POLLUTANT INDUCED MUCOCILIARY DYSFUNCTION IN AIRWAYS

众所周知，短期和长期暴露于 包括臭氧在内的气态污染物会改变结构和 呼吸道的功能。然而，确切的机制是通过 哪种呼吸道损伤导致功能异常仍有待进一步研究 澄清了。我们之前(04年和05年)已经表明，吸入 臭氧损害呼吸道粘液清除，这种损害是 主要是由于上皮性分泌物的缺陷，即 暂时与呼吸道炎症有关，它可能是 被选定的炎症介质模仿。我们现在提议 为了检验中心假设，所有三种表现形式 臭氧所致的呼吸道损伤，即气道平滑肌 高反应性、粘膜功能障碍和微血管 充血和渗漏与呼吸道有因果关系 发炎。通过一系列体内和体外研究，包括 绵羊短期暴露在中等水平的臭氧中 基础(2小时1 ppm)，我们将1)确定标记是否 炎症(白细胞、化学介质)与 体内呼吸道高反应性可使呼吸道通畅 肌肉在体外的高反应性，这可以通过 抗炎药，2)鉴定其成分 粘液纤毛相互作用受损最严重 确定哪些炎性介质发挥假定作用，3) 演示顺序激活的可能性 介导呼吸道上皮细胞的炎性物质 功能障碍，以及4)表征炎症的作用 呼吸道粘膜微血管反应的中介物。 长期接触臭氧(0.5ppm，每天4小时，每周5天，6 周)将被用来检验第二个假设 呼吸道上皮细胞的破坏会导致气道平滑肌 高反应性，因为减少了 上皮源性松弛因子。通过相互关联 呼吸道炎症的细胞学和生化指标 不同的生理终点和通过使用适当的 对手，我们希望获得可解释的数据，以便 测试该提案所依据的基本前提。我们相信 这项调查的结果将提供关于 臭氧诱导的呼吸道损伤的发病机制，以及一些 这种信息可以推断为一般的呼吸道疾病。 并构成药物干预的基础。

It is well recognized that short term and long term exposures to gaseous pollutants including ozone can alter the structure and function of the airways. However, the exact mechanisms by which airway injury leads to abnormal function remains to be clarified. We have previously shown (years 04 and 05) that inhaled ozone impairs airway mucus clearance, that this impairment is primarily due to a defect in epithelial secretion, that it is temporarily related to airway inflammation and that it can be mimicked by selected inflammatory mediators. We now propose to test the central hypothesis that all three manifestations of ozone-induced airway injury, i.e. airway smooth muscle hyperresponsiveness, mucosal dysfunction, and microvascular hyperemia and leakage are causally related to airway inflammation. With a set of in vivo and in vitro studies involving sheep exposed to intermediate levels of ozone on a short-term basis (1 ppm for 2 hrs), we will 1) determine if markers of inflammation (leukocyte, chemical mediators) associated with airway hyperresponsiveness in vivo can produce airway smooth muscle hyperesponsiveness in vitro and this can be modified by anti-inflammatory agents, 2) identify the component of mucociliary interaction which is most severely impaired and determine which imflammatory mediators play a putative role, 3) demonstrate the possibility of sequential activation of inflammatory products mediating airway epithelial cell dysfunction, and 4) characterize the role of inflammatory mediators in the microvascular responses of the airway mucosa. Long term exposure to ozone (0.5 ppm, 4 hrs/day, 5 days/week, 6 weeks) will be employed to test the secondary hypothesis that disruption of the airway epithelium causes airway smooth muscle hyperresponsiveness because of a decreased production of epithelium derived relaxant factors. By interrelating the cytologic and biochemical indices of airway inflammation with the various physiologic endpoints and by the use of appropriate antagonists, we expect to obtain interpretable data with which to test the basic premise underlying this proposal. We believe that the results of this investigation will provide useful information on the pathogenesis of ozone-induced airway injury, and that some of this information can be extrapolated to airway disease in general and form the basis for pharmacologic intervention.