Chronic bronchitis is a syndrome characterized clinically by cough and mucus hypersecretion and pathologically by mucus secretory apparatus hyperplasia and airway inflammation. It is often accompanied by physiological changes, including chronic airway obstruction and altered airway responsiveness. However, the mechanistic basis for these changes has yet to be established. A number of lines of evidence suggest that the tachykinins substance P (SP) and neurokinin A (NKA) associated with chemosensitive afferent nerves in the airways play a pivotal role in the pathogenesis of the changes in airway physiology observed. In particular, the tachykinins are released in response to airway irritation, in the proper location, and in amounts sufficient to account for the changes observed in chronic bronchitis. Evidence also exists that the inflammation associated with chronic irritation has the potential to alter tachykinin release and metabolism so as to substantially modify responses to tachykinins. Based on this evidence, they put forth the following hypothesis: chronic irritation and the resulting chronic inflammation of the airways results in changes in tachykinin release responses and metabolism of such a nature as to effect the physiological changes associated with chronic bronchitis. They will test this hypothesis by pursuing four specific aims. In the first and second, the contribution of tachykinins to the pathogenesis of lesions induced by chronic airway irritation and the effect of chronic irritation on tachykinin release, responses, and metabolism will be examined in a rat model of sulfur dioxide (SO2) induced chronic bronchitis. In the third, the effect of inflammatory agonists on tachykinin responses and metabolism will be assessed in human and rat airways in short-term organ culture. In the fourth, they will examine changes in tachykinin release and metabolism in human chronic airway disease and the effect of these changes on tachykinin responses. These experiments will provide information on the regulation of tachykinin responses and processing in chronic inflammation and the importance of these peptides in chronic bronchitis.
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