BIOCHEMICAL MECHANISMS OF REPERFUSION LUNG INJURY

缺血再灌注时产生的氧化剂损伤

Injury from oxidants generated during reperfusion of ischemic tissue has been reported in a number of organs but is not well studied in the lung. Reperfusion injury is a potentially important mechanism of disease in the lung, and might explain many manifestations of re-expansion pulmonary edema, pulmonary edema following lung transplantation, pulmonary embolism or even adult respiratory distress syndrome (ARDS). In other organs, the decline in cellular ATP during ischemia has been linked to generation of superoxide anion (02-) during reperfusion when 02 again becomes available. The lung might differ from other organs, however, in that intracellular ATP could fall even in the face of continued supply if vascular occlusion from micro or macroemboli prevented delivery of subtrate glucose to cells of the alveolar capillary unit. Under these conditions, oxidants could be generated even before reperfusion, since 02 availability is maintained by alveolar ventilation. The goal of this proposal is to study the biochemistry and pathophysiology of reperfusion injury in both ventilated and nonventilated perfused rabbits lungs. The contribution of oxidants to reperfusion injury will be assessed with free radical scavengers, inhibitors of oxidant production, and direct assay of superoxide (02-) generation by perfused lung. The time course of decline in high energy phosphates and their recovery after reperfusion will be monitored by HPLC analysis of ATP and its metabolites in lung tissue. The contribution of inflammatory mediators of arachidonic acid metabolism to reperfusion injury will be studied with inhibitors and measurement of mediators in lung perfusate. The effect of circulating blood leukocytes, red cells, and plasma proteins such as albumin, ceruloplasmin and transferrin on reperfusion injury will also be investigated. The biochemical mechanisms defined in this project should lead to an improved pathophysiologic understanding of several important lung diseases.