The intent of this project is to understand the mechanisms of the anti-inflammatory action of glucocorticosteroids on human cells and tissues and to relate these to their therapeutic effectiveness in human disease. This project will extend our previous studies on steroid produces an inhibition of IgE-dependent basophil histamine release. (2), Steroids do not inhibit the release of histamine, prostaglandin (PG) D2, PGF2a, thromboxane B2, or leukotriene (SRS) from purified human lung mast cells. (3), In human lung fragments steroids prevent the IgE-mediated release of arachidonate metabolites derived from cells other than mast cells. (I4), In guinea pig tracheal airway tissue steroids inhibit the leukotriene-dependent phase of antigen-induced contraction. Experiments proposed will test the mechanism by which glucocorticoids inhibit human basophil histamine release as well as examine why our experimentation with human lung mast cells fails to show an effect. The role of a glucocorticoid-induced inhibitor of phospholipase A2 in the response to steroids of human basophils human lung fragments and guinea pig and human airway tissue will be studied in detail. High performance liguid chromatography, raioimmunoassay and the radiometric PLA2 enzyme assay systems to be used are already established in this Division. Since arachidonate metabolism via the lipoxygenase pathways has been implicated in the pathology of asthma and other allergic diseases, we will assess the profile of arachidonate products produced, and determine the effects of steroids on the production of these metabolites in human lung and purified human lung macrophages. Finally, in vivo, steroids block the late (6-18 hours) reaction to inhaled antigen. Studies proposed will attempt to develop in vitro human lung model of this """"""""late phase reaction"""""""" to study the mechanism of steroid action. The studies proposed in this application will improve our understanding of allergic disease and the mechanism by which steroids prevent it. It is our hope that they will also help improve the therapy of these disabling diseases.
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