- Reperfusion injury
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 of reperfusion injury
The inflammatory response partially mediates 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. 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. Leukocytes may also bind to the endothelium of small capillaries, obstructing them and leading to more ischemia.
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; 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. 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.
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.
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. 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.
Hydrogen sulfide treatment
Ischemia/Reperfusion Protection in Obligatory Hibernators, Ground Squirrels
Obligatory hibernators such as the ground squirrels have been show to have 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. [1-9] 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. [10, 11] In addition, the increase in circulating lipids and lipid metabolism generates ketone bodies and activates peroxisomal proliferating-activated receptors (PPARs), both of which have been shown to be protective against I/R injury.
Lactate has long been an indicator of poor prognosis after I/R injury. [10, 11] Lactate is formed under anaerobic conditions when pyruvate, instead of being covered into acetyl-CoA and entering the tricarboxylic acid cycle (TCA) cycle, is converted into lactate to generate NAD+ needed for glycolysis to continue. Aside from being a marker for the level of anaerobic metabolism occurring, lactate increases interleukin- 1β (IL-1β), Interleukin-6 (IL-6), and tumor necrosis factor–α (TNF-α).  Multi organ failure is well known to be caused by a dysfunctional systemic inflammatory process. [11, 13] Elevated plasma levels of proinflammatory cytokines TNF-α, IL-1β, and IL-6 indicate a poor prognosis in animal and patient studies of MOF.  TNFα and IL-1β mediate neutorphil infiltration into tissues and organs. [14-17] Activated neutrophils damage organs and tissue via release of protolytic enzymes, ROS, and vasoactive substances. [15, 18] These cytokines have been shown to cause lung damage in rats after I/R (hemorrhagic shock). 
Ketone bodies (e.g. D- betahydroxybuterate; DBHB) are produced in the liver by fatty acid β-oxidation and condensation of resulting acetyl-CoA. Ketones are known to be protective but the mechanism has not yet been elucidated.  Examples of their protective properties include:
- Decreases in brain injury to neurons subject to ischemia. [21, 22]
- Reduced oxidative stress in cardiac tissue. [23, 24]
- Reduced oxidative stress in neurons by increasing NADH oxidation in the mitochondria and inhibiting reactive oxygen species (ROS) production. 
- Increased survival time in rats after hemorrhagic shock when resuscitated with a DBHB and melatonin (an antioxidant) infusion soultion. 
Interestingly, when DBHB is the major energy source during hemorrhagic shock, excess lactate and H+ are inhibited. 
PPARs (PPARα, PPARβ, and PPARγ) are transcription factors that are activated by fatty acids (which are elevated in ground squirrels during the winter season). When activated, PPARs regulate the transcription of genes involved in lipid and carbohydrate metabolism, inflammation, and expression of mitochondrial uncoupling protein 1 (UCP-1).  The result of PPAR activation on metabolism is an increase fatty acid metabolism and a decrease glucose metabolism. In hibernating ground squirrels, PPARα depresses dehydrogenase pyruvate complex (PDC) via upregulation of puruvate dehydrogenase kinase 4 (PDK4), thus blocking entrance of glycolitic products into the TCA cycle. [29, 30]
Activation of PPARs also decreases inflammatory gene expression. Specifically, they suppress nuclear factor kappa-beta (NFΚB) activity and target genes of nuclear factor of activated T cells (NFAT), activator protein 1 (AP1), and signal transducers and activators of transcription (STATs). [29, 31] PPARs also block expression of inflammatory cytokines (IL-6) and have been shown to induce apoptosis of macrophages exposed to TNFα and interferon-γ. [31, 32]
Finally, activated PPARS induce the expression of mitochondrial uncoupling protein 1 (UCP-1).  Mitochondrial UCP-1 has the potential to reduce ROS produced via the electron transport chain (ETC) when there is a sudden burst in oxygen levels (as occurs during reperfusion). UCP-1 works by allowing hydrogen ions to reenter the mitochondrial matrix and be uncoupled from the ETC and oxygen consumption. This prevents a back up of ETC-intermediates and an increase in ROS generation.
PPARs have shown a protective role in I/R injury. Some examples include:
- PPARγ activation reduced liver apoptosis in rats after hemorrhagic shock. 
- PPARγ activation reduces systemic inflammation and lung injury after hemorrhagic shock. [34, 35]
- PPARγ expression is altered in ground squirrel intestine during the hibernation season and may contribute to the I/R-resistant phenotype. 
- During cardiac I/R, hibernating ground squirrels have reduced damage to myocardial tissue. In correlation with this, they also showed elevated PPARα-induced myocardial fatty acid utilization, reduced NFΚB activity and, reduced levels of circulating inflammatory cytokines (TNFα and IL-6). 
Overall hibernation-season ground squirrels show reduced injury to I/R injury. Protection from such injury may be influenced by a seasonal switch from carbohydrate to lipid metabolism resulting in a decrease in lactate formation, increase in ketone bodies, and activation of PPARs.
- Crush syndrome
- Myocardial infarction — Reperfusion
- Therapeutic hypothermia
- Hypothermia therapy for neonatal encephalopathy
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Cardiovascular disease: vascular disease · Circulatory system pathology (I70–I99, 440–456) Arteries, arterioles
Veinsprimarily lower limb (Deep vein thrombosis)abdomen (Hepatic veno-occlusive disease, Budd–Chiari syndrome, May-Thurner syndrome, Portal vein thrombosis, Renal vein thrombosis)Other Arteries or veins Blood pressure
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