Oxidative Stress

Reactive oxygen species (ROS) are continuously generated during normal metabolism. Mitochondria, activated neutrophils, inflammation, medications, toxins, radiation, and reperfusion of ischemic tissue can all increase ROS production. At physiologic levels, ROS participate in cell signalling and antimicrobial defence. The problem begins when production outpaces the cell’s antioxidant defences. The most useful clinical model is not “free radicals are present.” They are always present. Oxidative stress means that the balance has shifted far enough to damage membrane lipids, proteins, DNA, or redox-sensitive enzymes. Ischemia–reperfusion is a classic example: oxygen returns to previously ischemic tissue, and the sudden increase in ROS can extend injury beyond the original period of poor perfusion. Glutathione is one of the cell’s major intracellular antioxidants. Glucose-6-phosphate dehydrogenase, or G6PD, is the rate-limiting enzyme of the pentose phosphate pathway. It generates NADPH, which allows cells to regenerate reduced glutathione and neutralize oxidants. Red blood cells are unusually dependent on this pathway because they have no mitochondria and no alternative source of NADPH. Under a substantial oxidant load, their hemoglobin and membrane are damaged first, producing hemolysis. This mechanism...