Lipid pathways are central to pathophysiology and potential treatment of inflammatory lung diseases including asthma and ARDS. The pathways are complex and interdependent. This program will use four interdependent projects to examine critical points of the pathways which have only recently been recognized. Regulatory mechanisms will be defined using normal cells, an normal cells primed in vitro. Thr program will address changes which occur during lung diseases which share the following characteristics of (i) mediation by leukocytes, (ii) excessive production of the products of these pathways (eicosnoids, lysophospholipids, PAF) and (iii) lung injury, in particular ARDS and asthma. Project I will examine biochemical and molecular regulation of the distinct cytosolic and granule-associated phospholipase A2 enzymes in phagocytes, and their unregulation after priming and during lung diseases. A coenzyme A-independent transacylase may also be critical in the release of AA and production of PAF; Project II will characterize the cellular localization and biochemical regulation of this transacylase, and characterize the coordinated regulation of the PLA2 and the transacylase. Bis(monoacylglycerol)phosphate (BMP) is a lipid unique to alveolar macrophages which may serve as an important store of AA; Project III will study mechanisms of BMP synthesis, establish the metabolic pathway by which AA is incorporated into BMP and determine conditions under which AA removal is related to eicosanoid synthesis. Prostanoid synthesis is mediated by prostaglandin G/H synthases, and PGH synthase II gene is induced during priming of alveolar macrophages; Project IV will compare synthesis, degradation and translation of pGH synthase I and II, in relation to priming and to eicosanoid synthesis of human blood PMN, THP-1 cells, blood monocytes and alveolar macrophages, and will then test the hypothesis that these genes are specifically upregulated in human alveolar macrophages during pulmonary inflammatory diseases (ARDS, asthma). The projects will be supported by three Core Laboratories. The Administrative Core will oversee the Program, help with budgets, organize meetings, and see to essential interaction between projects. The Lipid Analysis Core will provide state-of-the-art quantitation of lipid species and structural analysis of synthetic lipid analogs. The Clinical Core will recruit normal donors and patients with burns, ARDS and asthma, obtain blood and bronchoalveolar lavage, preprocess clinical samples (quantitate and isolate cells, derivitize BAL fluid for GC/mass spec analysis, etc), and obtain and maintain clinical data.
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