PROTECTIVE MECHANISMS CONTROLLING ACUTE AIRWAY REACTIONS

这项建议的长期目标是更好地理解 控制急性呼吸道反应的内在保护机制 吸入的刺激。拟议的工作是基于我们有两个主要发现 初步研究结果：(1)异常的气道反应性 吸入激动剂，或呼吸道高反应性，与减少的 (2)通过肺充气逆转支气管收缩的能力；及 众所周知的支气管收缩因子前列腺素F2Alpha(PGF2Alpha)可以 辅助促进支气管扩张，而这种支气管扩张剂的作用 在呼吸道反应性异常的状态下可能会改变。在这个项目中，我们 将重点放在肺膨胀和PGF2Alpha的支气管扩张效应上 在人体水平上使用呼吸道挑战技术。特定的 对肺膨胀的影响将进行研究，目的是 确立(1)呼吸道炎症作为异常原因的作用 对通货膨胀的反应；(2)肺提供的保护程度 针对各种化学介体的收缩效应的通货膨胀； (3)内源性支气管扩张剂物质(儿茶酚胺， 环氧合酶产物)与容量相关的支气管扩张；以及(4) 肺反冲压降低作为异常的决定因素的作用 对通货膨胀的反应。前列腺素F2Alpha对呼吸道影响的研究 将执行以下功能：(1)系统地描述 不同临床组间的支气管收缩和扩张作用； (2)探讨PGF2Alpha诱导的支气管松弛机制；(3) 探讨前列腺素F2Alpha诱导的支气管扩张与血管生成的关系 对其他激动剂的反应性；以及(4)评估 前列腺素F2Alpha诱导的支气管扩张对不同类型高血压的调节作用 实验诱发的哮喘。预计这项工作将对 大大有助于更好地理解 一般的病理性呼吸道反应，并导致 疾病有效药物治疗的更合理途径 以呼吸道功能障碍为特征。

The long term objective of this proposal is a better understanding of intrinsic protective mechanisms controlling acute airway reactions to inhaled stimuli. The proposed work is based on two major findings we have made in preliminary studies: (1) that abnormal airway responsiveness to inhaled agonists, or airway hyperreactivity, is related to a diminished capacity to reverse bronchoconstriction by lung inflation; and (2) that a well known bronchoconstrictor, prostaglandin F2Alpha (PGF2Alpha), can secondarily promote bronchodilatation and that this bronchodilator effect may be altered in states of abnormal airway reactivity. In this project we will focus on the bronchodilator effects of lung inflation and PGF2Alpha using airway challenge techniques at the in vivo level in man. Specific studies of the effects of lung inflation will be carried out with the aims of establishing (1) the role of airway inflammation as a cause of abnormal inflation responses; (2) the magnitude of protection afforded by lung inflation against the constrictor effects of various chemical mediators; (3) the role of endogenous bronchodilator substances (catecholamines, cyclo-oxygenase products) in volume-related bronchodilatation; and (4) the role of decreased lung recoil pressure as a determinant of abnormal inflation responses. Studies of the effects of PGF2Alpha on airway function will be carried out to (1) systematically characterize both the bronchoconstrictor and bronchodilator effect in various clinical groups; (2) explore the mechanism of PGF2Alpha-induced bronchial relaxation; (3) examine the relation between PGF2Alpha-induced bronchodilatation and responsiveness to other agonists; and (4) assess the importance of PGF2Alpha-induced bronchodilatation in modulating various types of experimentally induced asthma. This work is expected to contribute significantly toward a better understanding of mechanisms involved in pathologic airway reactions in general, and to lead to the development of more rational approaches to effective pharmacotherapy of diseases characterized by airways dysfunction.