EARLY EFFECTS OF OXYGEN ON LUNG METABOLIC FUNCTION

氧气对肺代谢功能的早期影响

基本信息

批准号：
6056186
负责人：
DAVID J BASSETT
金额：
$ 15.53万
依托单位：
WAYNE STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1992
资助国家：
美国
起止时间：
1992-01-15 至 2000-08-31
项目状态：
已结题

项目摘要

Acute lung epithelial injuries result in a rapid infiltration of polymorphonuclear granulocytes (PMNs) into the lung which because of their ability to release reactive O2 intermediates and proteinases into their local environment, have been implicated in the pathogenesis of several different lung disorders that include adult respiratory distress syndrome. The major objective of this study is to determine how oxygen treatment might adversely affects acutely-damaged lungs undergoing a PMN inflammatory response. The specific hypotheses to be tested are that PMNs infiltrating into an acutely-damaged lung render it more sensitive to the damaging effects of O2 exposure leading to an accelerated onset of pulmonary oxygen toxicity; and that treatment with the phenyl-urea compound EDU will ameliorate the adverse effects of subsequent oxygen exposure. These hypotheses will be tested by the following specific aims: l) A previously developed model of acute lung epithelial injury based on short-term exposure to ozone (>1ppm) will be used to determine how subsequent exposure to O2 alters the inflammatory process and contributes to enhanced lung injury. 2) Normal, neutropenic and EDU-pretreated rats will be used to establish whether the presence of PMNs within an injured lung contribute to the further damage associated with subsequent exposure to elevated concentrations of O2. 3) The effects of O2 exposure on lung inflammatory cell apoptosis (programmed cell death) will be examined as a possible mechanism by which increased release of PMN-derived proteinases might account for O2-induced damage of injured lungs. 4) The potential of EDU and related compounds to act as reactive oxygen intermediate scavengers will be assessed in acutely-injured lungs, by determining whether or not in vivo treatments ameliorate O2-induced damage to lung macromolecules. 5) The consequences of O2 exposure and/or PMN-derived reactive oxygen intermediate and proteinases on lung homeostatic and repair processes will be assessed as a method for determining the mechanisms and effectiveness of EDU-treatments. Since the management of acute lung injuries often requires the use of O2 therapy to maintain blood oxygenation, the results and model systems generated by this project are prerequisite to the future development of improved strategies for the safe clinical use of oxygen. Such development requires a detailed understanding of how PMNs and O2 adversely affect the ability of the lung to maintain homeostasis and to repair the initial damage without the development of any long term adverse pathological lesions.

急性肺上皮损伤导致肺组织快速浸润多形核粒细胞（PMN）进入肺部，因为它们释放活性 O2 中间体和蛋白酶的能力当地环境与多种疾病的发病机制有关不同的肺部疾病，包括成人呼吸窘迫综合征。本研究的主要目的是确定氧气治疗如何可能会对接受 PMN 的严重受损肺部产生不利影响炎症反应。要检验的具体假设是 PMN 渗透到严重受损的肺部使其对暴露于 O2 的破坏性影响会导致加速发作肺氧中毒；以及用苯基脲处理复合EDU将改善后续吸氧的不良影响接触。这些假设将通过以下具体目标进行检验： l) 先前开发的急性肺上皮损伤模型短期暴露于臭氧（>1ppm）将用于确定如何随后暴露于 O2 会改变炎症过程并有助于以加重肺损伤。 2) 正常、中性粒细胞减少和 EDU 预处理的大鼠将用于确定受伤者体内是否存在 PMN 肺部会导致与随后接触相关的进一步损害到 O2 浓度升高。 3）O2暴露对肺的影响炎症细胞凋亡（程序性细胞死亡）将被检查为 PMN 衍生蛋白酶释放增加的可能机制可能是氧气引起的肺部损伤的原因。 4）潜力 EDU 和相关化合物充当活性氧中间体将通过确定严重受损的肺部来评估清道夫体内治疗是否可以改善 O2 引起的肺损伤大分子。 5) O2 暴露和/或 PMN 衍生的后果活性氧中间体和蛋白酶对肺稳态的影响修复过程将被评估作为确定的方法 EDU 治疗的机制和有效性。自管理以来急性肺损伤通常需要使用 O2 疗法来维持血液氧合，该项目生成的结果和模型系统是未来制定改进的安全战略的先决条件临床上使用氧气。这样的开发需要详细的了解 PMN 和 O2 如何对肺维持功能产生不利影响体内平衡并修复最初的损伤而不发展任何长期不良病理病变。