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This proposal extends investigations of mechanisms regulating bronchomotor tone initiated in prior grant periods. In the current proposal, the endogenous regulation of bronchomotor tone will be examined at three levels: 1) neural and circulating humoral influences; 2) endogenous regulation through secretion of mediators from fixed and circulating blood elements; and 3) epithelial influences on airway smooth muscle contractility. In the prior grant period, studies were completed that elucidated the potential influence of the sympathetic and parasympathetic nervous systems in modulating mast cell degranulation and airway contractile responses during immune challenge. However, data in those studies could only be obtained for a period of less than 45 s after immune degranulation and only for autonomic stimuli preceding mast cell activation. Studies are proposed to extend these observations through a newly developed isolated-perfused preparation that selectively perfuses the bronchial circulation of small mammals through an open circuit. This preparation remains viable for greater than 6 h and permits continuous sampling of the mediator release during simultaneous measurement of airway smooth muscle response. Studies are proposed to evaluate the extended effects of autonomic regulation after immune degranulation. A biochemical analytic laboratory has been developed for computerized analysis of multiple mediators, including catecholamines, histamine, serotonin, and arachidonate metabolites. In a second series of investigations, we propose to extend studies on homeostatic inhibitory secretion of the sympathetic nervous system in swine that were initiated in the prior grant period. Preliminary data indicate that sympathetic secretion does not modulate bronchomotor tone during exogenous bronchoconstriction. Studies are proposed to examine further the effects of specific circulating mediators and physiological stimuli (hypoxemia, hypotension) on sympathetic output and how these modulate bronchomotor tone. Preliminary observations indicate complex interactions among multiple. regionally secreted contractile mediators that act simultaneously to both augment and inhibit airway smooth muscle contraction. Studies are proposed to elucidate further these interactions and their mechanisms. In a final series of studies, a dual isometric tracheal preparation will be utilized to examine the role of epithelial modulation of airway contractile responses in dogs in situ. Studies are designed to elucidate the role of both inhibitory and stimulatory substances by a method that evaluates these action in a physiological environment. The proposed studies will elucidate the site of action of mediators and neural interactions and their role in modulation of airway contractile responses. Data derived from these studies will suggest approaches for therapeutic interventions in asthma and obstructive airways disease in humans.
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