Upon reperfusion of ischemic tissues, reactive
oxygen metabolites are generated and are responsible for much of the organ damage. Experimental studies have revealed two main sources of these metabolites: 1) the oxidation of
hypoxanthine to
xanthine and on to
uric acid by the
oxidase form of
xanthine oxidoreductase and 2) neutrophils accumulating in ischemic and reperfused tissue. Blocking either source will reduce
reperfusion damage in a number of experimental situations. Although
xanthine oxidoreductase activity may be unmeasurably low in organs other than liver and intestine, it may be involved in
reperfusion injury elsewhere because of its localization in capillary endothelial cells. Time course considerations suggest that substrate accumulation and
NADH inhibition of
dehydrogenase activity may be more important in the pathogenesis than conversion of
xanthine dehydrogenase into the
oxidase form. Neutrophil accumulation may be partly due to
oxidants in the first place, suggesting a link between the two sources of reactive
oxygen metabolites. In the clinical context, many of the sequelae of perinatal
asphyxia may be accounted for by
reperfusion damage to organs such as brain, kidney, heart, liver, and lungs. During
asphyxia, substrates of
xanthine oxidase accumulate, upon
resuscitation the cosubstrate
oxygen is introduced, and evidence for
oxidant production and effects has been obtained. In the pathogenesis of brain damage after
asphyxia, both microvascular injury and parenchymal cell damage are important.
Oxygen metabolites are involved in the former, but in the latter process their role is less clear because
ischemia-reperfusion triggers not only
oxidant production but many other phenomena, including gene activation,
ATP depletion,
glutamate accumulation, and increase of intracellular
calcium. A severe insult results in cell
necrosis, but more moderate
asphyxia may cause delayed neuronal death through apoptosis. The time course of the changes in high energy
phosphates as well as of selective neuronal death suggest that in the first hours of life there is a "therapeutic window," with future possibilities for prevention of permanent damage.