Reperfusion injury

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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

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

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

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

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

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

Main article: Reperfusion therapy

Therapeutic hypothermia

See also: Hypothermia therapy for neonatal encephalopathy

However,[

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

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

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

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

Phase I clinical trial.[20]

Stem cell therapy

Recent investigations suggest a possible beneficial effect of

mesenchymal stem cells on heart and kidney reperfusion injury.[21][22]

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.[23][24]

Metformin

A series of 2009 studies published in the Journal of Cardiovascular Pharmacology suggest that Metformin may prevent cardiac reperfusion injury by inhibition of Mitochondrial Complex I and the opening of MPT pore and in rats.[25][26]

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.[6][27]

Cannabinoids

A study published in 2012 show that the

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

peroxisome proliferating-activated receptors (PPARs), both of which have been shown to be protective against I/R injury.[33]

See also

References

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  2. ^ a b Reperfusion Injury in Stroke at eMedicine
  3. ISBN 978-1-55009-399-5
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  4. ^
    PMID 15147994
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  5. S2CID 207990089
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  6. ^
    PMID 31037949
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  7. PMID 29211056
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  8. ^
    PMID 28914132
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  9. ISBN 978-1-4160-2215-2
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  10. PMID 9131256
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  11. ^ "Back to Life: The Science of Reviving the Dead". Newsweek. 22 July 2007.
  12. S2CID 5733761
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  13. 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. PMID 18669426
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  15. ^
    S2CID 1949575
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  16. ^
    PMID 26321103
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  17. S2CID 205575155
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  18. ^
    PMID 18669431
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  19. PMID 21142667
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  20. PMID 24507657
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  21. PMID 21498423
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  22. PMID 24220681
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  23. PMID 26928528
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  24. PMID 26093094
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  25. S2CID 21161059
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  26. S2CID 28815693
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  27. S2CID 201835094
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  28. PMID 21470208
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  29. PMID 21362471
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  30. PMID 16011475
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  31. S2CID 22894246
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  32. PMID 16751173
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  33. PMID 19384226
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External links

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