BIOCHEMICAL MECHANISMS OF REPERFUSION LUNG INJURY

再灌注肺损伤的生化机制

• 批准号: 3357932
• 负责人: THOMAS P KENNEDY
• 金额: $ 16.02万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1988
• 资助国家: 美国
• 起止时间: 1988-09-01 至 1993-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3357932
• 关键词: adenosine triphosphate; blood proteins; eicosanoid metabolism; enzyme inhibitors; erythrocytes; free radicals; high performance liquid chromatography; ischemia; laboratory rabbit; leukocytes; perfusion; pulmonary circulation; pulmonary edema; sheep; superoxides; vascular endothelium permeability

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.

缺血再灌注过程中产生的氧化损伤 据报道，在许多器官中都有组织，但情况并不好。 在肺部研究。 再灌注损伤是一个潜在的重要 肺部疾病的机制，并可能解释许多 复张性肺水肿的临床表现 肺移植后水肿、肺栓塞或 甚至成人呼吸窘迫综合征（ARDS）。 在其他器官中， 缺血期间细胞ATP的下降与 再灌注过程中超氧阴离子（O2-）的产生， 再次变得可用。 肺可能不同于其他 器官，然而，在细胞内ATP可以下降，即使在 如果由于微血管阻塞或 大栓塞阻止了底物葡萄糖向细胞的输送， 肺泡毛细血管单位。 在这些条件下，氧化剂可以 甚至在再灌注之前产生，因为O2的可用性是 通过肺泡通气维持。 本提案的目标是研究生物化学和 通气和再灌注损伤的病理生理学 非通气灌注兔肺。 氧化剂的贡献 将用自由基清除剂评估再灌注损伤， 氧化剂生成抑制剂和超氧化物的直接测定 (02-)通过灌注肺产生。 下降的时间过程 高能磷酸盐和它们在再灌注后的恢复将 通过HPLC分析肺中ATP及其代谢产物进行监测 组织. 炎症介质的作用 研究花生四烯酸代谢对再灌注损伤的影响 用抑制剂和测量肺灌注液中的介质。 循环血液白细胞、红细胞和血浆的影响 蛋白质如白蛋白、血浆铜蓝蛋白和转铁蛋白， 还将研究再灌注损伤。 生化 该项目中定义的机制应导致改进 对几种重要肺部疾病的病理生理学了解。