What Is a Reperfusion Injury?
After a certain period of ischemic tissue cells restore blood flow (reperfusion), the degree of tissue damage rapidly increases. Also called ischemia / reperfusion injury. The resulting clinical disease is called reperfusion syndrome. After reperfusion, there is a large amount of Ca inflow, and a large amount of oxygen free radicals are generated, which is the main pathogenesis of extensive tissue cell damage. The occurrence and development of various diseases such as delayed neuronal necrosis, irreversible shock, myocardial infarction, acute organ failure and organ transplant rejection are related to ischemia and reperfusion. A variety of Ca blockers (such as Isoptin), oxygen free radical scavengers (such as superoxide dismutase, coenzyme Q10, etc.) and traditional Chinese medicine (such as Salvia miltiorrhiza, Madder, etc.) all have certain effects on the prevention and treatment of ischemia and reperfusion damage. effect.
Reperfusion injury
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- After a certain period of ischemic tissue cells restore blood flow (reperfusion), the degree of tissue damage rapidly increases. Also called ischemia / reperfusion injury. The resulting clinical disease is called reperfusion syndrome. After reperfusion, there is a large amount of Ca inflow, and a large amount of oxygen free radicals are generated, which is the main pathogenesis of extensive tissue cell damage. Many clinical diseases such as delayed neuronal necrosis, irreversible shock,
- Reperfusion injury is related to the following mechanisms.
- Energy exhaustion-Ca ion inflow-oxygen radical formation. Under normal conditions, the Ca concentration in the inner and outer fluids maintains a gradient of 1: 10000 under the action of various energy-dependent pumps. Ca in most cells binds to mitochondria and endoplasmic reticulum. After ischemia and hypoxia, tissue ATP is rapidly depleted, causing Ca to be released from the mitochondria and endoplasmic reticulum. After the circulation was restored (ie, reperfusion), a large amount of extracellular fluid Ca was caused to flow in because the energy-dependent pump function had not been restored. As a result, the Ca concentration in the intracellular fluid rapidly increased to 200 times that of normal. This condition is called calcium overload. On the one hand, it directly causes vasoconstriction of important organs such as heart, brain, kidney, liver, and lung. On the other hand, it activates phospholipase A2, which releases arachidonic acid from the cell membrane. Under the action of oxygenase and cyclooxygenase, a variety of free radical intermediates, thromboxane and leukotriene are generated.
- The above substances have extremely deep biological activities; prostaglandin G (PGG2) and prostaglandin H2 are endogenous peroxides and have the properties and functions of free radicals; thromboxane A2 (TxA2) can contract smooth muscle and platelet aggregation; leukotriene (LT) can contract coronary arteries and reduce myocardial contractility; LTB4 is a powerful leukocyte chemotactic and aggregation factor that can exacerbate the inflammatory response; arachidonic acid hydrogen peroxide can be converted to LT. Although prostacyclin has the ability to antagonize TxA2, its production is often reduced by damage to vascular endothelial cells during ischemia and hypoxia. Xanthine dehydrogenase in cells is rapidly transformed into xanthine oxidase under the action of Ca and calcium-binding protein during ischemia and hypoxia. At the same time, adenosine triphosphate (ATP) is degraded to hypoxanthine. When blood flow is restored (reperfusion), molecular oxygen and hypoxanthine that enter the body serve as a substrate for xanthine oxidase, and react to form uric acid and superoxide anions.
- The structure and function of mitochondria are impaired: most of the oxygen molecules that enter the body in normal state, under the action of cytochrome oxidase complex, receive 4 electrons in mitochondria, which is reduced to water (ie, tetravalent reduction). Only about 1 ~ 2% of O2 is reduced by unit price, and 1 electron is generated to generate O $. This is called a breathing chain leak. After ischemia and reperfusion, mitochondrial function and structure were significantly impaired, tetravalent reduction was reduced, leakage increased, and as a result, O $ production increased.
- In addition, during ischemia-reperfusion, changes in certain enzymes can also increase O $. For example, the reduced coenzyme (NADPH) increases during ischemia, and O2 becomes O $ under the action of NADPH oxidase.
- The increase of O $ under any conditions, if it exceeds the body's ability to scavenge, will generate hydroxyl radicals (· OH) under iron catalysis. · In addition to denaturing proteins and other organic molecules, OH can react with the hydrophobic part of the cell's lipid membrane (especially at the double bond part) to generate lipid free radicals (L):
- L can react with oxygen to form lipid peroxy groups (alkperoxy, LOO), and LOO can react with other lipids to form L and LOOH (hydrolipid peroxide).
- The above reaction is called first-order initiation and can be carried out cyclically in a chain reaction.
- After the formation of LOOH, homogeneous splitting occurs spontaneously or under the catalysis of transition metal ions, and LOO and LO (lipidoxy) are formed again. LOO and LO can cause lipid peroxy reaction again, so that the reaction continues cyclically. This process is called secondary priming.
- Polyvalent unsaturated fatty acids are the main constituents of biofilms. Therefore, the process of lipid peroxide formation is the destruction of cells, which can cause changes in the liquidity, fluidity, cross-linking and permeability of membranes; mitochondrial oxidative phosphorylation disorders; lysosome rupture, and cell autolysis. OH and lipid radicals can extract H from nucleic acids and proteins, or react with addition to form nucleic acid and protein radicals. A protein free radical can react with another protein to form a dimer, trimer, or multimer, which denatures the protein and inactivates the enzyme protein. In addition, oxygen free radicals can also act on the DNA and cause the DNA to break. ; Act on sugar molecules, leading to disorders of glucose metabolism and cell receptor dysfunction. Lipid peroxide can be decomposed into aldehydes (such as malonaldehyde). It is a bifunctional compound that can react with amino-containing compounds such as proteins, nucleic acids, and brain phospholipids to cause cross-linking and loss of function. Certain thiol-containing enzymes are inactivated, eventually leading to cell failure or death. [1]
- It has long been confirmed that many ischemia-related diseases have clinical symptoms that often worsen after recanalization of blood vessels, restoration of blood circulation, or irreversible cell death. After the cardiopulmonary resuscitation, there is no reflow of the brain and subsequent brain death; severe heart rhythm disturbances after thrombolysis in acute myocardial infarction, etc., have been related to reperfusion injury. Clinical and experimental studies have confirmed that reperfusion injury is related to the pathogenesis of the following diseases: cerebral infarction, acute myocardial infarction, no-reflow phenomenon after cardiopulmonary resuscitation, stress ulcers, pancreatitis, burns, preservation and transplantation of isolated organs , Intestinal ischemia, necrotizing enterocolitis, intermittent claudication, acute tubular necrosis, liver failure after shock, and
- Any method and medicine to prevent the formation and scavenging of free radicals can be effective.
- Prevent reperfusion or significant decrease in blood flow of tissues and organs: during the ischemic period, the oxygen consumption of the tissue should be reduced as much as possible (such as lowering the temperature); Ca blockers should be used before reperfusion; In addition, special attention should be paid to preventing "reperfusion" injury caused by severe ischemia of tissues and organs: when the tissue is severely ischemic, the cells are hypoxic, but the concentration of Ca is not low, as a result, energy-dependent pump function and Ca within Flow and cause the formation of oxygen radicals. Studies have shown that during cardiopulmonary resuscitation, if the compression effect is not ideal and the cardiac output is too low, the degree of central nervous system damage is more serious than that of blood flow cessation. Therefore, the time and extent of tissue ischemia should be shortened and reduced as much as possible.
- Enzymes that scavenge oxygen radicals: Enzymes that scavenge oxygen radicals include peroxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-PX). Among them, CAT and GSH-PX do not directly scavenge oxygen radicals, but scavenge oxygen radical precursors or lipid peroxides. In addition, under the action of glutathione reductase, reduced coenzyme can turn oxidized glutathione into reduced glutathione, and regain its function. There are only a few reports of SOD applications.
- Vitamin C and Vitamin E: Vitamin E, also known as alpha tocopherol, mainly exists in cell membranes, mitochondrial membranes and endoplasmic reticulum membranes. It has a phenolic hydroxyl group, which can give its active hydrogen atom to free radicals, making it a stable molecule. It eventually becomes -tocoquinone. In this process, one -tocopherol molecule can scavenge two free radicals. In addition to directly eliminating free radicals, vitamin C can also restore -tocoquinone to a prototype of vitamin E, and continue to play its role in eliminating free radicals. Therefore, as long as there is a sufficient amount of vitamin C, the concentration of vitamin E can continue to work.
- Coenzyme Q10: an antioxidant and membrane stabilizer, is an electron carrier in the process of electron transfer in the mitochondrial respiratory chain. It has many functions such as scavenging free radicals produced by lipid peroxidation, preventing ischemic mitochondrial damage, and maintaining the integrity of myocardial calcium ion channels. At present, it has been used for a variety of diseases related to ischemia and reperfusion damage, such as angina pectoris, myocardial protection during coronary thrombolysis, and heart rhythm disorders.
- Deferoxamine: Fe is an indispensable catalyst in the formation of · OH, and · OH is an oxygen free radical that reacts with membrane lipids to generate ester peroxides that cause cell damage. Therefore, reducing Fe can prevent or reduce cell damage. Deferoxamine can chelate with iron ions to form complexes, reduce Fe ion concentration, and thus reduce the formation of · OH.
- Mannitol, allopurinol, glucose, magnesium sulfate, and the Chinese medicine madder and breviscapus have the effect of scavenging free radicals.