We propose here to test a model that examines the molecular and metabolic basis for the altered production of prostaglandins and leukotrienes by BCG-elicited rabbit alveolar macrophages. The metabolism of the elicited macrophages will be compared with the metabolism of normal resident alveolar macrophages. To achieve these goals we will isolate the alveolar macrophages and follow their metabolic activities using radiolabeled precursors of phospholipids since the phospholipids give rise to the arachidonate that is further metabolized by the cyclooxygenase and lipoxygenase pathways. We propose to explore five specific aims: 1) Determine the metabolic source of the arachidonate and the interrelationship between the source of the arachidonate, the mechanism of its release and its metabolism by the cyclooxygenase and/or lipoxygenase systems. 2) Determine the effect of pharmacologic agents on the metabolic pathways in order to probe the interactions of the two pathways. 3) Determine the activity of five key enzymes to establish the enzymatic potential of each cell type and to determine if BCG elicitation alters the activity of a particular enzyme. 4) Determine if changes in cell structure, as examined by electron microscopic and cell fractionation studies, account in part for the differences noted in metabolic activities. 5) Determine if regulatory factors are produced by BCG elicitation and steroid treatment that alter the production of the bioactive arachidonate metabolites.
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