We hypothesize that endogenous substance P is released in the course of certain bronchoconstrictor responses and that the substance P released enhances the airway narrowing resulting from such stimuli. Further, and of major importance, we hypothesize that the physiological expression of the contractile potential of substance P is limited by its degradation by specific endopeptidases. Thus under conditions when the endopeptidases responsible for substance P degradation are rendered inactive a state of airway hyper-responsiveness could ensue. To test this hypothesis we propose a series of experiments using guinea pigs as a test species. We will use specific protease inhibitors to delineate the role of substance P degradation in the expression of its contractile activity and to tentatively identify the specific class of protease(s) responsible for substance P inactivation. We will use the inhibitors so identified to determine if the action of certain bronchoactive mediators can be enhanced by pharmacologic manipulation of substance P degradation, thus implicating endogenous release of substance P as contributing to the observed bronchoconstrictor response. We will purify the endopeptidase(s) responsible for substance P inactivation and use these as immunogens to produce both monoclonal and polyclonal antibodies. The antibodies obtained will be used to demonstrate the specificity of the pharmacologic effect observed using protease inhibitors. These antibodies and antibodies against substance P will also be used in immunohistochemical studies to determine the anatomic relationships between substance P and its degradative enzyme(s) in the lung. Finally we will evaluate the hypothesis that ozone induced airway hyper-responsiveness in the guinea pig is associated with a loss of substance P degradative activity.
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