Abstract

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. ? ? ?

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
2R37HL036235-22
Application #
7213730
Study Section
Biochemistry and Biophysics of Membranes Study Section (BBM)
Program Officer
Noel, Patricia
Project Start
1988-12-01
Project End
2012-01-31
Budget Start
2007-04-06
Budget End
2008-01-31
Support Year
22
Fiscal Year
2007
Total Cost
$381,725
Indirect Cost

  Institution

Name
University of Washington
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195

  Publications

Nolin, James D; Lai, Ying; Ogden, Herbert Luke et al. (2017) Secreted PLA2 group X orchestrates innate and adaptive immune responses to inhaled allergen. JCI Insight 2:
Nolin, James D; Ogden, H Luke; Lai, Ying et al. (2016) Identification of Epithelial Phospholipase A2 Receptor 1 as a Potential Target in Asthma. Am J Respir Cell Mol Biol 55:825-836
Hallstrand, Teal S; Lai, Ying; Hooper, Kathryn A et al. (2016) Endogenous secreted phospholipase A2 group X regulates cysteinyl leukotrienes synthesis by human eosinophils. J Allergy Clin Immunol 137:268-277.e8
Vasilakaki, Sofia; Barbayianni, Efrosini; Leonis, Georgios et al. (2016) Development of a potent 2-oxoamide inhibitor of secreted phospholipase A2 guided by molecular docking calculations and molecular dynamics simulations. Bioorg Med Chem 24:1683-95
Vijay, Rahul; Hua, Xiaoyang; Meyerholz, David K et al. (2015) Critical role of phospholipase A2 group IID in age-related susceptibility to severe acute respiratory syndrome-CoV infection. J Exp Med 212:1851-68
Duchez, Anne-Claire; Boudreau, Luc H; Naika, Gajendra S et al. (2015) Platelet microparticles are internalized in neutrophils via the concerted activity of 12-lipoxygenase and secreted phospholipase A2-IIA. Proc Natl Acad Sci U S A 112:E3564-73
Berry, Evan; Hernandez-Anzaldo, Samuel; Ghomashchi, Farideh et al. (2015) Matrix metalloproteinase-2 negatively regulates cardiac secreted phospholipase A2 to modulate inflammation and fever. J Am Heart Assoc 4:
Yamamoto, Kei; Miki, Yoshimi; Sato, Mariko et al. (2015) The role of group IIF-secreted phospholipase A2 in epidermal homeostasis and hyperplasia. J Exp Med 212:1901-19
Guillaume, Carole; Payré, Christine; Jemel, Ikram et al. (2015) In vitro anti-Plasmodium falciparum properties of the full set of human secreted phospholipases A2. Infect Immun 83:2453-65
Rousseau, Matthieu; Belleannee, Clemence; Duchez, Anne-Claire et al. (2015) Detection and quantification of microparticles from different cellular lineages using flow cytometry. Evaluation of the impact of secreted phospholipase A2 on microparticle assessment. PLoS One 10:e0116812

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