PROTECTIVE MECHANISMS CONTROLLING ACUTE AIRWAY REACTIONS

长期目标是更好地了解内在保护性 控制对吸入刺激的急性气道反应的机制。 的 重点放在控制的两个具体方面，这两个方面都有助于保护 对抗过度或未减弱的支气管收缩;通过促进 支气管扩张 这些包括：（1）调节支气管张力 通过肺充气;和（2）通过独特的呼吸道张力调节 前列腺素（PG）F2刺激的内在支气管扩张机制 α的 这项研究的前提是， 这些调节功能可导致气道的过度状态 反应性或气道高反应性。 的具体目标 该项目将在人体支气管激发中进行体内水平的研究 在豚鼠和人体研究中， 气道组织 与支气管张力的容量调节相关的具体研究将在 目的是：（1）确定残疾人的作用; 肺膨胀扩张气道的能力，在异常 过敏原诱导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 肺膨胀和气道反应性的影响;（3） 抗炎剂在预防过敏原诱导的 支气管张力和气道反应性的容量调节;（4） 容量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;（5） 肺回缩压异常是肺容量调节受损的原因， 支气管张力 PGF 2 α的气道生理学和药理学研究将在 进行（1）解释为什么特应性与气道相关 对PGF 2 α但对其他化学刺激的高反应性：（2） 定义PGF 2的新型支气管扩张作用的特征 （3）在人与人之间建立一种关系， PGF2 α和气道高反应性的支气管扩张作用;（4） 明确PGF 2 α诱导的支气管扩张在调节 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 豚鼠和人气道组织中的PGF 2 α。 这项工作预计将有助于重要的新信息， 更好地理解病理性气道疾病的机制 反应能力，并导致制定更合理的方法 涉及以气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.