The goal of this proposal is to determine the importance of kinins as mediators of human allergic and inflammatory diseases. We have shown that kinins are generated in nasal secretions during both the immediate and late responses to allergen challenge, during the response of symptomatic individuals to nasal challenge with cold, dry air, and during symptomatic rhinovirus infections. We will evaluate the extent to which kinins contribute to the pathogenesis of these different types of rhinitis and asthma and will delineate the mechanisms of kinin formation and destruction during these conditions. Our recent demonstration that nasal provocation with bradykinin induces symptoms of rhinitis and a sore throat lends strong support to the hypothesis that kinins play an important role in inflammatory reactions of the upper airways. We will study the mechanisms by which kinins induce these symptoms. To determine the pathophysiological role of kinins in rhinitis, we will perform studies using angiotensin converting enzyme inhibitors in an attempt to reduce kinin destruction and to determine if increases kinin levels are associated with an increase in symptoms upon challenge with antigen, cold, dry air or rhinovirus. We will also study the ability of a new, competitive kinin antagonist (DArg0- Hyp3-DPhe7-bradykinin) to inhibit the effects of nasal challenge with kinins. If the compound proves to be an effective inhibitor of the response to kinin challenge in vivo, it will be used to elucidate the extent to which kinins contribute to the symptomatology of rhinitis in each of our model systems. We have made substantial progress in elucidating the mechanisms of kinin formation and metabolism during the immediate response to allergen challenge but have evidence that these mechanisms may differ during the late allergic response and during symptomatic rhinovirus infections. We will perform comparative biochemical analyses to determine the mechanisms regulating kinin levels in each type of rhinitis. Since glandular kallikrein plays a major role in kinin formation during the immediate allergic reaction in the nose, we will localize glandular kallikrein in the upper airways and will determine which factors control kallikrein secretion. Finally, we will continue our studies to determine the importance of kinins in inflammatory diseases of the lower airways, such as asthma. We will localize glandular kallikrein in the lower airways and will correlate kallikrein and kinin levels with the immediate and late clinical responses to segmental (localized) challenge in the lung. We will also study the mechanisms of kinin degradation in the lower airways. These studies will greatly increase our understanding of the role of kinins in human allergic and inflammatory reactions and may lead to new therapeutic approaches to combat these diseases in man.
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