Dr. White has the long term goal of pursuing independent investigation of the mechanism operative in the pathophysiology of asthma. REceipt of a Clinical Investigator Award will facilitate the development of Dr. White's investigative skills and experience by expanding his knowledge of several new cellular techniques as outlined in the propose studies. Dr. White and his sponsor, Dr. Alan Leff, have developed an educational environment which will provide the candidate essential training in emerging areas of airway cell biology and physiology. Sponsors and collaborators have been identified to mentor Dr. White's progression to an independent investigator. The proposed application will permit the candidate to develop a career as an academic physician-scientist committed to basic medical research into the pathophysiology of asthma and obstructive airways diseases.
The specific aims i n this proposal will extend earlier inquires into epithelial modulation of airway smooth muscle contractility which Dr. White has begun under the guidance of Dr. Leff. Three immediate goals are identified: 1) Determine the role of endothelin on airway smooth muscle contractility. A new in-situ isolated tracheal-epithelial preparation develop in guinea pigs will be used to measure both isometric force of contraction and lower airways resistance after either direct or intravenous stimulation of airways with endothelin-1. These experiments also will test the hypothesis that the airway epithelium modulates the action of a vascular-derived mediator of bronchoconstriction, and further test the hypothesis that the bronchoconstricting effects of endothelin are mediated by metabolites of the cyclooxygenase pathway. 2) Determine the secretion of eicosanoid mediators of airway smooth muscle contraction from airway epithelial cells after stimulation by endothelin or eosinophilic protein mediators. Specifically, changes in bioelectrical potential difference and secretion of eicosanoid mediators will be determined after stimulation of canine tracheal or third-generation bronchial epithelial membranes mounted in perfusion chambers. Mediator secretion will be stimulated by endothelin and the protein mediators eosinophils that have been demonstrated to elicit substantial changes in airway tone. These experiments will test the hypothesis that inflammatory protein mediators elicit important changes in epithelial secretion of important mediators of airway tone. 3) Determine the physiologic response of airway smooth muscle to epithelial ell conditioned medium after stimulation by endothelin or eosinophilic protein mediators. Utilizing the isolated tracheal-epithelial preparation and cultured tracheal epithelial cells, the studies performed in the second specific aim will be extended to test the hypothesis that epithelial cell activation by either endothelin or the protein mediators of eosinophils results in secretion of physiologically important mediators of airway contractile responses. Data derived from these studies should lead to identification of the mechanisms by which epithelium modulates bronchomotor tone. By clarifying the pathophysiology of epithelial modulation of airway contractile responses in animals, these studies should suggest basic physiological and pathophysiologic processes that regulate the tone of airways, and lead to new therapeutic approaches in the management of asthma.
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