The purpose of these investigations is to assess autonomic control mechanisms that regulate respiratory airways. Three sets of experiments will be performed. 1) During the prior grant period, a method was developed that permitted selective degranulation of third order canine bronchus in situ. These studies will be extended to determine the potential modulating role of sympathetic and parasympathetic stimulation on mast cell degranulation and bronchial smooth muscle response during antigen challenge. Studies wil be performed to determine: a) the potential inhibitory effect of (beta-adrenergic) sympathetic stimulation, and b) the potential augmenting influences of parasympathetic and c) Alpha-adrenergic stimulation on bronchial histamine secretion and bronchial smooth muscle contraction in natively allergic dogs. 2) During the prior grant period, the potential importance of adrenal secretion as the primary airway relaxing influence was demonstrated in dogs. These studies will be extended to determine the potential reflex homeostatic mechanisms that result from selective and diffuse airway smooth muscle contraction in a porcine model that allows a) selective typical stimulation of a single airway without systemic effects; b) simultaneous measurement of the response in central and peripheral airways; and c) measurement of physiological response to adrenal secretion using a graded stimulus that is not modulated by sympathetic or nonadrenergic inhibitory nerves. Measurements of bronchomotor response in swine will be compared to simultaneous measurements of endogenous catecholamine production to determine the magnitude of the sympathetic response to bronchoconstriction. 3) In the preceding grant period, studies were performed to establish standard conditions for in vitro study of the first six generations of canine airways and lung parenchymal strips that were comparable to results obtained (for the first 3 generations of airways) in vivo. These studies will be applied to sections 1) and 2) of current proposal to identify and quantify the specific site and generation of airway in which sympathetic/parasympathetic modulation is occurring. The proposed studies will elucidate autonomic control mechanisms and events related to mast cell degranulation in the lung. By studying homeostatic mechanisms and the specific site (generation of airway), the potential relevance of these mechanics to autonomic regulation of bronchomotor response in humans will be suggested. These data will suggest approaches for therapeutic intervention in human asthma and obstructive airway disease.
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