The eicosanoid family of lipid mediators modulates a number of inflammatory processes including ainway inflammation related to asthma. The eicosanoids are biosynthesized from arachidonic acid, which is liberated from the cellular phospholipids by a family of enzymes called phospholipase A2, The mammalian genome encodes 10 secreted phospholipases A2 (sPLA2s), and the role of these enzymes in mediating arachidonic acid release is under active investigation. Cells also contain a cytosolic PLA2 (cPI_A2alpha) that works in a coordinated rnanner with sPLA2s to maximize arachidonic acid release. Recently, we have expressed all of the mouse and human sPLA2s as recombinant proteins and have studied their enzymatic properties in vitro. Mammals also contin an sPI_A2 receptor, the M-type sPLA2 receptor, which was discovered by use of venom sPLA2s. We have shown that many of the mammalian sPLA2s are high affinity ligands for this receptor. The focus of our future studies is to explore the role of high specific activity sPl-A2s in the liberation of arachidonic acid leading to eicosanoids. We will study the molecular basis for the coordinated action of sPLA2s with CPLA2alpha. We will also develop and use tight binding sPLA2 inhibitors to probe the role of these enzymes in arachidonic acid release. We have generated mice that are deficient in human group X spLA2 and have shown that airway inflammation is maredly reduced in a mouse model of allergic asthma in this mouse. We will continue to study the role of group X sPI_A2 in promoting airway inflammation related to asthma. We are also generating mice that are deficient in the other high specific activity sPLA2s and also the M-type sPLA2 receptor. We will also test the possibility that the M-type sPLA2 receptor functions to clear sPLA2s from the extracellular fluid once they have been secreted from cells.
Our work on generation of eicosanoids is important for understanding several diseases that are intensified by eicosanoids. The two most important diseases impaced by our work are asthma and arthritis. Our work may lead to better therapeutics for the treatment of these widespread inflammatory diseases.
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