The eicosanoid family of lipid mediators modulates a number of inflammatory processes including airway inflammation related to asthma. The eicosanoids are biosynthesized from arachidonic acid, which is liberated from cellular phospholipids by a family of enzymes called phospholipase A2. The mammalian genome encodes 10 secreted phospholipases Aa (sPLA2s), and the role of these enzymes in mediating arachidonic acid release is under active investigation. Cells also contain a cytosolic PLA2 (cPLA2ct) that works in a coordinated manner with sPI_A2s 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. Only a subset of these sPLA2s are highly active at hydrolyzing phospholipids. We have generated antibodies to all of these enzymes, and have developed sensitive immunoassays and mass spectrometry assays that can be used to examine the profile of expression of sPLA2s in cells such as macrophages and mast cells. Mammals also contain an sPLA2 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 sPLA2s in the liberation of arachidonic acid leading to eicosanoids. We will study the molecular basis for the coordinated action of sPLA2s with cPLA2a. 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 markedly reduced in a mouse model of allergic asthma in this mouse. We will continue to study the role of group X sPLA2 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. Our working hypothesis is that high specific activity sPLA2s coordinate with cPLA2a for efficient arachidonic acid release. 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.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Method to Extend Research in Time (MERIT) Award (R37)
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Biochemistry and Biophysics of Membranes Study Section (BBM)
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Noel, Patricia
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University of Washington
Schools of Arts and Sciences
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