Reperfusion injury

Reperfusion injury is distinct from cerebral hyperperfusion syndrome (sometimes called "Reperfusion syndrome"), a state of abnormal cerebral vasodilation.

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. 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]


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;^[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 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 ATP (cellular energy currency) by mitochondria oxidative phosphorylation. Tissue damage due to the general energy deficit during ischemia is followed by reperfusion (increase of oxygen level) when the injury is enhanced. 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]