ischemia-reperfusion injury

Restoration of blood flow to ischemic tissues can result in recovery of cells if they are reversibly injured, or not affect the outcome if irreversible cell damage has occurred.

However, depending on the intensity and duration of the ischemic insult, variable numbers of cells may proceed to die after blood flow resumes, by necrosis as well as by apoptosis. The affected tissues often show neutrophilic infiltrates.

As noted earlier, this ischemia-reperfusion injury is a clinically important process in such conditions as myocardial infarction and stroke and may be amenable to therapeutic interventions.

How does reperfusion injury occur? The likely answer is that new damaging processes are set in motion during reperfusion, causing the death of cells that might have recovered otherwise.

Several mechanisms have been proposed:

 New damage may be initiated during reoxygenation by increased generation of oxygen free radicals from parenchymal and endothelial cells and from infiltrating leukocytes.

 Superoxide anions can be produced in reperfused tissue as a result of incomplete and vicarious reduction of oxygen by damaged mitochondria or because of the action of oxidases derived from leukocytes, endothelial cells, or parenchymal cells. Cellular antioxidant defense mechanisms may also be compromised by ischemia, favoring the accumulation of radicals. Free radical scavengers may be of therapeutic benefit.

 Reactive oxygen species can further promote the mitochondrial permeability transition, referred to earlier, which, when it occurs, precludes mitochondrial energization and cellular ATP recovery and leads to cell death.

 Ischemic injury is associated with inflammation as a result of the production of cytokines and increased expression of adhesion molecules by hypoxic parenchymal and endothelial cells. These agents recruit circulating polymorphonuclear leukocytes to reperfused tissue; the ensuing inflammation causes additional injury.

The importance of neutrophil influx in reperfusion injury has been demonstrated by experimental studies that have used anti-inflammatory interventions, such as antibodies to cytokines or adhesion molecules, to reduce the extent of the injury.

Recent data suggest that activation of the complement pathway may contribute to ischemia-reperfusion injury. The complement system is involved in host defense and is an important mechanism of immune injury.

Some IgM antibodies have a propensity to deposit in ischemic tissues, for unknown reasons, and when blood flow is resumed, complement proteins bind to the antibodies, are activated, and cause cell injury and inflammation. Knockout mice lacking several complement proteins are resistant to this type of injury.

Localization

 cerebral reperfusion injury
 myocardial reperfusion injury

References

 Robbins

 Yellon DM, Hausenloy DJ. Myocardial reperfusion injury. N Engl J Med. 2007 Sep 13;357(11):1121-35. PMID: 17855673

 Li C, Jackson RM: Reactive species mechanisms of cellular hypoxia-reoxygenation injury. Am J Physiol Cell Physiol 282:C227, 2002.

 Daemen MARC, De Vries B, Buurman WA: Apoptosis and inflammation in renal reperfusion injury. Transplantation 73:1693, 2002.

 Anaya-Prado R, et al: Ischemia/reperfusion injury. J Surg Res 105:248, 2002.

 Kaminski KA, et al: Oxidative stress and neutrophil activation - the two keystones of ischemia/reperfusion injury. Int J Cardiol 86:41, 2002.

 Thiagarajan RR, et al: The role of leukocyte and endothelial adhesion molecules in ischemia-reperfusion injury. Thromb Haemost 78:310, 1997.

 Riedemann NC, Ward PA: Complement in ischemia reperfusion injury. Am J Pathol 162:363, 2003.

 Weiser MR, et al: Reperfusion injury of ischemic skeletal muscle is mediated by natural antibody and complement. J Exp Med 183:2343, 1996.