The long-term objective is to examine the possible role of the macrophage in asthma. The focus will be on the lipoxygenase pathway of arachidonic acid metabolism in this cell because of convincing evidence that the products of this pathway are important mediators in asthma and airway hyperresponsiveness.
The specific aims will be to characterize the lipoxygenase products of human mononuclear phagocytes, including macrophages and monocytes, in the lung and examine the relationship of stimulation and activation of these cells to bronchoconstriction and airway hyperresponsiveness. The strategy of the project will be to characterize the lipoxygenase pathway of human homonuclear phagocytes isolated from the lung and the blood and to evaluate the effects of stimulation and in vitro conditioning on their lipoxygenase products. Lipid biochemical analysis will be performed using the techniques of chromatography and spectroscopy as well as other techniques for lipid analysis. The relevance of the findings in the biochemical studies to asthma will be initially evaluated by examining the physiologic significance of macrophage stimulation and activation on airway tone and responsiveness, in animals. In the future, parallel studies in human subjects may be possible to directly evaluate the relevance of the findings to asthma. The research may provide further understanding of the role of the macrophage in airway disease and will also lead to further insight into the biology of the mononuclear phagocyte in the lung. Because studies in human cells will be directly relevant to human disease, these investigations may suggest specific therapeutic approaches to airway disease mediated through the macrophage and its lipoxygenase pathway.
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