PULMONARY OXYGEN TOXICITY--MECHANISMS AND INTERVENTIONS

这项建议中的研究旨在提供对 肺氧中毒的基本机制。总体目标是 为了更好地了解细胞生物学变化导致的 肺表面活性物质系统在氧中毒时发生的变化，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)评估表面活性物质的变化 兔肺II型细胞的代谢和能量状态 在高氧性损伤和恢复过程中；(2)使用氧中毒模型 探讨表面活性物质代谢的协同调节机制 功能；(3)评估氧对表面活性物质清除能力的影响 在体内；(4)确定表面活性物质之间是否存在相关性 代谢和细胞增殖能力；(5)测定能力 使用抗氧化剂来防止亚致死性II型肺泡细胞损伤。这些 将通过评估基础水平和刺激表面活性物质来实现目标 合成、分泌和重新摄取(磷脂和脱脂蛋白) 在氧气中毒和恢复期间(在室内空气中)使用放射性标记 磷脂和蛋白质。此外，ATP、NADH、NADPH水平将 结合DNA链的测量在这些细胞中进行评估 NICKS和ADP-核糖基化反应。II型细胞增殖过程中 给药可以阻止氧气中毒的恢复。 抑制多胺的合成，这将被用来确定 抑制增殖会影响表面活性物质的代谢。最后， 向第II类运送巯基保护剂和其他抗氧化剂 细胞将通过已公布的气管内给药方法实现。这个 然后将分析抗氧化剂增强的细胞以确定这是否 治疗干预改善肺表面活性物质代谢的变化 并将这些发现与体内的 这些治疗的生理效果。

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.