BIOCHEMICAL/CELLULAR DETERMINANTS OF LUNG OZONE INJURY

肺臭氧损伤的生化/细胞决定因素

基本信息

批准号：
3253532
负责人：
DAVID J BASSETT
金额：
$ 22.17万
依托单位：
WAYNE STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1991
资助国家：
美国
起止时间：
1991-10-17 至 1995-06-30
项目状态：
已结题

项目摘要

The initial interaction of ozone with lung tissue results in damage to alveolar and bronchiolar epithelia and the infiltration of polymorphonuclear leukocytes (PMNs). Preliminary studies have demonstrated that these cells have the potential to increase the generation of reactive oxygen intermediates within the lung. A possible contribution of these cells to the development of lung injury was further demonstrated by decreased ozone-induced lung permeability damage in rats made neutropenic by cyclophosphamide pretreatment. The present proposal is designed to identify the biochemical determinants of initial ozone injury, and to test the hypothesis that ozone-induced inflammatory cells contribute to the initial epithelial damage, and subsequently interfere with epithelial and extracellular matrix repair processes. The initial biochemical and cellular events associated with the first 6 hours of exposure of rats to ozone concentrations of < 1.0 ppm will be established by correlating changes in lung metabolic capabilities with infiltration of PMNs and increases in lung permeability. The biochemical and cellular determinants of initial lung cell injury will be investigated using sensitive measurements of lipid damage, enzyme inactivation, and increased permeability in lungs isolated from O3-exposed rats with altered anti- oxidant enzyme activities and tissue glutathione levels, and with increased and decreased lung PMN contents. Lung PMN content will be increased by pretreatment by intratracheal administration with a chemotactic peptide. PMN-infiltration will be diminished by pretreatment with rabbit anti-sera against rat PMNs. Measurements of lavage cell superoxide-anion generation and luminol-amplified chemiluminescence will be used to establish the potential of infiltrating inflammatory cells to contribute to O3-induced lung damage. The consequences of altered anti-oxidant defenses, PMN infiltration, and continued ozone exposure on epithelial and extracellular matrix repair processes will be evaluated in lungs isolated from rats exposed for 6 hours a day to 0.5 ppm ozone for up to 14 days. Measurements of cell turnover and extracellular matrix protein synthesis will be correlated with changes in lung intermediary metabolism and with specific cell metabolic functions. These studies are designed to increase our understanding of the mechanisms of ozone-induced lung injury and identify how differences in inflammatory cell infiltration and in anti-oxidant defenses might account for differences in susceptibility to the damaging effects of ozone exposure observed in humans.

臭氧与肺组织的最初相互作用会导致肺组织损伤肺泡和细支气管上皮及其浸润多形核白细胞（PMN）。初步研究表明这些细胞有可能增加反应性物质的产生肺内的氧气中间体。这些的可能贡献进一步证明了细胞对肺损伤发展的影响减少臭氧引起的中性粒细胞减少大鼠肺通透性损伤通过环磷酰胺预处理。本提案旨在确定初始臭氧损伤的生化决定因素，并进行测试假设臭氧诱导的炎症细胞有助于最初的上皮损伤，随后干扰上皮和细胞外基质修复过程。最初的生化和与大鼠暴露于环境的前 6 小时相关的细胞事件 < 1.0 ppm 的臭氧浓度将通过关联确定 PMN 浸润导致肺代谢能力发生变化肺通透性增加。生化和细胞决定因素最初的肺细胞损伤将使用敏感的方法进行研究脂质损伤、酶失活和增加的测量从暴露于 O3 的大鼠中分离出的肺通透性发生改变氧化酶活性和组织谷胱甘肽水平，并且随着增加并降低肺中 PMN 含量。肺中 PMN 含量将增加通过气管内施用趋化肽进行预处理。兔抗血清预处理可减少 PMN 浸润对抗大鼠 PMN。灌洗细胞超氧阴离子产生的测量鲁米诺放大化学发光将用于建立浸润炎症细胞有助于 O3 诱导的潜力肺部损伤。抗氧化防御改变的后果，PMN 上皮细胞和细胞外细胞浸润以及持续的臭氧暴露将在大鼠分离的肺中评估基质修复过程每天暴露在 0.5 ppm 臭氧中 6 小时，持续时间长达 14 天。测量值细胞周转和细胞外基质蛋白合成的影响与肺中间代谢的变化以及特定的细胞代谢功能。这些研究旨在提高我们的了解臭氧引起的肺损伤的机制并确定炎症细胞浸润和抗氧化剂的差异如何防御可能会解释对破坏性的敏感性的差异观察到人类暴露于臭氧的影响。