The long-term objective of this project is to define the possible role of pulmonary-localized blood leukocytes (eosinophils, neutrophils, monocytes/macrophages) in the pathogenesis of airway hyperreactivity in asthmatics, chronic bronchitics, and smokers. Based on the hypothesis that inflammatory cells recruited to sites of recurrent bronchial provocation have functional and, in some circumstances, irreversible deleterious effects on the surrounding mucosa and smooth muscle, experiments with the following specific aims will be performed. 1. Examination of the relationship of the physiologic responses in airways of asthmatics, chronic bronchitics, and smokers to the cellular (eosinophils, neutrophils, monocytes/macrophages) and soluble inflammatory mediators (major basic protein, collagenase, eicosanoids) released into bronchoalveolar lavage fluid. Emphasis will be placed on defining the level of metabolic activation of locally released leukocytes by fluorescent-activated cell sorter analyses, radioisotopic techniques, and chemotactic factor release by cultured monocytes/macrophages. 2. Evaluation of the biochemical effects of artificially-generated oxidants and eosinophils, neutrophils, and monocytes on rabbit and human airway epithelium monolayers in vitro. Alterations in epithelial bioelectric properties (conductance of the paracellular pathway), ATP levels, and production of PGE2 and PGI2 will be correlated with fluxes of H2O2 and O2 generated chemically and by intact neutrophils or eosinophils. 3. Determination of the importance of endogenous epithelial anti-oxidant scavengers (catalase, superoxide dismustase, glutathione peroxidase, glutathione) in susceptibility to damage by toxic oxygen molecules. Dissection of the possible role of leukocytes in damaging bronchial epithelium should improve our understanding of their contribution to airway reactivity and may offer insights into defining methods to interrupt the pathogenesis of chronic obstructive syndromes.
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