The proposed research projects are directed to the elucidation of the roles of leukotrienes and other lipoxygenase products of arachidonic acid in the mediation of the PMN leukocyte, monocyte, and T-lymphocyte components of human hypersensitivity reactions. The pathways of lipoxygenation of arachidonic acid and of the metabolism of leukotriene in human leukocytes will be characterized in relation to the products, the biochemical events critical to the activation of lipoxygenation and further metabolism, and the endogenous regulatory mechanisms. The 5-lipoxygenase of neutrophils and the 15-lipoxygenase of eosinophils, which represent the respective predominant activities of human leukocytes, will be purified for comparative studies of subcellular distribution, structural properties, and susceptibility to feed-back regulation and pharmacological inhibitors. Modulation by leukotrienes of diverse leukocyte functions and of the release of leukocyte principles which alter function will be examined in order to elucidate the fundamental differences between the activities of leukotrienes and of peptide chemotactic factors in inflammatory responses. The leukocyte receptors for leukotrienes will be defined with respect to binding characteristics, structural properties, cellular behavior, interactions with other receptors and membrane proteins, and coupling to the biochemical sequence of events that is critical to the initiation of specific leukocyte functions. The requirements for the 5-lipoxygenation of endogenous arachidonic acid in the activation of leukocytes will be delineated by the application of selective native and pharmacological inhibitors, studies of the reversal of the suppressed functions of inhibitor-treated leukocytes by defined lipoxygenase products, and the isolation of intracellular intermediates for analyses of their effects on intact leukocytes. The overall goal of the research is a more comprehensive knowledge of the characteristics of the lipoxygenase products which selectively recruit and activate different populations of leukocytes in the course of adaptive immune responses.
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