PROTECTIVE MECHANISMS CONTROLLING ACUTE AIRWAY REACTIONS

长期目标是更好地理解固有保护 控制对吸入刺激的急性呼吸道反应的机制。这个 重点是控制的两个具体方面，这两个方面都用来保护 对抗过度或有增无减的支气管收缩；通过促进 支气管扩张。其中包括：(1)支气管运动张力的调节 通过肺充气；以及(2)通过一种独特的 前列腺素(PG)F2刺激的内源性支气管扩张机制 阿尔法。这项研究是基于这样一个前提，即任何一个缺陷 这些调节功能可能会导致呼吸道状态的夸大 反应性，或呼吸道高反应性。《公约》的具体目标 该项目将在活体水平上进行人体支气管挑战 豚鼠和人的实验和体外水平的研究 呼吸道组织。 与支气管运动张力的容量调节相关的具体研究将 实施的目的是：(1)确定受损者的角色 肺扩张能力在肺充盈异常演变中的作用 变应原诱导气道炎症后的气道反应性；(2) 变应原诱导的呼吸道炎症改变扩张器的机制 肺充气和气道反应性的影响；(3) 抗炎药在预防变应原诱导的小鼠皮肤异常中的作用 支气管运动张力和气道反应性的容量调节；(4) 体积调节在确定乙酰甲胆碱形状中的作用 哮喘受试者的剂量-反应曲线；以及(5) 肺反冲压异常是肺容量调节受损的原因 支气管运动音调。 将对PGF2α的呼吸道生理学和药理学进行研究 进行的目的是(1)解释为什么特应性与呼吸道有关 对PGF2α和其他化学刺激的高反应性：(2) 明确前列腺素F2的新型支气管扩张作用的特征 人中的阿尔法；(3)建立人的缺陷之间的关系 前列腺素F2α的支气管扩张作用与气道高反应性； 明确前列腺素F2α诱导的支气管扩张在调节中的重要性 对临床相关的支气管活动刺激的呼吸道反应；和(5) 明确以下物质的支气管扩张作用的机制和特点 豚鼠和人呼吸道组织中的PGF2α。 这项工作有望为 更好地理解病理性呼吸道的发病机制 响应性，并导致开发更合理的方法 以呼吸道功能障碍为特征的疾病的有效治疗。

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.