POLLUTANT INDUCED MUCOCILIARY DYSFUNCTION IN THE AIRWAYS

点击翻译按钮获取中文摘要

It has been previously shown that short-term and long-term exposures to gaseous pollutants alter mucosal function in the airways. The mechanisms underlying the associated depression in mucociliary clearance have been partially elucidated. In particular, it has been shown that changes in mucosal secretion rather than primary ciliary dysfunction are responsible for this defect. However, it is not known if the observed functional changes are caused by a direct effect of the pollutant on the mucociliary apparatus or indirectly by the concomitant airway inflammation in analog to the previously shown role of airway inflammation in pollutant induced airway hyperreactivity. The purpose of this proposal is therefore to determine in sheep if 1) the impairment of mucosal function by short-term low-level O3 exposure (0.5-1 ppm for 2 hours) is associated with leukocytes influx into the airway, 2) the prevention of leukocyte migration also prevents pollutant induced mucosal dysfunction, 3) mucosal dysfunction is related to inflammatory mediators, 4) the newborn airway is more vulnerable to pollutant induced mucosal dysfunction than the adult airway, and 5) pollutant induced mucosal dysfunction alters bacterial clearance in central airways and if the bacterial clearance is modified by the inflammatory response. The studies will be carried out in lambs and adult sheep and focus on the trachea. Mucosal function will be assessed in vivo by the determination of mucociliary transport with a radiographic technique and airway wall water content using a double gas bolus method to detect mucosal edema formation. Airway inflammation will be assessed by tracheal lavage and biopsy, and the role of chemical mediators by mediator assay in lavage fluid, and the use of appropriate antagonists. A bacterial aerosol will be used to determine the persistence of viable bacteria in the trachea. To suppress the inflammatory response, pluronic F-68, a potent inhibitor of leukocyte migration will be used. We expect these studies to delineate the role of inflammation in the impairment of mucosal function by O3. The results might form the basis for pharmacologic modification of pollutant induced mucociliary dysfunction.