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). 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.

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 hypoxic brain injury in stroke. Similar failure processes are involved in brain failure following reversal of cardiac arrest; 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.

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 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. 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.

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.

Regards
Meria Den
Managing Editor
Stroke Research & Therapy