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.
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