The purpose of these investigations is to assess autonomic control mechanisms that regulate respiratory airways. Five sets of experiments will be performed utilizing canine or porcine models. 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 of mast cell degranulation and bronchial muscle response during antigen challenge. 2) During the prior grant period, the potential importance of adrenal secretion as the primary airway relaxing influence was demonstrated. These studies will be extended to determine potential reflex homeostatic mechanisms that result from selective and diffuse airway smooth muscle contraction in a porcine model. Measurements of bronchomotor response will be compared to simultaneous measurements of endogenous catecholamine production. 3) In the preceding grant period, studies were performed to establish standard conditions for in vitro study of the first 3 generations of canine airways that were comparable to results obtained in vivo. These conditions will be extended to quantitate the topographical distribution of airway contractile responses to greater than 7 generations of airways in vitro. 4) A new in situ model of airway reactivity has been developed in the swine. Studies will be performed to determine whether the porcine response to pharmacological agonists and consequences of pulmonary gas exchange resemble more closely the human condition. 5) A new porcine tracheal superfusion preparation has been developed during the prior grant period that will permit selective mast cell degranulation and long-term sequential sampling of the products of mast cell degranulation. This """"""""flow-through"""""""" system will permit a full range of physiological interventions and measurements of tracheal smooth muscle response, but will exclude systemic effects that have occurred with prior preparations of isolated airways in situ. The proposed studies will elucidate autonomic control mechanisms and events related to mast cell degranulation in major resistance airways. Improved models for airway reactivity and ventilation/perfusion relationships will be developed that will suggest approaches for therapeutic intervention in human asthma and obstructive airway disease.
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