KININS AS MEDIATORS OF REACTIONS

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Our central premise is that kinins are important mediators of inflammatory reactions of the human airways, such as asthma, and allergic and viral rhinitis. This is based upon evidence of kinin generation during these conditions and on the ability of bradykinin to induce relevant symptoms when applied to the airway mucosa. The mechanisms by which bradykinin elicits symptoms in the human airways, however, are poorly understood. We hypothesize that some effects of kinins on airway function are mediated by stimulation of sensory nerves, and that the responsiveness of these nerves is enhanced during airway inflammation. We also hypothesize that blocking the actions of kinins will modulate the symptoms and pathogenesis of asthma and rhinitis. We will test these hypotheses using: 1) Unilateral nasal provocation to directly monitor changes in airflow, plasma exudation, and reflex glandular secretion. To study the role of kinins in asthma, we will use 2) whole lung challenge to study bronchoconstriction and cough, and 3) endobronchial challenge to examine effects of kinins on peripheral airway resistance and on vascular permeability in the lower airways. In the upper airways, we will compare the effects of bradykinin provocation in perennial rhinitics, normals, and in seasonal rhinitics before and after allergen challenge. We will use agents that modify nerve function to determine which actions of kinins may be neurally mediated in each patient group. Neural responsiveness seems to be increased in perennial rhinitics. We will determine the effects of capsaicin desensitization of C-fibers, and of topical glucocorticoids (to reduce inflammation), on the responses of these subjects to bradykinin. We will use the kinin receptor antagonist, Hoe 140, to confirm the specificity of kinin effects in the upper airways and to determine the role of kinins in the pathogenesis of allergic and viral rhinitis. In the lower airways, there are differences in the ability of allergen challenge to induce increased reactivity to bradykinin compared to the direct spasmogen, methacholine. To determine if increased reactivity to bradykinin reflects enhanced neural responsiveness, we will examine the effects of agents that alter nerve function on responses to bradykinin before and after allergen challenge. We will determine if allergen-induced increased reactivity to bradykinin is associated with increased reactivity to other stimuli that reportedly act via neural mechanisms and will also determine if inducing tachyphylaxis to bradykinin reduces the response to such stimuli. We will define the effects of kinins on peripheral airway resistance and plasma transudation in asthmatics and normals. The effects of glucocorticoids on responses of asthmatics to kinins will be examined. Finally, we will use Hoe 140 to confirm the specificity of kinin responses and to monitor the role of kinins in baseline pulmonary function and reactivity of symptomatic asthmatics. These studies should provide important insights into the role of kinins in the pathogenesis of asthma and rhinitis and may lead to novel therapies for the treatment of these conditions.