Normal cellular respiration produces partially reduced reactive oxygen metabolites. Mitochondria reduce most molecular oxygen completely to water, with the addition of four electrons by the mitochondrial respiratory chain. A fraction of oxygen used metabolically (usually less than 5 per cent) undergoes the addition of a single electron to form the superoxide anion (O2-); this process occurs mainly in the ubiquinone-cytochrome B and NADH dehydrogenase regions of the electron transport chain. Production of incompletely reduced oxygen increases proportionately with the increase in intracellular PO2. At physiological pH, superoxide is protonated to form the perhydroxyl radical (O2H-), a stronger oxidant that diffuses through cell membranes. Superoxide formed within mitochondria may interact with cellular constituents directly, but most reacts further to form hydrogen peroxide and reactive hydroxyl radicals (OH ■) by redox cycling in the presence of catalytic iron or copper. In hyperoxia, the elevated intracellular PO2 and the law of mass action dictate that mitochondria and other intracellular organelles will form excess superoxide. Iron is normally present in low-molecular-weight complexes, and the production of excess superoxide results in the iron-catalyzed formation of hydroxyl radicals. These highly reactive radicals engage in destructive oxidation and reduction reactions with cell components.
Superoxide can also react rapidly (rate constant greater than 109 l/mol/s) with -NO formed by inflammatory cells (e.g. alveolar macrophages) or lung parenchymal cells. This mechanism may be particularly important during sepsis and the reoxygenation phase of ischemia-reperfusion injury. Excess -NO reacts with superoxide to form peroxynitrite (ONOO-), which mediates several cytotoxic effects of -NO such as oxidation of Fe-S centers in respiratory enzymes. Peroxynitrite is a strong long-lived oxidant that decomposes at physiological pH to form a species with the reactivity of hydroxyl radicals ('OH -+NO2'). Important proteins that contain tyrosine residues, including surfactant protein A and manganese superoxide dismutase, may be nitrated and functionally inhibited by peroxynitrite.
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