Bronchial asthma is characterized by the triad of airway smooth muscle contraction, mucociliary dysfunction and edema. Two of these manifestations involve the mucosa. During the previous and current grant periods, we conducted a series of experiments in an attempt to characterized airway mucociliary function in a sheep model of allergic bronchoconstriction. Those studies have demonstrated that antigen challenge leads to an impairment of mucociliary clearance which is related to chemical mediators of anaphylaxis, is caused by abnormal airway secretory functions, and persists for several days. The overall objective of the present proposal is to extend those observations to other aspects of mucosal function and to assess the role of inflammation in the demonstrated defects. Specifically, we will determine if, in the same sheep model, 1) the sustained mucociliary dysfunction after antigen challenge is causally related to inflammation, 2) the depth and distribution of airway mucus influences the bronchial responsiveness to inhaled bronchoconstrictor aerosols, 3) the allergic airway is characterized by an inappropriate adaptation in epithelial water transport to osmotic stimuli and this abnormality is caused by inflammatory cell products, and 4) thermal stress produces differential vascular responses in allergic and non- allergic airways due to differences in mediator generation of autonomic responsiveness. The in vitro techniques will include the measurement of tracheal mucus velocity, respiratory mechanics, aerosol deposition, tracheal mucosal blood flow and tissue volume. In vitro techniques will include the measurement of mucus glycoprotein, ion, water fluxes and hydraulic conductivity in tracheal tissue, and determination of the interaction among ciliary beat frequency, mucus depth, mucus rheology and mucus transport rate. These physiologic parameters will be correlated with histopathologic and humoral indices (RIA and HPLC) of inflammation. Most of the proposed in vivo and in vitro methods have been previously used and validated in this and other laboratories. We expect to show that in the allergic airway, mucosal defects re involved in the abnormal airway responses to physical and pharmacologic stimuli and are related to inflammation. The results may form the basis for new treatment strategies in patients with bronchial asthma.
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