MODULATION OF INFLAMMATORY RESPONSES IN THE LUNG

支气管哮喘的病理生理学涉及可逆性气道 阻塞，粘液分泌过多，血管通透性增加， 支气管高反应性和气道炎症。 虽然渗透 肺内有炎性细胞，如中性粒细胞（PMN），嗜酸性粒细胞， 肥大细胞已经在两种自然的动物的灌洗液中观察到， 发生哮喘和人类哮喘模型中，这些所起的作用 哮喘的发病机制中的肺细胞是未知的。 整体 本提案的目的是确定IgE介导的 在患有特应性哮喘的人中改变的炎症反应。 为 例如，不清楚这种反应是否只是更大（增加） 释放的介质和募集的细胞的量），如果响应是 更有效（如果每个细胞的介质释放增加），或者如果 反应更有效（终末器官对细胞和介质的反应 增加）。 为了验证这些假设，特应性哮喘患者和 特应性非哮喘对照将接受支气管镜抗原激发 进入肺的局部区域，并聚集炎性细胞， 介质在稍后的时间通过支气管肺泡灌洗（BAL）恢复。 到 检验炎症反应更大，尿 激发后即刻的白三烯（LT）E4水平和总水平， 来自抗原激发节段的BAL液中的分类细胞计数 将在局部抗原激发后24小时定量。 的假设 还将测试LTB 4负责吸引PMN后， 抗原激发 为了验证炎症反应 效率更高（哮喘患者肺部招募的细胞更多， “炎症”比那些从非哮喘患者，即他们已经“启动” 对于介质释放的增加），介质的体外释放 从中性粒细胞，嗜酸性粒细胞和巨噬细胞募集到肺， 局部抗原激发;颗粒定量细胞化学分析 通过BAL回收的中性粒细胞、嗜酸性粒细胞和巨噬细胞的含量;以及 中性粒细胞弹性蛋白酶、嗜酸性粒细胞产物（主要碱性蛋白酶） 蛋白、阳离子蛋白）和巨噬细胞β-葡萄糖醛酸酶 将被确定。 巨噬细胞被激活的机制 还将测定氧化剂释放增加。 测试 假设炎症反应更有效地产生 与非哮喘受试者相比， 气道炎症反应和白蛋白流入气道 将被确定。 嗜酸性粒细胞主要是 还将测试该模型中导致肺损伤的原因。 这些 研究将提供有关功能的重要信息， 炎症细胞在过敏性支气管哮喘发病机制中的作用。 在 此外，他们还将提供发展所需的关键信息， 使用抗哮喘药治疗哮喘的新策略。

The pathophysiology of bronchial asthma involves reversible airway obstruction, mucus hypersecretion, an increase in vascular permeability, bronchial hyperreactivity, and airway inflammation. While infiltration of the lung with inflammatory cells such as neutrophils (PMNs), eosinophils, and mast cells has been observed in lavage fluid in both naturally occurring asthma and in human models of asthma, the role played by these cells in the lung in the pathogenesis of asthma is unknown. The overall goal of this proposal is to identify those aspects of the IgE-mediated inflammatory response that are modified in humans with atopic asthma. For example, it is not clear if this response is simply larger (an increased quantity of mediators released and cells recruited), if the response is more efficient (if the mediator release per cell is increased), or if the response is more effective (the end organ response to cells and mediators is increased). In order to test these hypotheses, atopic asthmatics and atopic nonasthmatic controls will undergo bronchoscopic antigen challenge into a localized portion of the lung with recruited inflammatory cells and mediators recovered at a later time by bronchoalveolar lavage (BAL). To test the hypothesis that the inflammatory response is larger, urinary leukotriene (LT) E4 levels immediately after challenge and total and differential cell counts in BAL fluid from the antigen challenged segment 24 hr after local antigen challenge will be quantitated. The hypothesis will also be tested that LTB4 is responsible for attracting PMNs after antigen challenge. To test the hypothesis that the inflammatory response is more efficient (cells recruited to the lungs of asthmatics are more "inflammatory" than those from nonasthmatics, i.e. they have been "primed" for an increase in mediator release), the in vitro release of mediators from neutrophils, eosinophils and macrophages recruited to the lung by local antigen challenge; a quantitative cytochemical analysis of granule content of neutrophils, eosinophils, and macrophages recovered by BAL; and the concentrations of neutrophil elastase, eosinophil products (major basic protein, cationic protein), and macrophage beta-glucuronidase in BAL fluid will be determined. The mechanism by which macrophages are primed for an increase in oxidant release will also be determined. To test the hypothesis that the inflammatory response is more effective in producing pathophysiologic changes in asthmatic than in nonasthmatic subjects, the airway inflammatory response and the influx of albumin into the airways will be determined. the hypothesis that eosinophils are primarily responsible for lung injury in this model will also be tested. These studies will provide important information concerning the function of inflammatory cells in the pathogenesis of allergic bronchial asthma. In addition, they will provide crucial information needed in order to develop novel strategies for the treatment of asthma using antiinflammatory agents.