LUNG CELLULAR HYPOXIA AND OXIDANT STRESS

肺细胞缺氧和氧化应激

• 批准号: 2031024
• 负责人: Robert M Jackson
• 金额: $ 23.28万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-07-08 至 2000-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2031024
• 关键词: aconitate hydratase; cytochrome oxidase; enzyme activity; enzyme induction /repression; genetically modified animals; laboratory mouse; laboratory rabbit; lung alveolus; lung ischemia /hypoxia; oxidative stress; respiratory epithelium; superoxide dismutase

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.

描述（改编自申请人摘要）：肺组织缺血 以及由于血流和通气中断而导致的细胞缺氧， 如在肺移植期间，肺不张或血栓栓塞，导致 再氧合期间的急性肺损伤与急性肺损伤难以区分 呼吸窘迫综合征 线粒体均含锰 超氧化物歧化酶（MnSOD）和细胞溶质，含铜锌 超氧化物歧化酶（CuZnSOD）是重要细胞内抗氧化剂。 MnSOD集中在肺泡上皮II型细胞中，并保护肺泡上皮II型细胞。 肺通过诱导对氧化应激的反应而免受氧化损伤。 MnSOD 蛋白质在II型细胞中相对丰富，MnSOD减少， 增加肺泡细胞对氧化应激的敏感性，包括 由高氧和TNF-α引起的。 这个假设 通过该应用测试的是，缺氧降低了小鼠中SOD的表达， 肺泡Ⅱ型细胞SOD活性降低 是在再氧合和其它过程中氧化损伤的诱发因素 氧化应激的类型。 具体目标是：1）确定 缺氧引起肺泡型上皮细胞减少的生物学意义 II细胞SOD表达; 2）确定缺氧减少的机制 肺泡II型细胞中SOD的表达;以及3）确定是否充满 通过基因转移的MnSOD逆转了对氧化剂的敏感性增加 应力 这些研究将通过使用隔离型 II细胞和转基因小鼠的体内实验， 研究SOD表达减少对细胞凋亡的影响。 对肺中氧化应激的反应。 MnSOD基因敲除小鼠 将用于定义MnSOD特异性降低的重要性 表情 由于缺氧对肺泡Ⅱ型细胞SOD的影响 表达尚未得到充分研究，这项研究将填补我们的空白， 肺泡II型细胞生物学知识和缺氧对 抗氧化防御 有可能产生具体的新的 关于缺氧诱导的SOD的生物学重要性的信息 从肺泡II型细胞的消耗和缺氧的机制， 降低II型细胞中的SOD， 将SOD活性恢复到缺氧前的水平，以恢复对 氧化应激