Earlier work by the principal investigator and his associates has demonstrated that the removal of the bronchial epithelium causes hyperresponsiveness of canine airway smooth muscle. The principal goals of the proposed research are: (a) to continue to define the extent of the modulation by the epithelium of the responsiveness of airway smooth muscle in health and disease (asthma); (b) to determine the identity of the bronchoactive factors secreted by the epithelial cells; and (c) to start to explore interactions between epithelium and pulmonary blood vessels. Tissues of the dog and the guinea-pig will be studied throughout the projected five year period; certain experiments will be performed on material from sheep and humans (as available). The proposed approach involves mainly physiological (measurement of contractile responses, bioassay studies, electrophysiological studies) and pharmacological studies, although in certain series biochemical (measurement of metabolites of arachidonic acid, levels of cyclic nucleotides) and histological determinations will be prfomred. It is expected that the proposed research will increase our understanding of the factors which affect bronchial tone, and in particular improve our knowledge of the interactions between the different cells in the bronchial wall which can play a role in the increased reactivity of the airways observed in obstructive lung disease and bronchial asthma. The studies on pulmonary blood vessels should help to explain how changes in pulmonary vascular responsiveness may lead to alterations in the ventilation-perfusion ratio, and possibly provide an explanation for hypoxic pulmonary vasoconstriction.
