KININS AS MEDIATORS OF HUMAN REACTIONS

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Bradykinin (BK) is a potent proinflammatory peptide that has been implicated in the pathogenesis of rhinitis and asthma. Despite the potential importance of this peptide in airway diseases, however, the mechanisms by which BK exerts its effects in the airways are poorly understood. We have shown that the airways of subjects with active allergic disease are hyperreactive to BK and that this hyperreactivity is mediated by neural reflexes that are not observed in the airways of asymptomatic subjects. BK appears to be unique in this regard. We can reproduce this hyperreactivity experimentally using repeated localized allergen challenge. This proposal will combine in vivo studies in human upper and lower airways with complementary studies in an in vivo guinea pig model (in which reflex components can be further dissected) to perform the first rigorous analysis of how neural responses to BK are altered in allergic disease, and to begin to delineate which components of allergic inflammation underly these altered neural responses. Allergic inflammation could enhance airway responses to BK at one or more sites along the reflex pathway. We will determine whether allergic inflammation enhances airway responsiveness to BK by: 1) sensitizing afferent nerve terminals innervating the airway mucosa; 2) acting on the efferent limb of airway parasympathetic nerves to increase cholinergic and/or impair noncholinergic (NANC) effector responses; or 3) altering the central processing of airway afferent activity or altering synaptic transmission in airway parasympathetic ganglia. We will establish whether the ability to induce neural responsiveness to BK is a unique feature of allergic inflammation, by determining whether experimental rhinovirus infection of normal subjects also induces neural hyperreactivity to BK. Based on the results of such studies, we will determine whether to focus further on the role of inflammatory components that are characteristic of allergic inflammation (e.g. mast cell/eosinophil products, selected cytokines) in the alteration of neural responsiveness or to examine other inflammatory components. These rigorous studies will not only clarify the role of BK in airway diseases, but will also have broader relevance by providing new and important insights into how neural function is altered in asthma and rhinitis.