LUNG CELLULAR HYPOXIA AND OXIDANT STRESS

描述(改编自申请人的摘要)：肺组织缺血 以及由于血流和换气中断而导致的细胞缺氧 在肺移植过程中，肺不张或血栓栓塞症会导致 复氧时的急性肺损伤与急性肺损伤难以区分 呼吸窘迫综合征。线粒体中的含锰元素 超氧化物歧化酶与胞内含铜、锌 超氧化物歧化酶是细胞内重要的抗氧化剂。 MnSOD集中在肺泡II型上皮细胞中，保护肺泡上皮细胞 肺通过诱导氧化应激而受到氧化损伤。锰超氧化物歧化酶 在II型细胞中蛋白质相对丰富，而MnSOD减少，通过 本身会增加肺泡细胞对氧化应激的敏感性，包括 由高氧和肿瘤坏死因子-α产生。这个假设将会是 这一应用证明，低氧降低了大鼠脑内超氧化物歧化酶的表达 肺泡II型细胞及肺泡II型细胞超氧化物歧化酶活性降低 是复氧和其他过程中氧化剂损伤的易感因素 氧化应激的类型。要解决的具体目标是：1)确定 缺氧性肺泡型减少的生物学意义 II细胞超氧化物歧化酶的表达；2)确定低氧减少的机制 肺泡II型细胞中超氧化物歧化酶的表达；以及3)决定是否再充盈 通过基因转移获得的MnSOD逆转了对氧化剂敏感性的增加 压力。这些研究将使用隔离类型的组合来完成 兔Ii细胞和转基因小鼠体内实验 探讨超氧化物歧化酶表达降低对细胞的影响 肺部对氧化应激的反应。杂合子MnSOD基因敲除小鼠 将用于定义特定降低MnSOD值的重要性 表情。低氧对肺泡II型细胞超氧化物歧化酶的影响 表达还没有被充分调查，这项研究将填补我们在 肺泡II型细胞生物学知识及缺氧对肺泡II型细胞生物学的影响 抗氧化剂防御。存在产生特定新消息的潜力 关于低氧诱导的超氧化物歧化酶生物学重要性的信息 肺泡II型细胞的耗竭及其缺氧机制 降低II型细胞中的超氧化物歧化酶及丹参的潜在治疗作用 将超氧化物歧化酶活性恢复到缺氧前的水平，以恢复对 氧化应激。

DESCRIPTION (Adapted from the applicant's abstract): Lung tissue ischemia and cellular hypoxia due to interruption of blood flow and ventilation such as during lung transplantation, atelectasis, or thromboembolism, result in acute lung injury during reoxygenation which is indistinguishable from acute respiratory distress syndrome. Both mitochondrial manganese-containing superoxide dismutase (MnSOD) and cytosolic, copper zinc containing superoxide dismutase (CuZnSOD) are critical intracellular antioxidants. MnSOD is concentrated in alveolar epithelial Type II cells and protects the lung from oxidant injury by induction in response to oxidant stress. MnSOD protein is relatively abundant in Type II cells and a decrease in MnSOD, by itself, increases sensitivity of alveolar cells to oxidant stress, including that produced by hyperoxia and TNF-alpha. The hypothesis that will be tested by this application is that hypoxia decreases SOD expression in alveolar Type II cells and that decreased alveolar Type II cell SOD activity is a predisposing factor for oxidant injury during reoxygenation and other types of oxidant stress. The specific aims to be addressed are: 1) define the biological importance of the hypoxia-induced decreases in alveolar Type II cell SOD expression; 2) identify the mechanisms by which hypoxia reduces SOD expression in alveolar Type II cells; and 3) determine whether repletion of MnSOD by gene transfer reverses the increased sensitivity to oxidant stress. These studies will be done by using a combination of isolated Type II cells from rabbits and in vivo experiments on transgenic mice to investigate the impact of the reduction in SOD expression on the cellular responses to oxidant stress in the lung. Heterozygous MnSOD knockout mice will be used to define the importance of specific decreases in MnSOD expression. Since the effects of hypoxia on alveolar Type II cell SOD expression has not been fully investigated, this study will fill gaps in our knowledge of alveolar Type II cell biology and the effects of hypoxia on antioxidant defenses. The potential exists for generating specific new information regarding the biological importance of hypoxia-induced SOD depletion from alveolar Type II cells and the mechanisms by which hypoxia decreases SOD in Type II cells and the potential therapeutic efficacy of restoring SOD activity to pre-hypoxia levels for restoring resistance to oxidant stress.