The important role of abnormal airway secretions in bronchial asthma is recognized by clinicians and pathologists; however, the pathophysiologic significance of this abnormality has been insufficiently examined in the past. During the previous and current grant periods, a series of experiments have been conducted in our laboratory in an attempt to characterize airway mucociliary function in a sheen model of allergic bronchoconstriction. Those studies have demonstrated that antigen-induced bronchoconstriction is associated with an impairment of mucociliary transport, that this impairment is related to chemical mediators of anaphylaxis (notably leukotriences), that antigen challenge causes ciliostimulation and mucus hypersecretion, and that allergic mucociliary dysfunction persists for several days. The objectives of the present proposal are to further clarify the mechanisms underlying abnormal mucociliary function in asthma, and to determine if this defect has physiologic consequences that might be clinically significant. In vivo measurements of mucociliary activity (mucociliary transport, mucus rheology) combined with in vitro determinations of its component functions (ciliary activity, mucus secretion and water transport) will be obtained in sheep with Ascaris suum hypersensitivity to 1) demonstrate that the airway hyperresponsiveness in bronchial asthma is associated with """"""""mucociliary hyperresponsiveness"""""""" which includes both facilitated release of secretagogues and enhanced target tissue responsiveness to secretagogues and chemical mediators of anaphylaxis, 2) determine the mechanisms underlying prolonged allergic mucociliary dysfunction, 3) establish a relation between the accumulation of mucus in peripheral airways and minimal airway obstruction during prolonged allergic mucociliary dysfunction, and 4) determine if mucoiliary dysfunction impairs bacterial clearance from the airways. Most of the proposed methods have been previously used and validated in this and other laboratories. We expect that the information derived from these studies will contribute to the understanding of the mechanisms controlling the secretion and transport of airway mucus in allergic asthma, and demonstrate some of the detrimental consequences of asthma-associated mucociliary dysfunction. The obtained results will form the basis for pharmacologic intervention.
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