Editing Reperfusion injury (section)

==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 |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">{{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" />

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"/>

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 |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>