Mechanisms of neutrophil-dependent and neutrophil-independent endothelial cell injury.
The acute inflammatory process is initiated when an extravascular stimulus provokes capillary dilatation and increased permeability, and recruits circulating neutrophils to the site. Damage to vascular structures is seen at these sites and evidence of injury occurs early in the evolution of the lesion. Studies carried out over the past 10 years in a number of laboratories have elucidated many of the biochemical events that lead to endothelial cell damage at sites of inflammation. Activated neutrophils bind tightly to the target cells and this is accompanied by neutrophil generation of superoxide anion and hydrogen peroxide and by release of granule enzymes. Neutrophil-derived hydrogen peroxide gains access to the interior of the target cell where it induces a breakdown of cellular ATP and a build-up of ATP metabolites. Among these are xanthine and hypoxanthine, substrates for xanthine oxidase. Exposure of the target cell to other neutrophil products (specifically, elastase) induces the interconversion of xanthine dehydrogenase to xanthine oxidase. Formation of uric acid from hypoxanthine and xanthine by the oxidase form of the enzyme results concomitantly in the generation of superoxide anion. In addition to providing a source of intracellular reducing equivalents, the target (endothelial) cell is also the source of iron. Target cell iron, maintained in the reduced form by intracellular oxidants, combines with neutrophil-derived hydrogen peroxide to form the highly reactive (and highly toxic) hydroxyl radical. This oxidant is most likely the direct mediator of injury.
Varani
J
J
Department of Pathology, University of Michigan Medical School, Ann Arbor 48109.
Ward
P A
PA
D004730:Endothelium, Vascular / Q000293:injuries*; D006801:Humans; D007249:Inflammation / Q000473:pathology*; D007501:Iron / Q000378:metabolism; D018375:Neutrophil Activation; D009504:Neutrophils / Q000502:physiology*; D010084:Oxidation-Reduction; D013482:Superoxide Dismutase / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D014969:Xanthine Oxidase / Q000037:antagonists & inhibitors
D014409:Tumor Necrosis Factor-alpha; D013481:Superoxides; D007501:Iron; D013482:Superoxide Dismutase; D014969:Xanthine Oxidase