PULMONARY OXYGEN TOXICITY--MECHANISMS AND INTERVENTIONS

本提案中的研究旨在深入了解 肺氧中毒的基本机制。 总的目标是 为了更好地理解细胞生物学改变， 氧中毒时发生的肺表面活性物质系统变化，以及 确定针对患者的治疗干预措施的疗效， 细胞水平。 具体目标是（1）评估表面活性剂的变化 分离自兔的II型肺细胞的代谢和能量状态 在高氧损伤和恢复过程中;（2）采用氧中毒模型 确定表面活性剂代谢的协调调节机制， 功能;（3）评估氧诱导的表面活性剂清除率变化 体内;（4）确定表面活性剂之间是否存在相关性 代谢和细胞增殖能力;以及（5）确定 抗氧化剂来防止亚致死的II型肺细胞损伤。 这些 通过评估基础水平和刺激表面活性剂， 合成、分泌和再摄取（磷脂和脱辅基蛋白） 在氧中毒和恢复期间（在室内空气中），使用放射性标记的 磷脂和蛋白质。 此外，ATP、NADH、NADPH的水平将 在这些细胞中结合DNA链的测量进行评估 切口和ADP-核糖基化反应。 II型细胞增殖 从氧中毒中恢复可以通过给予药剂 其抑制多胺合成，这将用于确定是否 增殖抑制影响表面活性剂代谢。 最后， 巯基保护剂和其它抗氧化剂向II型糖尿病的递送 细胞将通过公开的体内递送方法获得。 的 然后将分析抗氧化剂增强的细胞，以确定这是否 治疗干预改善表面活性物质代谢的变化 在氧化应激期间，这些发现将与体内 这些治疗的生理功效。

The studies in this proposal are designed to provide insight into the fundamental mechanisms of pulmonary oxygen toxicity. The overall goal is to better understand the cell biological alterations responsible for the pulmonary surfactant system changes which occur in oxygen toxicity, and determine the efficacy of therapeutic interventions directed at the cellular level. Specific goals are (1) to assess changes in surfactant metabolism and energy status in type II pneumocytes isolated from rabbits during hyperoxic injury and recovery; (2) to use the oxygen toxicity model to determine mechanisms of coordinate regulation of surfactant metabolic functions; (3) to assess oxygen-induced changes in clearance of surfactant in vivo; (4) to determine whether there is a correlation between surfactant metabolism and cell proliferative ability; and (5) to determine the ability of antioxidants to prevent sublethal type II pneumocyte damage. These goals will be achieved by assessing basal level and stimulated surfactant synthesis, secretion, and re-uptake (of both phospholipids and apoproteins) during oxygen toxicity and recovery (in room air) using radiolabeled phospholipids and proteins. In addition, levels of ATP, NADH, NADPH will be assessed in these cells in conjunction with measurements of DNA strand nicks and ADP-ribosylation reactions. Type II cell proliferation during recovery from oxygen toxicity can be halted by administration of agents which inhibit polyamine synthesis, which will be used to determine whether inhibition of proliferation affects surfactant metabolism. Finally, delivery of sulfhydryl protective agents and other antioxidants to type II cells will be achieved by published methods of intratracheal delivery. The antioxidant augmented cells will then be analyzed to determine whether this therapeutic intervention ameliorates changes in surfactant metabolism during oxidant stress and these findings will be compared to the in vivo physiological efficacy of these treatments.