EARLY EFFECTS OF OXYGEN ON LUNG METABOLIC FUNCTION

氧气对肺代谢功能的早期影响

• 批准号: 3347833
• 负责人: DAVID J BASSETT
• 金额: $ 11.29万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-01-15 至 1994-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3347833
• 关键词: NAD(P)H dehydrogenase; adenosine triphosphate; antioxidants; bioenergetics; carbon; cell type; cellular pathology; cytotoxicity; early diagnosis; electron microscopy; enzyme inhibitors; enzyme mechanism; fatty acid biosynthesis; fatty acid metabolism; glucose 6 phosphate; glutathione; glyceraldehyde 3 phosphate dehydrogenase; glycolysis; histopathology; hyperoxia; laboratory rat; lung disorder; microscopy; mitochondria; molecular site; morphology; neutrophil; nutrition related tag; oxidation reduction reaction; oxidative phosphorylation; oxygen tension; pathologic process; pentose phosphate; pulmonary edema; pyruvate dehydrogenase; radionuclides; radiotracer; respiratory epithelium; respiratory function; scintillation counter; spectrometry; thin layer chromatography; toxicant interaction; vitamin E deficiency

It is well established that exposure of experimental animals to hundred percent oxygen for longer than 48 hours results in adverse alterations of lung structure and function. It is the objective of this project to use an isolated perfused rat lung preparation to assess changes in lung metabolic function that occur prior to observable alterations in pathology. Based on previous studies demonstrating early oxygen-induced impairment of lung pyruvate metabolism, the specific hypothesis that oxygen inactivation of mitochondrial enzymes results from failure of cellular anti-oxidant defense mechanisms, is to be tested by the following specific aims. The effects of oxygen on lung mitochondrial function will be determined by measurement of changes in perfused lung fatty acid metabolism, pyruvate dehydrogenase activity and oxidation of cytosolic reducing equivalents following in vivo exposures to 100% oxygen. The possible mechanisms of mitochondrial impairment will be investigated by measurements of metabolic function in the presence of specific inhibitors of lung anti-oxidant defense mechanisms. Differences in the way endothelial and epithelial cells are affected by oxygen will be determined by measurements of changes in isolated cell metabolic function when exposed in vitro to oxygen. Possible protective effects of pretreatment with heterocyclic urea compounds, that increase lung superoxide dismutase and catalase activities, will be assessed in pretreated perfused lungs and cultured cells by measuring changes in the sensitivity of metabolic functions to the adverse effects of oxygen-exposure. In order to establish the possible role of polymorphonuclear leukocytes (PMNs) in oxygen-induced lung injury and to correlate early injury with enhanced PMN adherence, metabolic functions will be assessed in isolated lungs and endothelial cells exposed to oxygen in the presence of PMNs. These studies will provide a better understanding of the early biochemical events that lead to oxygen toxicity, and so provide the basis for the future development of protective interventions when oxygen has to be used to treat severe hypoxemia resulting from respiratory failure and acute lung injury.

众所周知，实验动物暴露于 百分百氧气持续超过 48 小时会导致不良后果 肺结构和功能的改变。 这是目标 该项目使用分离的灌注大鼠肺制剂 评估之前发生的肺代谢功能的变化 病理学上可观察到的改变。 根据之前的研究 证明早期氧诱导的肺丙酮酸损伤 新陈代谢，具体假设是氧失活 线粒体酶是细胞抗氧化失败的结果 防御机制，是要通过以下具体目标来检验的。 氧气对肺线粒体功能的影响 通过测量灌注肺脂肪酸的变化来确定 代谢、丙酮酸脱氢酶活性和氧化 体内暴露于 100% 后的胞质还原当量 氧。 线粒体损伤的可能机制 通过测量代谢功能来研究 肺部抗氧化防御的特异性抑制剂的存在 机制。 内皮细胞和上皮细胞途径的差异 细胞受氧的影响将通过测量来确定 体外暴露时分离细胞代谢功能的变化 到氧气。 预处理的可能保护作用 杂环脲化合物，增加肺超氧化物 歧化酶和过氧化氢酶活性，将在预处理中进行评估 通过测量灌注肺和培养细胞的变化 代谢功能对不利影响的敏感性 氧气暴露。 为了确定可能的作用 多形核白细胞（PMN）在氧诱导性肺损伤中的作用 并将早期损伤与增强的 PMN 依从性联系起来， 将在离体肺中评估代谢功能 在 PMN 存在的情况下，内皮细胞暴露于氧气。 这些 研究将有助于更好地理解早期 导致氧中毒的生化事件，从而提供 为未来制定保护性干预措施奠定基础 必须使用氧气来治疗由以下原因引起的严重低氧血症 呼吸衰竭和急性肺损伤。