Reperfusion injury

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Reperfusion injury
Classification and external resources
MeSH D015427

Reperfusion injury is the tissue damage caused when blood supply returns to the tissue after a period of ischemia or lack of oxygen. 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 restoration of normal function.

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. These "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] 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 a decrease function in his 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 part in the brain's ischemic cascade, which is involved in stroke and brain trauma. 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 ulcers.[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]

In prolonged ischemia (60 minutes or more), hypoxanthine is formed as breakdown product of 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 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.[5]

Reperfusion injury is a primary concern in liver transplantation surgery.[6]

Treatment[edit]

A study of aortic cross-clamping, a common procedure in cardiac surgery, demonstrated a strong potential benefit with further research ongoing.[citation needed]

Therapeutic hypothermia[edit]

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 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.[7] 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.[8]

Hydrogen sulfide treatment[edit]

There are some preliminary studies that seem to indicate that treatment with hydrogen sulfide (H2S) can have a protective effect against reperfusion injury.[9]

Cyclosporine[edit]

In addition to its well-known immunosuppressive capabilities, the one-time administration of cyclosporine at the time of percutaneous coronary intervention (PCI) has been found to deliver a 40 percent reduction in infarct size in a small group proof of concept study of human patients with reperfusion injury published in The New England Journal of Medicine in 2008.[10]

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.[11]

The opening of the MPT pore leads to the inrush of water into the mitochondria, resulting in mitochondrial disfunction 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.[12]

Cyclosporine has been confirmed in studies to inhibit the actions of cyclophilin D, a protein which is induced by excessive intracellular calcium flow to interact with other pore components and help open the MPT pore. Inhibiting cyclophilin D has been shown to prevent the opening of the MPT pore and protect the mitochondria and cellular energy production from excessive calcium inflows.[11]

In 2008, an editorial in the New England Journal of Medicine called for more studies to determine if cyclosporine can become a treatment to ameliorate reperfusion injury by protecting mitochondria.[12] 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 are expected to be announced later in 2014.

Note: This same process of mitochondrial destruction through the opening of the MPT pore is implicated in making traumatic brain injuries much worse.[13] Cyclosporine is currently in a phase II/III (adaptive) clinical study in Europe to determine its ability to ameliorate neuronal cellular damage in traumatic brain injury.

Stem cell therapy[edit]

Recent investigations suggest a possible beneficial effect of mesenchymal stem cells on heart and kidney reperfusion injury.[14][15]

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.[16][17][18] 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.[19]

See also[edit]

References[edit]

  1. ^ Carden, DL; Granger, DN (Feb 2000). "Pathophysiology of ischaemia-reperfusion injury.". The Journal of pathology 190 (3): 255–66. PMID 10685060. 
  2. ^ a b Clark, Wayne M. (January 5, 2005). "Reperfusion Injury in Stroke". eMedicine. WebMD. Retrieved 2006-08-09. 
  3. ^ Crippen, David. "Brain Failure and Brain Death: Introduction". ACS Surgery Online, Critical Care, April 2005. Retrieved 2007-01-09. 
  4. ^ a b Mustoe T. (2004). "Understanding chronic wounds: a unifying hypothesis on their pathogenesis and implications for therapy". American Journal Of Surgery 187 (5A): 65S–70S. doi:10.1016/S0002-9610(03)00306-4. PMID 15147994. 
  5. ^ John L. Atlee (2007). Complications in anesthesia. Elsevier Health Sciences. pp. 55–. ISBN 978-1-4160-2215-2. Retrieved 25 July 2010. 
  6. ^ Lemasters JJ. (1997). "Reperfusion injury after liver preservation for transplantation". Annual Review of Pharmacology and Toxicology 37: 327–38. doi:10.1146/annurev.pharmtox.37.1.327. PMID 9131256. 
  7. ^ Adler, Jerry. "Back From the Dead." Newsweek. July 23, 2007.
  8. ^ Polderman, Kees H. "Application of therapeutic hypothermia in the ICU." Intensive Car Med. (2004) 30:556-575.
  9. ^ 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.
  10. ^ Piot C., Croiselle P., Staat P. et al. "Effect of Cyclosporine on Reperfusion Injury in Acute Myocardial Infaction." New England Journal of Medicine 359 (5): 473-481 2008.
  11. ^ a b Javadov S., Karmazyn M. "Mitochondrial Permeability Transition Pore Opening as an Endpoint to Initiate Cell Death and as a Putative Target for Cardioprotection." Cell Physiol Biochem 20:1-22 2007.
  12. ^ a b Hausenloy D. and Yellon D. "Time to take myocardial reperfusion injury seriously." New England Journal of Medicine Editorial comment 359 (5): 518-520 2008.
  13. ^ Sullivan, P., Sebastian, A., Hall, E. "Therapeutic window analysis of the neuroprotective effects of cyclosporine A after traumatic brain injury." Journal of Neurotrauma 2011; Feb;28:311–318.
  14. ^ van der Spoel TI (Sep 2011). "Human relevance of pre-clinical studies in stem cell therapy: systematic review and meta-analysis of large animal models of ischaemic heart disease.". Cardiovasc Res 91 (4): 649–58. PMID 21498423. 
  15. ^ Zhao JJ (Jan 2014). "Protection of mesenchymal stem cells on acute kidney injury.". J Mol Med Rep 9 (1): 91–96. PMID 24220681. 
  16. ^ Dark, J (2005). "Annual lipid cycles in hibernators: integration of physiology and behavior.". Annual review of nutrition 25: 469–97. doi:10.1146/annurev.nutr.25.050304.092514. PMID 16011475. 
  17. ^ Andrews, MT (May 2007). "Advances in molecular biology of hibernation in mammals.". BioEssays : news and reviews in molecular, cellular and developmental biology 29 (5): 431–40. doi:10.1002/bies.20560. PMID 17450592. 
  18. ^ Kurtz, CC; Lindell, SL, Mangino, MJ, Carey, HV (November 2006). "Hibernation confers resistance to intestinal ischemia-reperfusion injury.". American journal of physiology. Gastrointestinal and liver physiology 291 (5): G895–901. doi:10.1152/ajpgi.00155.2006. PMID 16751173. 
  19. ^ Zingarelli, B; Hake, PW, O'Connor, M, Burroughs, TJ, Wong, HR, Solomkin, JS, Lentsch, AB (June 2009). "Lung injury after hemorrhage is age dependent: role of peroxisome proliferator-activated receptor gamma.". Critical Care Medicine 37 (6): 1978–87. doi:10.1097/CCM.0b013e31819feb4d. PMC 2765201. PMID 19384226. Retrieved 11 December 2011. 

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