The objective is an increased understanding of the mechanism by which antiinflammatory steroids alleviate allergic diseases in man. These studies represent the logical outgrowth of our initial studies, which showed that: 1) steroids prevent the release of histamine and sulfidopeptide leukotrienes from human basophils, 2) steroids do not inhibit the release of inflammatory mediators from purified human lung mast cells, 3) steroids inhibit the release of cyclooxygenase metabolites from nonmast cell sources in human lung fragments and from monocytes purified from blood, 4) steroids inhibit the unstimulated binding of purified human neutrophils (PMN) to monolayers of human vascular endothelial cells (VEC) but do not inhibit the stimulus-induced binding of PMN to VEC, 5) human lung fragments release a material which induces VEC to become adhesive, causing marked increases in PMN adherence, and 6) steroids inhibit the release of this adhesiveness-inducing activity from human lung fragments. Studies in this proposal are aimed at establishing the in vivo relevance of the inhibitory steroid action on human basophils. We will further explore the mechanism of this effect and characterize a leukocyte-derived antagonist. We will determine whether steroids prevent the release of arachidonic acid metabolites from human cells (e.g., eosinophils, monocytes, lung fragments, etc.) by inducing the synthesis of a phospholipase A2 inhibitor such as has been identified in animal studies. Since steroid therapy in vivo blocks the """"""""late phase reaction"""""""" (LPR) following antigen challenge in man, studies are planned to establish an in vitro model of the LPR in which products of purified human lung mast cells will be tested for their ability to initiate adherence of purified human leukocytes (especially neutrophils and eosinophils) to monolayers of cultured human VEC. With such a model system, we will study in vitro the mechanism by which steroids prevent the accumulation of leukocytes during the LPR. These experiments will be designed to establish whether the steroid action is expressed on the leukocyte, the VEC, or both. We will characterize the lung fragment-derived factor which induces adhesiveness of VEC. These studies will be aimed at assessing the role of such a factor in inducing the LPR as well as exploring the hypothesis that inhibition of the release of the factor is an important antiinflammatory mechanism of steroids. It is our opinion that an increased understanding of the mechanism of antiinflammatory steroid action will result in a better understanding of inflammatory diseases and aid in the development of new therapeutic agents.
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