last1=Le Lamer |first1=Sophie |last2=Paradis |first2=Stéphanie |last3=Rahmouni |first3=Hidayat |last4=Chaimbault |first4=Corinne |last5=Michaud |first5=Magali |last6=Culcasi |first6=Marcel |last7=Afxantidis |first7=Jean |last8=Latreille |first8=Mathilde |last9=Berna |first9=Patrick |last10=Berdeaux |first10=Alain |last11=Pietri |first11=Sylvia |last12=Morin |first12=Didier |last13=Donazzolo |first13=Yves |last14=Abitbol |first14=Jean-Louis |last15=Pruss |first15=Rebacca M |last16=Schaller |first16=Sophie |title=Translation of TRO40303 from myocardial infarction models to demonstration of safety and tolerance in a randomized Phase I trial |journal=Journal of Translational Medicine |date=December 2014 |volume=12 |issue=1 |pages=38 |doi=10.1186/1479-5876-12-38 |pmid=24507657 |pmc=3923730 |doi-access=free }}</ref>


===Stem cell therapy===
===Stem cell therapy===


Recent investigations suggest a possible beneficial effect of [[mesenchymal stem cells]] on heart and kidney reperfusion injury.<ref name=" pmid = 21498423 ">{{cite journal | author = van der Spoel TI | 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 |date=Sep 2011 | pmid = 21498423 | pages = 649–58 | doi=10.1093/cvr/cvr113| doi-access = free }}</ref><ref name=" pmid = 24220681">{{cite journal | author = Zhao JJ | title = Protection of mesenchymal stem cells on acute kidney injury. | journal = Mol Med Rep | volume = 9 | issue = 1|date=Jan 2014 | pmid = 24220681 | url = http://www.spandidos-publications.com/mmr/9/1/91 | pages = 91–96 | doi=10.3892/mmr.2013.1792| doi-access = free }}</ref>
Recent investigations suggest a possible beneficial effect of [[mesenchymal stem cells]] on heart and kidney reperfusion injury.<ref>{{cite journal |last1=van der Spoel |first1=T. I. G. |last2=Jansen of Lorkeers |first2=S. J. |last3=Agostoni |first3=P. |last4=van Belle |first4=E. |last5=Gyongyosi |first5=M. |last6=Sluijter |first6=J. P. G. |last7=Cramer |first7=M. J. |last8=Doevendans |first8=P. A. |last9=Chamuleau |first9=S. A. J. |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=Cardiovascular Research |date=1 September 2011 |volume=91 |issue=4 |pages=649–658 |doi=10.1093/cvr/cvr113 |pmid=21498423 |doi-access=free }}</ref><ref>{{cite journal |last1=Zhao |first1=Jing-Jie |last2=Liu |first2=Jun-Li |last3=Liu |first3=Ling |last4=Jia |first4=Hong-Ying |title=Protection of mesenchymal stem cells on acute kidney injury |journal=Molecular Medicine Reports |date=January 2014 |volume=9 |issue=1 |pages=91–96 |doi=10.3892/mmr.2013.1792 |pmid=24220681 |doi-access=free }}</ref>


=== Superoxide dismutase ===
=== 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.<ref>{{Cite journal|last=Jiang|first=Yuhang|last2=Arounleut|first2=Phonepasong|last3=Rheiner|first3=Steven|last4=Bae|first4=Younsoo|last5=Kabanov|first5=Alexander V.|last6=Milligan|first6=Carol|last7=Manickam|first7=Devika S.|date=2016-06-10|title=SOD1 nanozyme with reduced toxicity and MPS accumulation|journal=Journal of Controlled Release|series=Thirteenth International Nanomedicine and Drug Delivery Symposium|volume=231|pages=38–49|doi=10.1016/j.jconrel.2016.02.038|pmid=26928528}}</ref><ref>{{Cite journal|last=Jiang|first=Yuhang|last2=Brynskikh|first2=Anna M.|last3=S-Manickam|first3=Devika|last4=Kabanov|first4=Alexander V.|date=2015-09-10|title=SOD1 nanozyme salvages ischemic brain by locally protecting cerebral vasculature|journal=Journal of Controlled Release|volume=213|pages=36–44|doi=10.1016/j.jconrel.2015.06.021|pmc=4684498|pmid=26093094}}</ref>
[[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.<ref>{{Cite journal|last1=Jiang|first1=Yuhang|last2=Arounleut|first2=Phonepasong|last3=Rheiner|first3=Steven|last4=Bae|first4=Younsoo|last5=Kabanov|first5=Alexander V.|last6=Milligan|first6=Carol|last7=Manickam|first7=Devika S.|date=2016-06-10|title=SOD1 nanozyme with reduced toxicity and MPS accumulation|journal=Journal of Controlled Release|series=Thirteenth International Nanomedicine and Drug Delivery Symposium|volume=231|pages=38–49|doi=10.1016/j.jconrel.2016.02.038|pmid=26928528}}</ref><ref>{{Cite journal|last1=Jiang|first1=Yuhang|last2=Brynskikh|first2=Anna M.|last3=S-Manickam|first3=Devika|last4=Kabanov|first4=Alexander V.|date=2015-09-10|title=SOD1 nanozyme salvages ischemic brain by locally protecting cerebral vasculature|journal=Journal of Controlled Release|volume=213|pages=36–44|doi=10.1016/j.jconrel.2015.06.021|pmc=4684498|pmid=26093094}}</ref>


=== Metformin ===
=== Metformin ===
A series of 2009 studies published in the Journal of Cardiovascular Pharmacology suggest that [[Metformin]] may prevent cardiac reperfusion injury by inhibition of [[Electron transport chain|Mitochondrial Complex I]] and the opening of MPT pore and in rats.<ref>{{Cite journal|last=Paiva|first=Marta|last2=Riksen|first2=Niels P.|last3=Davidson|first3=Sean M.|last4=Hausenloy|first4=Derek J.|last5=Monteiro|first5=Pedro|last6=Gonçalves|first6=Lino|last7=Providência|first7=Luís|last8=Rongen|first8=Gerard A.|last9=Smits|first9=Paul|date=2009-05-01|title=Metformin prevents myocardial reperfusion injury by activating the adenosine receptor|journal=Journal of Cardiovascular Pharmacology|volume=53|issue=5|pages=373–378|doi=10.1097/FJC.0b013e31819fd4e7|issn=1533-4023|pmid=19295441}}</ref><ref>{{Cite journal|last=Bhamra|first=Gurpreet S.|last2=Hausenloy|first2=Derek J.|last3=Davidson|first3=Sean M.|last4=Carr|first4=Richard D.|last5=Paiva|first5=Marta|last6=Wynne|first6=Abigail M.|last7=Mocanu|first7=Mihaela M.|last8=Yellon|first8=Derek M.|date=2008-05-01|title=Metformin protects the ischemic heart by the Akt-mediated inhibition of mitochondrial permeability transition pore opening|journal=Basic Research in Cardiology|volume=103|issue=3|pages=274–284|doi=10.1007/s00395-007-0691-y|issn=0300-8428|pmid=18080084}}</ref>
A series of 2009 studies published in the Journal of Cardiovascular Pharmacology suggest that [[Metformin]] may prevent cardiac reperfusion injury by inhibition of [[Electron transport chain|Mitochondrial Complex I]] and the opening of MPT pore and in rats.<ref>{{cite journal |last1=Paiva |first1=Marta |last2=Riksen |first2=Niels P |last3=Davidson |first3=Sean M |last4=Hausenloy |first4=Derek J |last5=Monteiro |first5=Pedro |last6=Gonçalves |first6=Lino |last7=Providência |first7=Luís |last8=Rongen |first8=Gerard A |last9=Smits |first9=Paul |last10=Mocanu |first10=Mihaela M |last11=Yellon |first11=Derek M |title=Metformin Prevents Myocardial Reperfusion Injury by Activating the Adenosine Receptor |journal=Journal of Cardiovascular Pharmacology |date=May 2009 |volume=53 |issue=5 |pages=373–378 |doi=10.1097/FJC.0b013e31819fd4e7 |pmid=19295441 |s2cid=21161059 }}</ref><ref>{{cite journal |last1=Bhamra |first1=Gurpreet S. |last2=Hausenloy |first2=Derek J. |last3=Davidson |first3=Sean M. |last4=Carr |first4=Richard D. |last5=Paiva |first5=Marta |last6=Wynne |first6=Abigail M. |last7=Mocanu |first7=Mihaela M. |last8=Yellon |first8=Derek M. |title=Metformin protects the ischemic heart by the Akt-mediated inhibition of mitochondrial permeability transition pore opening |journal=Basic Research in Cardiology |date=May 2008 |volume=103 |issue=3 |pages=274–284 |doi=10.1007/s00395-007-0691-y |pmid=18080084 |s2cid=28815693 }}</ref>

=== Riboflavin ===
In neonatal in vivo model of brain ischemia/reperfusion, tissue injury can be alleviated by the administration of FMN precursor, riboflavin that prevents inactivation of mitochondrial complex I.<ref name="Stepanova Sosunov Niatsetskaya et al 2019"/><ref>{{cite journal |last1=Ten |first1=Vadim |last2=Galkin |first2=Alexander |title=Mechanism of mitochondrial complex I damage in brain ischemia/reperfusion injury. A hypothesis |journal=Molecular and Cellular Neuroscience |date=October 2019 |volume=100 |pages=103408 |doi=10.1016/j.mcn.2019.103408 |pmid=31494262 |s2cid=201835094 }}</ref>


=== Cannabinoids ===
=== Cannabinoids ===
A study published in 2012 show that the [[Synthetic cannabinoids|synthetic]] analogue of the [[Cannabinoid|phytocannabinoid]] [[Tetrahydrocannabivarin]] (THCV), Δ<sup>8</sup>-Tetrahydrocannabivarin (Δ<sup>8</sup>-THCV) and its [[metabolite]] 11-OH-Δ<sup>8</sup>-THCV, prevent [[Liver|hepatic]] [[Ischemia|ischaemia]]/reperfusion injury by decreasing [[oxidative stress]] and [[Inflammation|inflammatory]] responses through cannabinoid [[Cannabinoid receptor type 2|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 [[Cannabinoid receptor type 1|CB1]] [[Cannabinoid receptor antagonist|antagonist]] tended to enhance it.<ref>{{Cite journal|last=Bátkai|first=Sándor|last2=Mukhopadhyay|first2=Partha|last3=Horváth|first3=Bėla|last4=Rajesh|first4=Mohanraj|last5=Gao|first5=Rachel Y|last6=Mahadevan|first6=Anu|last7=Amere|first7=Mukkanti|last8=Battista|first8=Natalia|last9=Lichtman|first9=Aron H|date=2012|title=Δ8-Tetrahydrocannabivarin prevents hepatic ischaemia/reperfusion injury by decreasing oxidative stress and inflammatory responses through cannabinoid CB2 receptors|journal=British Journal of Pharmacology|volume=165|issue=8|pages=2450–2461|doi=10.1111/j.1476-5381.2011.01410.x|issn=0007-1188|pmc=3423240|pmid=21470208}}</ref>
A study published in 2012 show that the [[Synthetic cannabinoids|synthetic]] analogue of the [[Cannabinoid|phytocannabinoid]] [[Tetrahydrocannabivarin]] (THCV), Δ<sup>8</sup>-Tetrahydrocannabivarin (Δ<sup>8</sup>-THCV) and its [[metabolite]] 11-OH-Δ<sup>8</sup>-THCV, prevent [[Liver|hepatic]] [[Ischemia|ischaemia]]/reperfusion injury by decreasing [[oxidative stress]] and [[Inflammation|inflammatory]] responses through cannabinoid [[Cannabinoid receptor type 2|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 [[Cannabinoid receptor type 1|CB1]] [[Cannabinoid receptor antagonist|antagonist]] tended to enhance it.<ref>{{cite journal |last1=Bátkai |first1=Sándor |last2=Mukhopadhyay |first2=Partha |last3=Horváth |first3=Bėla |last4=Rajesh |first4=Mohanraj |last5=Gao |first5=Rachel Y |last6=Mahadevan |first6=Anu |last7=Amere |first7=Mukkanti |last8=Battista |first8=Natalia |last9=Lichtman |first9=Aron H |last10=Gauson |first10=Lisa A |last11=Maccarrone |first11=Mauro |last12=Pertwee |first12=Roger G |last13=Pacher |first13=Pál |title=Δ8-Tetrahydrocannabivarin prevents hepatic ischaemia/reperfusion injury by decreasing oxidative stress and inflammatory responses through cannabinoid CB2 receptors: Δ8-Tetrahydrocannabivarin for reperfusion injury |journal=British Journal of Pharmacology |date=April 2012 |volume=165 |issue=8 |pages=2450–2461 |doi=10.1111/j.1476-5381.2011.01410.x |pmid=21470208 |pmc=3423240 }}</ref>


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 [[Nitrate|nitrative]] stress, and thereby [[cell death]] and [[Tissue (biology)|tissue]] injury, but independent from classical CB1 and CB2 receptors.<ref>{{Cite journal|last=Mukhopadhyay|first=Partha|last2=Rajesh|first2=Mohanraj|last3=Horváth|first3=Béla|last4=Bátkai|first4=Sándor|last5=Park|first5=Ogyi|last6=Tanashian|first6=Galin|last7=Gao|first7=Rachel Y|last8=Patel|first8=Vivek|last9=Wink|first9=David A.|date=2011-05-15|title=Cannabidiol protects against hepatic ischemia/reperfusion injury by attenuating inflammatory signaling and response, oxidative/nitrative stress, and cell death|journal=Free Radical Biology & Medicine|volume=50|issue=10|pages=1368–1381|doi=10.1016/j.freeradbiomed.2011.02.021|issn=0891-5849|pmc=3081988|pmid=21362471}}</ref>
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 [[Nitrate|nitrative]] stress, and thereby [[cell death]] and [[Tissue (biology)|tissue]] injury, but independent from classical CB1 and CB2 receptors.<ref>{{cite journal |last1=Mukhopadhyay |first1=Partha |last2=Rajesh |first2=Mohanraj |last3=Horváth |first3=Béla |last4=Bátkai |first4=Sándor |last5=Park |first5=Ogyi |last6=Tanchian |first6=Galin |last7=Gao |first7=Rachel Y. |last8=Patel |first8=Vivek |last9=Wink |first9=David A. |last10=Liaudet |first10=Lucas |last11=Haskó |first11=György |last12=Mechoulam |first12=Raphael |last13=Pacher |first13=Pál |title=Cannabidiol protects against hepatic ischemia/reperfusion injury by attenuating inflammatory signaling and response, oxidative/nitrative stress, and cell death |journal=Free Radical Biology and Medicine |date=May 2011 |volume=50 |issue=10 |pages=1368–1381 |doi=10.1016/j.freeradbiomed.2011.02.021 |pmid=21362471 |pmc=3081988 }}</ref>


==Reperfusion protection in obligate hibernators==
==Reperfusion protection in obligate hibernators==
[[Hibernation|Obligatory hibernators]] such as the [[ground squirrel]]s show resistance to ischemia/reperfusion (I/R) injury in liver, heart, and small intestine during the hibernation season when there is a switch from [[carbohydrate metabolism]] to [[lipid metabolism]] for cellular energy supply.<ref name="lipid cycles">{{cite journal|last=Dark|first=J|title=Annual lipid cycles in hibernators: integration of physiology and behavior.|journal=Annual Review of Nutrition|year=2005|volume=25|pages=469–97|pmid=16011475|doi=10.1146/annurev.nutr.25.050304.092514}}</ref><ref name="ground squirrels">{{cite journal|last=Andrews|first=MT|title=Advances in molecular biology of hibernation in mammals.|journal=BioEssays |date=May 2007|volume=29|issue=5|pages=431–40|pmid=17450592|doi=10.1002/bies.20560}}</ref><ref name="squirrel hibernation">{{cite journal|last=Kurtz|first=CC |author2=Lindell, SL |author3=Mangino, MJ |author4=Carey, HV|title=Hibernation confers resistance to intestinal ischemia-reperfusion injury.|journal=American Journal of Physiology. Gastrointestinal and Liver Physiology|date=November 2006|volume=291|issue=5|pages=G895–901|pmid=16751173|doi=10.1152/ajpgi.00155.2006}}</ref> This metabolic switch limits [[anaerobic metabolism]] and the formation of [[Lactic acid|lactate]], a herald of poor prognosis and [[multi-organ failure]] (MOF) after I/R injury. In addition, the increase in lipid metabolism generates [[ketone bodies]] and activates [[PPAR|peroxisome proliferating-activated receptors]] (PPARs), both of which have been shown to be protective against I/R injury.<ref name="ppar and hemorrhage">{{cite journal|last=Zingarelli|first=B |author2=Hake, PW |author3=O'Connor, M |author4=Burroughs, TJ |author5=Wong, HR |author6=Solomkin, JS |author7=Lentsch, AB|title=Lung injury after hemorrhage is age dependent: role of peroxisome proliferator-activated receptor gamma.|journal=Critical Care Medicine|date=June 2009|volume=37|issue=6|pages=1978–87|pmid=19384226|doi=10.1097/CCM.0b013e31819feb4d|pmc=2765201}}</ref>
[[Hibernation|Obligatory hibernators]] such as the [[ground squirrel]]s show resistance to ischemia/reperfusion (I/R) injury in liver, heart, and small intestine during the hibernation season when there is a switch from [[carbohydrate metabolism]] to [[lipid metabolism]] for cellular energy supply.<ref name="lipid cycles">{{cite journal|last=Dark|first=J|title=Annual lipid cycles in hibernators: integration of physiology and behavior.|journal=Annual Review of Nutrition|year=2005|volume=25|pages=469–97|pmid=16011475|doi=10.1146/annurev.nutr.25.050304.092514}}</ref><ref name="ground squirrels">{{cite journal|last=Andrews|first=MT|title=Advances in molecular biology of hibernation in mammals.|journal=BioEssays |date=May 2007|volume=29|issue=5|pages=431–40|pmid=17450592|doi=10.1002/bies.20560|s2cid=22894246 }}</ref><ref name="squirrel hibernation">{{cite journal |last1=Kurtz |first1=Courtney C. |last2=Lindell |first2=Susanne L. |last3=Mangino |first3=Martin J. |last4=Carey |first4=Hannah V. |title=Hibernation confers resistance to intestinal ischemia-reperfusion injury |journal=American Journal of Physiology. Gastrointestinal and Liver Physiology |date=November 2006 |volume=291 |issue=5 |pages=G895–G901 |doi=10.1152/ajpgi.00155.2006 |pmid=16751173 }}</ref> This metabolic switch limits [[anaerobic metabolism]] and the formation of [[Lactic acid|lactate]], a herald of poor prognosis and [[multi-organ failure]] (MOF) after I/R injury. In addition, the increase in lipid metabolism generates [[ketone bodies]] and activates [[PPAR|peroxisome proliferating-activated receptors]] (PPARs), both of which have been shown to be protective against I/R injury.<ref name="ppar and hemorrhage">{{cite journal |last1=Zingarelli |first1=Basilia |last2=Hake |first2=Paul W. |last3=O’Connor |first3=Michael |last4=Burroughs |first4=Timothy J. |last5=Wong |first5=Hector R. |last6=Solomkin |first6=Joseph S. |last7=Lentsch |first7=Alex B. |title=Lung injury after hemorrhage is age dependent: Role of peroxisome proliferator-activated receptor γ |journal=Critical Care Medicine |date=June 2009 |volume=37 |issue=6 |pages=1978–1987 |doi=10.1097/CCM.0b013e31819feb4d |pmid=19384226 |pmc=2765201 }}</ref>


==See also==
==See also==
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==References==
==References==
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{{Reflist}}


== External links ==
== External links ==
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{{DEFAULTSORT:Reperfusion Injury}}
{{DEFAULTSORT:Reperfusion Injury}}

Latest revision as of 20:45, 1 February 2024

Reperfusion injury
Other namesReperfusion insult
Native records of contractile activity of the left ventricle of isolated rat heart perfused under Langendorff technique. Curve A - contractile function of the heart is greatly depressed after ischemia-reperfusion. Curve B - a set of short ischemic episodes (ischemic preconditioning) before prolonged ischemia provides functional recovery of contractile activity of the heart at reperfusion.
SpecialtyCardiology Edit this on Wikidata

Reperfusion injury, sometimes called ischemia-reperfusion injury (IRI) or reoxygenation injury, is the tissue damage caused when blood supply returns to tissue (re- + perfusion) after a period of ischemia or lack of oxygen (anoxia or hypoxia). The absence of oxygen and nutrients from blood during the ischemic period creates a condition in which the restoration of circulation results in inflammation and oxidative damage through the induction of oxidative stress rather than (or along with) restoration of normal function.

Reperfusion injury is distinct from cerebral hyperperfusion syndrome (sometimes called "Reperfusion syndrome"), a state of abnormal cerebral vasodilation.

Mechanisms

[edit]

Reperfusion of ischemic tissues is often associated with microvascular injury, particularly due to increased permeability of capillaries and arterioles that lead to an increase of diffusion and fluid filtration across the tissues. Activated endothelial cells produce more reactive oxygen species but less nitric oxide following reperfusion, and the imbalance results in a subsequent inflammatory response.[1] The inflammatory response is partially responsible for the damage of reperfusion injury. White blood cells, carried to the area by the newly returning blood, release a host of inflammatory factors such as interleukins as well as free radicals in response to tissue damage.[2] The restored blood flow reintroduces oxygen within cells that damages cellular proteins, DNA, and the plasma membrane. Damage to the cell's membrane may in turn cause the release of more free radicals. Such reactive species may also act indirectly in redox signaling to turn on apoptosis. White blood cells may also bind to the endothelium of small capillaries, obstructing them and leading to more ischemia.[2]

Reperfusion injury plays a major part in the biochemistry of hypoxic brain injury in stroke. Similar failure processes are involved in brain failure following reversal of cardiac arrest;[3] control of these processes is the subject of ongoing research. Repeated bouts of ischemia and reperfusion injury also are thought to be a factor leading to the formation and failure to heal of chronic wounds such as pressure sores and diabetic foot ulcer.[4] Continuous pressure limits blood supply and causes ischemia, and the inflammation occurs during reperfusion. As this process is repeated, it eventually damages tissue enough to cause a wound.[4]

The main reason for the acute phase of ischemia-reperfusion injury is oxygen deprivation and, therefore, arrest of generation of ATP (cellular energy currency) by mitochondria oxidative phosphorylation. Tissue damage due to the general energy deficit during ischemia is followed by reperfusion (increase of oxygen level) when the injury is enhanced. Mitochondrial complex I is thought to be the most vulnerable enzyme to tissue ischemia/reperfusion but the mechanism of damage is different in different tissues. For example brain ischemia/reperfusion injury is mediated via complex I redox-dependent inactivation.[5] It was found that lack of oxygen leads to conditions in which mitochondrial complex I loses its natural cofactor, flavin mononucleotide (FMN) and become inactive.[6] When oxygen is present the enzyme catalyzes a physiological reaction of NADH oxidation by ubiquinone, supplying electrons downstream of the respiratory chain (complexes III and IV). Ischemia leads to dramatic increase of succinate level.[7] In the presence of succinate mitochondria catalyze reverse electron transfer so that fraction of electrons from succinate is directed upstream to FMN of complex I.[8] Reverse electron transfer results in a reduction of complex I FMN, increased generation of ROS, followed by a loss of the reduced cofactor (FMNH2) and impairment of mitochondria energy production.[8] The FMN loss by complex I and I/R injury can be alleviated by the administration of FMN precursor, riboflavin.[6]

Reperfusion can cause hyperkalemia.[9]

Reperfusion injury is a primary concern in liver transplantation surgery.[10]

Treatment

[edit]
Main article: Reperfusion therapy

Therapeutic hypothermia

[edit]
See also: Hypothermia therapy for neonatal encephalopathy

However,[clarification needed] the therapeutic effect of hypothermia does not confine itself to metabolism and membrane stability. Another school of thought focuses on hypothermia's ability to prevent the injuries that occur after circulation returns to the brain, or what is termed reperfusion injuries. In fact an individual suffering from an ischemic insult continues suffering injuries well after circulation is restored. In rats it has been shown that neurons often die a full 24 hours after blood flow returns. Some theorize that this delayed reaction derives from the various inflammatory immune responses that occur during reperfusion.[11] These inflammatory responses cause intracranial pressure, pressure which leads to cell injury and in some situations cell death. Hypothermia has been shown to help moderate intracranial pressure and therefore to minimize the harmful effect of a patient's inflammatory immune responses during reperfusion. Beyond this, reperfusion also increases free radical production. Hypothermia too has been shown to minimize a patient's production of deadly free radicals during reperfusion. Many now suspect it is because hypothermia reduces both intracranial pressure and free radical production that hypothermia improves patient outcome following a blockage of blood flow to the brain.[12]

Hydrogen sulfide treatment

[edit]

There are some preliminary studies in mice that seem to indicate that treatment with hydrogen sulfide (H2S) can have a protective effect against reperfusion injury.[13]

Cyclosporin

[edit]

In addition to its well-known immunosuppressive capabilities, the one-time administration of cyclosporin 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.[14]

Cyclosporin 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.[15]

However, the studies CIRCUS and CYCLE (published in September 2015 and February 2016 respectively) looked at the use of cyclosporin as a one time IV dose given right before perfusion therapy (PCI). Both studies found there is no statistical difference in outcome with cyclosporin administration.[16][17]

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.[15]

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 cardioprotective strategy.[18]

In 2008, an editorial in the New England Journal of Medicine called for more studies to determine if cyclosporin can become a treatment to ameliorate reperfusion injury by protecting mitochondria.[18] To that end, in 2011 the researchers involved in the original 2008 NEJM study initiated a phase III clinical study of reperfusion injury in 1000 myocardial infarction patients in centers throughout Europe. Results of that study were announced in 2015 and indicated that "intravenous cyclosporine did not result in better clinical outcomes than those with placebo and did not prevent adverse left ventricular remodeling at 1 year."[16] This same process of mitochondrial destruction through the opening of the MPT pore is implicated in making traumatic brain injuries much worse.[19]

TRO40303

[edit]

TRO40303 is a new cardioprotective 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.[20]

Stem cell therapy

[edit]

Recent investigations suggest a possible beneficial effect of mesenchymal stem cells on heart and kidney reperfusion injury.[21][22]

Superoxide dismutase

[edit]

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.[23][24]

Metformin

[edit]

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.[25][26]

Riboflavin

[edit]

In neonatal in vivo model of brain ischemia/reperfusion, tissue injury can be alleviated by the administration of FMN precursor, riboflavin that prevents inactivation of mitochondrial complex I.[6][27]

Cannabinoids

[edit]

A study published in 2012 show that the synthetic analogue of the phytocannabinoid Tetrahydrocannabivarin (THCV), Δ8-Tetrahydrocannabivarin (Δ8-THCV) and its metabolite 11-OH-Δ8-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 Δ8-THCV, while a CB1 antagonist tended to enhance it.[28]

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.[29]

Reperfusion protection in obligate hibernators

[edit]

Obligatory hibernators such as the ground squirrels show resistance to ischemia/reperfusion (I/R) injury in liver, heart, and small intestine during the hibernation season when there is a switch from carbohydrate metabolism to lipid metabolism for cellular energy supply.[30][31][32] This metabolic switch limits anaerobic metabolism and the formation of lactate, a herald of poor prognosis and multi-organ failure (MOF) after I/R injury. In addition, the increase in lipid metabolism generates ketone bodies and activates peroxisome proliferating-activated receptors (PPARs), both of which have been shown to be protective against I/R injury.[33]

See also

[edit]

References

[edit]
  1. ^ Carden, Donna L.; Granger, D. Neil (February 2000). "Pathophysiology of ischaemia-reperfusion injury". The Journal of Pathology. 190 (3): 255–266. doi:10.1002/(SICI)1096-9896(200002)190:3<255::AID-PATH526>3.0.CO;2-6. PMID 10685060. S2CID 37383438.
  2. ^ a b Reperfusion Injury in Stroke at eMedicine
  3. ^ Hendry, Robert; Crippen, David (2007). "Brain failure and brain death". In Fink, Mitchell P.; Jurkovic, Gregory J. (eds.). ACS Surgery: Principles and Practice. B C Decker. pp. 1609–1612. ISBN 978-1-55009-399-5.
  4. ^ a b Mustoe, Thomas (May 2004). "Understanding chronic wounds: a unifying hypothesis on their pathogenesis and implications for therapy". The American Journal of Surgery. 187 (5): S65–S70. doi:10.1016/S0002-9610(03)00306-4. PMID 15147994.
  5. ^ Galkin, A (November 2019). "Brain Ischemia/Reperfusion Injury and Mitochondrial Complex I Damage". Biochemistry. Biokhimiia. 84 (11): 1411–1423. doi:10.1134/S0006297919110154. PMID 31760927. S2CID 207990089.
  6. ^ a b c Stepanova, Anna; Sosunov, Sergey; Niatsetskaya, Zoya; Konrad, Csaba; Starkov, Anatoly A.; Manfredi, Giovanni; Wittig, Ilka; Ten, Vadim; Galkin, Alexander (20 September 2019). "Redox-Dependent Loss of Flavin by Mitochondrial Complex I in Brain Ischemia/Reperfusion Injury". Antioxidants & Redox Signaling. 31 (9): 608–622. doi:10.1089/ars.2018.7693. PMC 6657304. PMID 31037949.
  7. ^ Sahni, Prateek V; Zhang, Jimmy; Sosunov, Sergey; Galkin, Alexander; Niatsetskaya, Zoya; Starkov, Anatoly; Brookes, Paul S; Ten, Vadim S (February 2018). "Krebs cycle metabolites and preferential succinate oxidation following neonatal hypoxic-ischemic brain injury in mice". Pediatric Research. 83 (2): 491–497. doi:10.1038/pr.2017.277. PMC 5866163. PMID 29211056.
  8. ^ a b Stepanova, Anna; Kahl, Anja; Konrad, Csaba; Ten, Vadim; Starkov, Anatoly S; Galkin, Alexander (December 2017). "Reverse electron transfer results in a loss of flavin from mitochondrial complex I: Potential mechanism for brain ischemia reperfusion injury". Journal of Cerebral Blood Flow & Metabolism. 37 (12): 3649–3658. doi:10.1177/0271678X17730242. PMC 5718331. PMID 28914132.
  9. ^ Atlee, John L. (2007). Complications in Anesthesia. Elsevier Health Sciences. pp. 55–. ISBN 978-1-4160-2215-2.
  10. ^ Lemasters and, John J.; Thurman, Ronald G. (April 1997). "Reperfusion injury after liver preservation for transplantation". Annual Review of Pharmacology and Toxicology. 37 (1): 327–338. doi:10.1146/annurev.pharmtox.37.1.327. PMID 9131256.
  11. ^ "Back to Life: The Science of Reviving the Dead". Newsweek. 22 July 2007.
  12. ^ Polderman, Kees H. (1 April 2004). "Application of therapeutic hypothermia in the ICU: opportunities and pitfalls of a promising treatment modality. Part 1: Indications and evidence". Intensive Care Medicine. 30 (4): 556–575. doi:10.1007/s00134-003-2152-x. PMID 14767591. S2CID 5733761.
  13. ^ Elrod, John W; Calvert, John W; Duranski, Mark R; Lefer, David J (31 October 2006). "Abstract 947: Hydrogen Sulfide Donor Protects Against Acute Myocardial Ischemia-Reperfusion Injury". Circulation. 114 (suppl_18): II_172. doi:10.1161/circ.114.suppl_18.II_172-a (inactive 31 January 2024).{{cite journal}}: CS1 maint: DOI inactive as of January 2024 (link)
  14. ^ Piot, Christophe; Croisille, Pierre; Staat, Patrick; Thibault, Hélène; Rioufol, Gilles; Mewton, Nathan; Elbelghiti, Rachid; Cung, Thien Tri; Bonnefoy, Eric; Angoulvant, Denis; Macia, Christophe; Raczka, Franck; Sportouch, Catherine; Gahide, Gerald; Finet, Gérard; André-Fouët, Xavier; Revel, Didier; Kirkorian, Gilbert; Monassier, Jean-Pierre; Derumeaux, Geneviève; Ovize, Michel (31 July 2008). "Effect of Cyclosporine on Reperfusion Injury in Acute Myocardial Infarction". New England Journal of Medicine. 359 (5): 473–481. doi:10.1056/NEJMoa071142. PMID 18669426.
  15. ^ a b Javadov, Sabzali; Karmazyn, Morris (2007). "Mitochondrial Permeability Transition Pore Opening as an Endpoint to Initiate Cell Death and as a Putative Target for Cardioprotection". Cellular Physiology and Biochemistry. 20 (1–4): 1–22. doi:10.1159/000103747. PMID 17595511. S2CID 1949575.
  16. ^ a b Cung, Thien-Tri; Morel, Olivier; Cayla, Guillaume; Rioufol, Gilles; Garcia-Dorado, David; Angoulvant, Denis; Bonnefoy-Cudraz, Eric; Guérin, Patrice; Elbaz, Meier; Delarche, Nicolas; Coste, Pierre; Vanzetto, Gerald; Metge, Marc; Aupetit, Jean-François; Jouve, Bernard; Motreff, Pascal; Tron, Christophe; Labeque, Jean-Noel; Steg, Philippe Gabriel; Cottin, Yves; Range, Grégoire; Clerc, Jérome; Claeys, Marc J.; Coussement, Patrick; Prunier, Fabrice; Moulin, Frédéric; Roth, Olivier; Belle, Loïc; Dubois, Philippe; Barragan, Paul; Gilard, Martine; Piot, Christophe; Colin, Patrice; De Poli, Fabien; Morice, Marie-Claude; Ider, Omar; Dubois-Randé, Jean-Luc; Unterseeh, Thierry; Le Breton, Hervé; Béard, Thierry; Blanchard, Didier; Grollier, Gilles; Malquarti, Vincent; Staat, Patrick; Sudre, Arnaud; Elmer, Eskil; Hansson, Magnus J.; Bergerot, Cyrille; Boussaha, Inesse; Jossan, Claire; Derumeaux, Geneviève; Mewton, Nathan; Ovize, Michel (10 September 2015). "Cyclosporine before PCI in Patients with Acute Myocardial Infarction". New England Journal of Medicine. 373 (11): 1021–1031. doi:10.1056/NEJMoa1505489. hdl:10044/1/41761. PMID 26321103.
  17. ^ Ottani, Filippo; Latini, Roberto; Staszewsky, Lidia; La Vecchia, Luigi; Locuratolo, Nicola; Sicuro, Marco; Masson, Serge; Barlera, Simona; Milani, Valentina; Lombardi, Mario; Costalunga, Alessandra; Mollichelli, Nadia; Santarelli, Andrea; De Cesare, Nicoletta; Sganzerla, Paolo; Boi, Alberto; Maggioni, Aldo Pietro; Limbruno, Ugo (February 2016). "Cyclosporine A in Reperfused Myocardial Infarction". Journal of the American College of Cardiology. 67 (4): 365–374. doi:10.1016/j.jacc.2015.10.081. PMID 26821623. S2CID 205575155.
  18. ^ a b Hausenloy, Derek J.; Yellon, Derek M. (31 July 2008). "Time to Take Myocardial Reperfusion Injury Seriously". New England Journal of Medicine. 359 (5): 518–520. doi:10.1056/NEJMe0803746. PMID 18669431.
  19. ^ Sullivan, Patrick G.; Sebastian, Andrea H.; Hall, Edward D. (February 2011). "Therapeutic Window Analysis of the Neuroprotective Effects of Cyclosporine A after Traumatic Brain Injury". Journal of Neurotrauma. 28 (2): 311–318. doi:10.1089/neu.2010.1646. PMC 3037811. PMID 21142667.
  20. ^ Le Lamer, Sophie; Paradis, Stéphanie; Rahmouni, Hidayat; Chaimbault, Corinne; Michaud, Magali; Culcasi, Marcel; Afxantidis, Jean; Latreille, Mathilde; Berna, Patrick; Berdeaux, Alain; Pietri, Sylvia; Morin, Didier; Donazzolo, Yves; Abitbol, Jean-Louis; Pruss, Rebacca M; Schaller, Sophie (December 2014). "Translation of TRO40303 from myocardial infarction models to demonstration of safety and tolerance in a randomized Phase I trial". Journal of Translational Medicine. 12 (1): 38. doi:10.1186/1479-5876-12-38. PMC 3923730. PMID 24507657.
  21. ^ van der Spoel, T. I. G.; Jansen of Lorkeers, S. J.; Agostoni, P.; van Belle, E.; Gyongyosi, M.; Sluijter, J. P. G.; Cramer, M. J.; Doevendans, P. A.; Chamuleau, S. A. J. (1 September 2011). "Human relevance of pre-clinical studies in stem cell therapy: systematic review and meta-analysis of large animal models of ischaemic heart disease". Cardiovascular Research. 91 (4): 649–658. doi:10.1093/cvr/cvr113. PMID 21498423.
  22. ^ Zhao, Jing-Jie; Liu, Jun-Li; Liu, Ling; Jia, Hong-Ying (January 2014). "Protection of mesenchymal stem cells on acute kidney injury". Molecular Medicine Reports. 9 (1): 91–96. doi:10.3892/mmr.2013.1792. PMID 24220681.
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