PROTECTIVE MECHANISMS CONTROLLING ACUTE AIRWAY REACTIONS

控制急性气道反应的保护机制

• 批准号: 3350510
• 负责人: James E Fish
• 金额: $ 14.38万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1985
• 资助国家: 美国
• 起止时间: 1985-07-01 至 1989-09-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3350510
• 关键词: Ambrosia; airborne allergen; antiinflammatory agents; asthma; bronchodilators; bronchomotion; bronchospasm; colchicine; corticosteroids; histamine; human subject; human tissue; methacholine; plethysmography; prostaglandins; respiratory airway pressure; respiratory airway volume; respiratory disorder chemotherapy; respiratory function; respiratory hypersensitivity; respiratory muscles; respiratory pharmacology; smooth muscle; tissue /cell culture

The long term objective is a better understanding of inherent protective mechanisms that control acute airway responses to inhaled stimuli. The focus is on two specific aspects of control, both of which serve to protect against excessive or unabated bronchoconstriction; by promoting bronchodilatation. These include: (1) the regulation of bronchomotor tone by lung inflation; and (2) the regulation of airway tone by a unique intrinsic bronchodilator mechanism stimulated by Prostaglandin (PG) F2 alpha. This research is based on the premise that a defect in either of these regulatory functions may lead to exaggerated states of airway reactivity, or airway hyperresponsiveness. The specific aims of the project will be pursued at the in vivo level in human bronchial challenge experiments and at the in vitro level in studies of guinea pig and human airway tissue. Specific studies related to volume regulation of bronchomotor tone will be carried out with the aim of establishing (1) the role of an impaired capacity to dilate airways by lung inflation in the evolution of abnormal airway responsiveness after allergen-induced airway inflammation; (2) the mechanisms whereby allergen-induced airway inflammation alters the dilator effects of lung inflation and airway responsiveness; (3) the effects of anti-inflammatory agents in preventing allergen-induced abnormalities in the volume regulation of bronchomotor tone and airway responsiveness; (4) the role of volume regulation in determining the shape of methacholine dose-response curves in asthmatic subjects; and (5) the importance of abnormal lung recoil pressures as a cause of impaired volume regulation of bronchomotor tone. Studies of the airway physiology and pharmacology of PGF2 alpha will be carried out to (1) explain why atopy is associated with airway hyperresponsiveness to PGF2 alpha but to other chemical stimuli: (2) define the characteristics of the novel bronchodilator effects of PGF2 alpha in man; (3) establish the relation between a defect in the bronchodilator effects of PGF2 alpha and airway hyperresponsiveness; (4) define the importance of PGF2 alpha-induced bronchodilatation in modulating airway responses to clinically relevant bronchoactive stimuli; and (5) define the mechanisms and characteristics of the bronchodilator effects of PGF2 alpha in isolated guinea pig and human airway tissue. This work is expected to contribute significant new information toward a better understanding of the mechanisms involved in pathologic airway responsiveness, and to lead to the development of more rational approaches to effective therapy of diseases characterized by airway dysfunction.

长期目标是更好地理解固有的保护作用 控制对吸入刺激的急性气道反应的机制。 这 重点是控制的两个具体方面，这两个方面都旨在保护 防止支气管过度收缩或持续收缩；通过促进 支气管扩张。 这些包括：（1）支气管运动张力的调节 通过肺充气； (2) 通过独特的气道张力调节 前列腺素 (PG) F2 刺激的内在支气管扩张机制 阿尔法。 这项研究基于以下前提： 这些调节功能可能会导致气道状态夸大 反应性或气道高反应性。 该计划的具体目标 该项目将在人体支气管挑战的体内水平上进行 豚鼠和人类研究中的实验和体外水平 气道组织。 与支气管运动张力的音量调节相关的具体研究将 进行的目的是确定 (1) 受损者的作用 在异常进化过程中通过肺充气扩张气道的能力 过敏原引起的气道炎症后的气道反应性； （2） 过敏原诱导的气道炎症改变扩张器的机制 肺充气和气道反应性的影响； (3) 的影响 抗炎剂可预防过敏原引起的异常 支气管运动张力和气道反应性的容量调节； (4) 体积调节在决定乙酰甲胆碱形状中的作用 哮喘受试者的剂量反应曲线； (5) 的重要性 异常的肺反冲压力是容量调节受损的原因 支气管运动音。 PGF2 α 气道生理学和药理学的研究将 进行的目的是（1）解释为什么特应性与气道有关 对 PGF2 α 但对其他化学刺激的过度反应：(2) 定义 PGF2 新型支气管扩张作用的特征 人类的阿尔法； (3) 建立缺陷之间的关系 PGF2α 的支气管扩张作用和气道高反应性； (4) 定义 PGF2 α 诱导的支气管扩张在调节中的重要性 对临床相关支气管活性刺激的气道反应；和（5） 定义支气管扩张作用的机制和特征 离体豚鼠和人类气道组织中的 PGF2 α。 这项工作预计将为 更好地理解病理气道涉及的机制 响应能力，并导致开发更合理的方法 有效治疗以气道功能障碍为特征的疾病。