Bronchial hyperreactivity is a characteristic feature of asthma which causes impairment and disability in millions of Americans. The experiments proposed in this application are specifically aimed to determine the role of vagal bronchopulmonary C-fiber afferents in the enhanced bronchomotor responses to inhaled irritants caused by exposure to ozone and toluene diisocyanate (TDI). The major working hypothesis of this proposal is that the C-fiber endings are sensitized by certain arachidonic acid metabolites which are released as a result of the airway epithelial injury caused by exposure to ozone or TDI. Thus, a given level of stimulation to these sensory endings, either chemical or mechanical, may evoke an exaggerated afferent stimulation and a greater release of sensory neuropeptides which can in turn lead to neurogenic inflammation in the airways. Series of studies are designed to answer the following questions: 1) Is the sensitivity of bronchopulmonary C-fiber endings enhanced when airway inflammation and bronchial hyperreactivity are induced by ozone or TDI? 2) Arachidonic acid metabolites PGE2, PGI2 and LTB4 are known to sensitize the C-fiber endings in cutaneous and other tissue beds. Is the release of these inflammatory mediators involved in enhancing the sensitivity of bronchopulmonary C.fiber endings during airway inflammation? 3) Is the tissue content and/or the irritants-induced release of sensory neuropeptides (substance P, neurokinin A and calcitonin gene.related peptide) increased in the ozone- or TDI-induced hyperreactive airways? These proposed experiments will be carried out in anesthetized guinea.pigs. Activity of the C-fiber afferents arising from endings in the lungs and airways will be measured directly using the """"""""single-fiber"""""""" recording technique while chemical and mechanical stimulations (e.g., cigarette smoke and lung inflation) are applied. Release of sensory neuropeptides from these endings will be measured with the radioimmunoassay technique in an isolated perfused lung preparation, and the changes in lung mechanics will be measured simultaneously. Results obtained from these studies will improve our understanding of: 1) the basic physiological and pharmacological properties of the bronchopulmonary C-fiber afferents, and 2) the mechanisms by which these endings are involved in the development of bronchial hyperreactivity induced by epithelial injury and airway inflammation.
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