The principal objective of this project is to determine the effect that exposure of the lung to specific antigen has on bronchopulmonary function in the immunologically-sensitized dog. The project is based upon previous studies in sensitized animals and combines the use of physiologic, pharmacologic and biochemical approaches to investigate the mechanisms through which these changes in airway function occur. Our working hypothesis is that repeated antigen exposure modifies airway function by altering the profile of mediators, specifically those derived from arachidonic acid (i.e. eicosanoids), which are synthesized within the airway tissues. Whether this alteration is due to changes in metabolism within existing airway cells or do to the antigen-induced influx of new cells, is not known. Specifically, the research will a) determine the role of eicosanoids in the acute bronchospasm of antigen challenge, b) investigate the effects of repeated antigen exposure on eicosanoid synthesis, in vivo, c) investigate the activity of enzymes of the eicosanoid metabolic pathway in microsomal preparations of airway tissues from repeatedly exposed and control dogs, as well as in specific cells isolated from the lungs of these animals, and d) determine the effects of repeated antigen exposure on non-specific airways reactivity in vivo and on the contractile reactivity of lung tissues, in vitro. The proposed studies therefore represent a multidisciplined approach to the influence of antigen exposure on lung function in that they will utilize in vivo and in vitro techniques to correlate changes in physiologic functions with underlying biochemical mechanisms at various levels of the tracheobronchial tree. It is anticipated that these studies will provide useful new information about mediator metabolism in the airways of the allergic lung.
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