Varani J, Ward P A
Department of Pathology, University of Michigan Medical School, Ann Arbor 48109.
Biol Signals. 1994 Jan-Feb;3(1):1-14. doi: 10.1159/000109521.
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.
当血管外刺激引发毛细血管扩张和通透性增加，并将循环中的中性粒细胞募集到该部位时，急性炎症过程就开始了。在这些部位可见血管结构受损，且在病变发展早期就出现损伤迹象。过去10年里，许多实验室开展的研究已经阐明了许多导致炎症部位内皮细胞损伤的生化事件。活化的中性粒细胞紧密结合到靶细胞上，同时中性粒细胞会产生超氧阴离子和过氧化氢，并释放颗粒酶。中性粒细胞衍生的过氧化氢进入靶细胞内部，在那里它会导致细胞ATP分解并积累ATP代谢产物。其中包括黄嘌呤和次黄嘌呤，它们是黄嘌呤氧化酶的底物。靶细胞暴露于其他中性粒细胞产物（特别是弹性蛋白酶）会诱导黄嘌呤脱氢酶向黄嘌呤氧化酶的相互转化。该酶的氧化酶形式将次黄嘌呤和黄嘌呤转化为尿酸的过程同时会产生超氧阴离子。除了提供细胞内还原当量的来源外，靶（内皮）细胞也是铁的来源。靶细胞中的铁通过细胞内氧化剂维持在还原形式，它与中性粒细胞衍生的过氧化氢结合形成高反应性（且剧毒）的羟基自由基。这种氧化剂很可能是损伤的直接介质。
