THE PROBLEM: EFFECTS OF ISCHAEMIC HYPOXIA
Cells of normally functioning organs derive their energy from the oxidation of substrates obtained from the circulating blood (glucose, fatty acids, amino acids, or ketones); in the case of liver and muscle energy is obtained from breakdown of endogenous glycogen. Energy is stored within cells as phosphate bonds of adenosine triphosphate (ATP), creatine phosphate, and other nucleotides. Cellular composition is maintained in homeostasis by numerous enzymic reactions acting in concert under the directions of hormones or key compounds such as cyclic adenosine monophosphate.
Ischaemic damage
Ischaemia cuts off nutrients and oxygen supply to the organ. Continuing metabolic activity of the organ's parenchymal and other cells causes a cascade of events leading to irreversible cell damage and death. Metabolism becomes anaerobic; glycolysis causes depletion of high energy phosphate compounds. Degradation of ATP increases cellular levels of adenosine, inosine, and hypoxanthine. Depletion of the cell's energy stores inactivates Na⫀- K⫀-ATPase, the enzyme system controlling the sodium pump of the cell membrane. As fuel reserves disappear, sodium and chloride, freely permeable electrolytes which are normally actively excluded from the cell, diffuse into the cell down concentration gradients. As the osmotic force of non-permeable cellular proteins and anions is no longer balanced by the extrusion of sodium, water floods the increasingly swollen cell. Mitochondrial respiration is inhibited, and calcium enters the cytosol and mitochondria. Anaerobic metabolism temporarily uses glucose stores to generate ATP, but lactic acid is also produced, leading to progressive intracellular acidosis which activates lysosomal lytic enzymes leading to autolysis.
Most organs and cells can tolerate ischaemic hypoxia for 30 to 60 min without permanent damage. Parenchymal cells of most transplantable organs are generally similar in their tolerance to ischaemia. Rapidly metabolizing tissues are less tolerant: the heart is particularly vulnerable because it continues to beat until all energy reserves are depleted. Most organs are irreversibly damaged by 90 to 120 min of ischaemia at body temperatures. Vascular damage occurs along with the parenchymal effects: the cells of the vascular endothelial lining bear the brunt of this injury. These effects are slowed, but not reversed, by cooling.
Reperfusion damage
Reperfusion injury is an added hazard which contributes to irreversible damage. Accumulation of metabolic end products such as hypoxanthine, under anaerobic conditions, can set the stage for reperfusion injury. When blood flow is restored, oxygen influx leads to the formation of toxic compounds such as hydroxen peroxide, and superoxide and hydroxyl radicals. These active free radicals of oxygen produce further cellular, membrane, and microvascular injury. Under normal circumstances these harmful radicals are short lived, as they are rapidly cleared by endogenous scavenging mechanisms. Ischaemia depletes these endogenous mediators.
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