Reperfusion injury

Reperfusion injury, also called ischemia-reperfusion injury (IRI) or reoxygenation injury.

The interruption of arterial blood to an organ leads to hypoxic injury and cell death, and when blood flow is restored, inflammatory cells infiltrate the ischemic tissues, which results in additional reperfusion injury and organ dysfunction.

Reperfusion leads to biochemical imbalances within the cell that lead to cell death and increased infarct size, calcium overload and excessive production of reactive oxygen species.

Ischemic tissue injury with reperfusion affects a wide range of clinical conditions, including myocardial infarction, acute kidney injury, stroke, solid organ transplantation, and cardiac arrest.

These changes occurin the first few minutes after reperfusion set off biochemical changes that result in the opening of the mitochondrial permeability transition pore (MPT pore) in the mitochondrial membrane of cardiac cells.

The mitochondrial permeability transition pore opening leads to water entering the mitochondria, resulting in mitochondrial dysfunction and collapse.

With mitochondrial collapse calcium is released to overwhelm the next mitochondria in a series of events that cause mitochondrial energy production supporting the cell to be reduced or stopped completely.

Without mitochondrial energy production cellular death results.

It is the tissue damage caused when blood supply returns to 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.

Individuals suffering from an ischemic insult continues suffering injuries well after circulation is restored: this delayed reaction may derive from the various inflammatory immune responses that occur during reperfusion.

Inflammatory responses may cause increased intracranial pressure, leadingto cell injury and in some situations cell death.

Reperfusion injury is a major contributor to organ dysfunction after return of spontaneous circulation and it is worsened by hyperoxia.

Postarrest hyperoxia may reduce cerebral blood flow and cardiac output by increasing vascular resistance.

The  acute phase of ischemia-reperfusion injury is oxygen deprivation and, therefore, arrest of generation of ATP by mitochondria oxidative phosphorylation. 

Mitochondrial complex I is thought to be the most vulnerable enzyme to tissue ischemia/reperfusion.

In prolonged ischemia hypoxanthine is formed as a breakdown product of ATP metabolism. 

Reperfusion of ischemic tissues is often associated with microvascular injury, due to increased permeability of capillaries and arterioles that lead to an increase of diffusion and fluid filtration across the tissues. 

Following repercussion endothelial cells produce more reactive oxygen species but less nitric oxide and the imbalance results in an inflammatory response.

Excessive nitric oxide produced during reperfusion reacts with superoxide to produce  potent reactive species.

Reactive oxygen species attack cell membrane lipids, proteins, and glycosaminoglycans, causing further damage. 

Reperfusion can cause hyperkalemia.

Reperfusion injury is a primary concern following liver transplantation surgery.

Damage by reperfusion injury is partly due to inflammation.


Reperfusion brings white blood cells that release inflammatory factors such as interleukins as well as free radicals in response to tissue damage.

White blood cells may also bind to the endothelium of small capillaries, causing their obstruction and leading to more ischemia.

The repercussion of  blood flow reintroduces oxygen within cells that damages cellular proteins, DNA, and the plasma membrane. 

As damage to the cell’s plasma membrane occurs it may  cause the release of more free radicals. 

Free radicals may also act indirectly in redox signaling to turn on apoptosis. 


Ischemic tissues have decreased function of free radical scavengers because of cell injury. 

When  blood flow is reestablished, oxygen species contained in the blood will damage the ischemic tissue because the function of the scavengers is decreased.



As xanthine oxidase is a result of the higher availability of oxygen, resulting  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.

Refers the presence of reperfusion of ischemic areas of myocardium after thrombolytic therapy, percutaneous intervention or coronary artery bypass surgery that can be associated with arrhythmias, myocardial stunning, microvascular dysfunction and cell death.

Abrupt reperfusion of ischemic myocardium can itself injure the myocardium.

Experimental data indicates about 50% of myocardial injury is due to reperfusion injury with an infarct.

Experimental studies with ischemic post-conditioning, a method in which myocardial reperfusion during percutaneous intervention is interrupted with several low pressure inflations of the angioplasty balloon to temporarily re-occlude the coronary artery, has been shown to reduce the size of myocardial infarct by 40% at 6 months, and to improve left ventricular ejection fraction by 7% at 1 year.

The protective signal transduction pathway underlying postconditioning linked to activation of the reperfusion injury salvage kinase pathway (Hausenloy).

Experimental studies reveal that drugs can activate the reperfusion salvage kinase pathway and limit the size of the infarct when given as an adjunct to primary PCI.

Complement activation associated with acute inflammation seen with ischemia and reperfusion injury with anaphylotoxins C3a and C5a and C5b-9 membrane attack complex formed during the process and related to increased vascular permeability, endothelial activation, activation of hemostasis, apoptosis and cell lysis.

Ischemic preconditioning and reperfusion injury salvage kinase pathway mediate protective actions by acting on the mitochondria permeability transition pore.


((Hypothermia)) has been shown to help moderate intracranial pressure and minimize the harmful effect of a patient’s inflammatory immune responses during reperfusion. 

Reperfusion increases free radical production. 

Hypothermia minimizes a patient’s production of deadly free radicals during reperfusion. 

Hypothermia reduces both intracranial pressure and free radical production that improving patient outcome following a blockage of blood flow to the brain.


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