during Experimental Sepsis a 2Aof Inflammation by Cytosolic Phospholipase Modulation of Lipid and Protein Mediators

Cytosolic phospholipase A 2 (cid:1) (cPLA 2 (cid:1) ) is one of the key enzymes in lipid mediator generation. It preferentially hydrolyzes arachidonoyl-phospholipid in response to cellular stimuli, liberating arachidonic acid, the shared precursor of PGs and leukotrienes. Mice with disruption of the cPLA 2 (cid:1) gene exhibit a more than 80% decrease in the generation of these lipid mediators, leading to dramatic phenotypes in various models of inflammatory and allergic disease. In this study, we use the cecal ligation and puncture model of sepsis along with multiplex quantitation systems to explore interactions between eicosanoids and protein mediators. cPLA 2 (cid:1) -deficient mice exhibited significantly less weight loss accompanied by decreased generation of PGs, leukotriene B 4 , IL-6, and CCL2. Despite these differences, genetic ablation of cPLA 2 (cid:1) did not provide any survival advantage. Unexpectedly, abundant production of 12-hydroxy-eicosatetraenoic acid, another arachidonic acid-derived lipid mediator, was found to be unaffected by disruption of the cPLA 2 (cid:1) gene. Eicosanoid production preceded the production of cytokines. Eicosanoid modulation of IL-6 and CCL2 expression was suggested by scattergram analyses. These results provide in vivo evidence for the rapid generation of eicosanoids, regulatory role(s) for cPLA 2 (cid:1) -derived lipid mediators on protein mediator production, and the existence of a robust cPLA 2 (cid:1) -independent pathway(s) of eicosanoid generation. The Journal of Immunology, 2008, 181: 3558–3566.

[1]  L. Moldawer,et al.  Cecal Ligation and Puncture , 2010, Current protocols in immunology.

[2]  D. Brenner,et al.  Inherited human cPLA(2alpha) deficiency is associated with impaired eicosanoid biosynthesis, small intestinal ulceration, and platelet dysfunction. , 2008, The Journal of clinical investigation.

[3]  Charles N. Serhan,et al.  Resolvin E1 and protectin D1 activate inflammation-resolution programmes , 2007, Nature.

[4]  James G. Bollinger,et al.  Importance of group X–secreted phospholipase A2 in allergen-induced airway inflammation and remodeling in a mouse asthma model , 2007, The Journal of experimental medicine.

[5]  F. Bozza,et al.  INCREASED SUSCEPTIBILITY TO SEPTIC AND ENDOTOXIC SHOCK IN MONOCYTE CHEMOATTRACTANT PROTEIN 1/CC CHEMOKINE LIGAND 2-DEFICIENT MICE CORRELATES WITH REDUCED INTERLEUKIN 10 AND ENHANCED MACROPHAGE MIGRATION INHIBITORY FACTOR PRODUCTION , 2006, Shock.

[6]  C. Leslie,et al.  Properties of the Group IV phospholipase A2 family. , 2006, Progress in lipid research.

[7]  Takao Shimizu,et al.  Biochemical properties and pathophysiological roles of cytosolic phospholipase A2s. , 2006, Biochimica et biophysica acta.

[8]  Edward A Dennis,et al.  The phospholipase A2 superfamily and its group numbering system. , 2006, Biochimica et biophysica acta.

[9]  J. Siddiqui,et al.  Mechanisms of Mortality in Early and Late Sepsis , 2006, Infection and Immunity.

[10]  Takao Shimizu,et al.  The Lipoxin Receptor ALX: Potent Ligand-Specific and Stereoselective Actions in Vivo , 2006, Pharmacological Reviews.

[11]  G. FitzGerald,et al.  COX-2-derived prostacyclin protects against bleomycin-induced pulmonary fibrosis. , 2006, American journal of physiology. Lung cellular and molecular physiology.

[12]  C. Funk.  Lipoxygenase pathways as mediators of early inflammatory events in atherosclerosis. , 2006, Arteriosclerosis, thrombosis, and vascular biology.

[13]  E. Gelfand,et al.  CD8+ T lymphocytes and leukotriene B4: novel interactions in the persistence and progression of asthma. , 2006, The Journal of allergy and clinical immunology.

[14]  R. Baron,et al.  Pathobiology of sepsis: are we still asking the same questions? , 2006, American journal of respiratory cell and molecular biology.

[15]  J. Johndrow,et al.  Anti-inflammatory actions of lipoxin A4 and aspirin-triggered lipoxin are SOCS-2 dependent , 2006, Nature Medicine.

[16]  S. Narumiya,et al.  Suppression of allergic inflammation by the prostaglandin E receptor subtype EP3 , 2005, Nature Immunology.

[17]  Garret A FitzGerald,et al.  Biological basis for the cardiovascular consequences of COX-2 inhibition: therapeutic challenges and opportunities. , 2005, The Journal of clinical investigation.

[18]  D. Remick,et al.  EVALUATION OF ENDOTOXIN MODELS FOR THE STUDY OF SEPSIS , 2005, Shock.

[19]  J. Leonard,et al.  Cytosolic phospholipase A2α–deficient mice are resistant to experimental autoimmune encephalomyelitis , 2005, The Journal of experimental medicine.

[20]  A. Dmitrienko,et al.  LY315920NA/S-5920, a selective inhibitor of group IIA secretory phospholipase A2, fails to improve clinical outcome for patients with severe sepsis* , 2005, Critical care medicine.

[21]  J. Miyazaki,et al.  Protective role for cytosolic phospholipase A2α in autoimmune diabetes of mice , 2005 .

[22]  Takao Shimizu,et al.  A multiplex quantitation method for eicosanoids and platelet-activating factor using column-switching reversed-phase liquid chromatography-tandem mass spectrometry. , 2005, Analytical biochemistry.

[23]  Takao Shimizu,et al.  Identification of Novel Cytosolic Phospholipase A2s, Murine cPLA2δ, ϵ, and ζ, Which Form a Gene Cluster with cPLA2β* , 2005, Journal of Biological Chemistry.

[24]  Takao Shimizu,et al.  Pathway-oriented profiling of lipid mediators in macrophages. , 2005, Biochemical and biophysical research communications.

[25]  S. Kunkel,et al.  Opposing and Hierarchical Roles of Leukotrienes in Local Innate Immune versus Vascular Responses in a Model of Sepsis1 , 2005, The Journal of Immunology.

[26]  J. V. Sarma,et al.  Novel chemokine responsiveness and mobilization of neutrophils during sepsis. , 2004, The American journal of pathology.

[27]  G. Laurent,et al.  Cardiovascular , Pulmonary and Renal Pathology Severity of Lung Injury in Cyclooxygenase-2-Deficient Mice Is Dependent on Reduced Prostaglandin E 2 Production , 2008 .

[28]  D. Friend,et al.  Targeted Gene Disruption Reveals the Role of the Cysteinyl Leukotriene 2 Receptor in Increased Vascular Permeability and in Bleomycin-induced Pulmonary Fibrosis in Mice* , 2004, Journal of Biological Chemistry.

[29]  Jilly F. Evans,et al.  Leukotriene B4 Strongly Increases Monocyte Chemoattractant Protein-1 in Human Monocytes , 2004, Arteriosclerosis, thrombosis, and vascular biology.

[30]  B. Haribabu,et al.  Leukotriene B4 Receptor (BLT-1) Modulates Neutrophil Influx into the Peritoneum but Not the Lung and Liver during Surgically Induced Bacterial Peritonitis in Mice , 2004, Clinical Diagnostic Laboratory Immunology.

[31]  Lawrence J. Marnett,et al.  Cyclooxygenase-1-dependent Prostaglandin Synthesis Modulates Tumor Necrosis Factor-α Secretion in Lipopolysaccharide-challenged Murine Resident Peritoneal Macrophages* , 2004, Journal of Biological Chemistry.

[32]  Makoto Murakami,et al.  Secretory phospholipase A2. , 2004, Biological & pharmaceutical bulletin.

[33]  J. Uddin,et al.  Defective lipoxin-mediated anti-inflammatory activity in the cystic fibrosis airway , 2004, Nature Immunology.

[34]  K. Okubo,et al.  Cloning of a Gene for a Novel Epithelium-specific Cytosolic Phospholipase A2, cPLA2δ, Induced in Psoriatic Skin* , 2004, Journal of Biological Chemistry.

[35]  D. Friend,et al.  Cysteinyl leukotriene 1 receptor controls the severity of chronic pulmonary inflammation and fibrosis. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[36]  G. Martin,et al.  A global perspective on the epidemiology of sepsis , 2004, Intensive Care Medicine.

[37]  S. Opal,et al.  Recombinant human platelet-activating factor acetylhydrolase for treatment of severe sepsis: Results of a phase III, multicenter, randomized, double-blind, placebo-controlled, clinical trial* , 2004, Critical care medicine.

[38]  S. Siegelbaum,et al.  12-Lipoxygenase Metabolites of Arachidonic Acid Mediate Metabotropic Glutamate Receptor-Dependent Long-Term Depression at Hippocampal CA3-CA1 Synapses , 2003, The Journal of Neuroscience.

[39]  S. Narumiya.  Prostanoids in immunity: roles revealed by mice deficient in their receptors. , 2003, Life sciences.

[40]  P. Ward,et al.  The enigma of sepsis. , 2003, The Journal of clinical investigation.

[41]  Takao Shimizu,et al.  Cytosolic Phospholipase A2α–deficient Mice Are Resistant to Collagen-induced Arthritis , 2003, The Journal of experimental medicine.

[42]  Takao Shimizu,et al.  An Essential Role of Cytosolic Phospholipase A2α in Prostaglandin E2–mediated Bone Resorption Associated with Inflammation , 2003, The Journal of experimental medicine.

[43]  D. Mannino,et al.  The epidemiology of sepsis in the United States from 1979 through 2000. , 2003, The New England journal of medicine.

[44]  Mitchell M. Levy,et al.  2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference , 2003, Intensive Care Medicine.

[45]  Jilly F. Evans,et al.  International Union of Pharmacology XXXVII. Nomenclature for Leukotriene and Lipoxin Receptors , 2003, Pharmacological Reviews.

[46]  Stephen F. Lowry,et al.  Efficacy and safety of LY315920Na/S-5920, a selective inhibitor of 14-kDa group IIA secretory phospholipase A2, in patients with suspected sepsis and organ failure , 2003, Critical care medicine.

[47]  Takao Shimizu,et al.  Roles for cytosolic phospholipase A2α as revealed by gene-targeted mice , 2002 .

[48]  J. Siddiqui,et al.  Six at Six: Interleukin-6 Measured 6 H After the Initiation of Sepsis Predicts Mortality Over 3 Days , 2002, Shock.

[49]  J. Bonventre,et al.  Cytosolic phospholipase A2 in hypoxic pulmonary vasoconstriction , 2002 .

[50]  Y. Ouchi,et al.  A pivotal role of cytosolic phospholipase A2 in bleomycin-induced pulmonary fibrosis , 2002, Nature Medicine.

[51]  T. Grosser,et al.  Role of Prostacyclin in the Cardiovascular Response to Thromboxane A2 , 2002, Science.

[52]  Y. Urade,et al.  Prostaglandin D2 in Sleep-Wake Regulation: Recent Progress and Perspectives , 2002, The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry.

[53]  M. Peters-Golden,et al.  Protection from pulmonary fibrosis in leukotriene-deficient mice. , 2002, American journal of respiratory and critical care medicine.

[54]  C. Funk,et al.  Prostaglandins and leukotrienes: advances in eicosanoid biology. , 2001, Science.

[55]  T. Standiford,et al.  Selective inhibition of COX-2 improves early survival in murine endotoxemia but not in bacterial peritonitis. , 2001, American journal of physiology. Lung cellular and molecular physiology.

[56]  B. Koller,et al.  Mixed messages: modulation of inflammation and immune responses by prostaglandins and thromboxanes. , 2001, The Journal of clinical investigation.

[57]  Y. Sugimoto,et al.  Regulation of TNFalpha and interleukin-10 production by prostaglandins I(2) and E(2): studies with prostaglandin receptor-deficient mice and prostaglandin E-receptor subtype-selective synthetic agonists. , 2001, Biochemical pharmacology.

[58]  J. Bonventre,et al.  Renal concentrating defect in mice lacking group IV cytosolic phospholipase A(2). , 2001, American journal of physiology. Renal physiology.

[59]  M. Murakami,et al.  Role of cytosolic phospholipase A2 in the production of lipid mediators and histamine release in mouse bone-marrow-derived mast cells. , 2000, The Biochemical journal.

[60]  Takao Shimizu,et al.  Suppression of Intestinal Polyposis inApc Δ 716 Knockout Mice by an Additional Mutation in the Cytosolic Phospholipase A2Gene* , 2000, The Journal of Biological Chemistry.

[61]  J. Bonventre,et al.  Specific physiological roles of cytosolic phospholipase A(2) as defined by gene knockouts. , 2000, Biochimica et biophysica acta.

[62]  M. Peters-Golden,et al.  GM-CSF Regulates Bleomycin-Induced Pulmonary Fibrosis Via a Prostaglandin-Dependent Mechanism , 2000, The Journal of Immunology.

[63]  Y. Ouchi,et al.  Acute lung injury by sepsis and acid aspiration: a key role for cytosolic phospholipase A2 , 2000, Nature Immunology.

[64]  H. Shindou,et al.  Roles of cytosolic phospholipase A(2) and platelet-activating factor receptor in the Ca-induced biosynthesis of PAF. , 2000, Biochemical and biophysical research communications.

[65]  R. Strieter,et al.  Endogenous MCP-1 influences systemic cytokine balance in a murine model of acute septic peritonitis. , 2000, Experimental and molecular pathology.

[66]  R. Strieter,et al.  Endogenous monocyte chemoattractant protein-1 (MCP-1) protects mice in a model of acute septic peritonitis: cross-talk between MCP-1 and leukotriene B4. , 1999, Journal of immunology.

[67]  K. Austen,et al.  Cytosolic phospholipase A2 is essential for both the immediate and the delayed phases of eicosanoid generation in mouse bone marrow-derived mast cells. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[68]  D. Rader,et al.  Disruption of the 12/15-lipoxygenase gene diminishes atherosclerosis in apo E-deficient mice. , 1999, The Journal of clinical investigation.

[69]  S. Narumiya,et al.  Prostanoid receptors: structures, properties, and functions. , 1999, Physiological reviews.

[70]  C. Funk,et al.  Increased platelet sensitivity to ADP in mice lacking platelet-type 12-lipoxygenase. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[71]  J. Miyazaki,et al.  Role of cytosolic phospholipase A2 in allergic response and parturition , 1997, Nature.

[72]  M. Moskowitz,et al.  Reduced fertility and postischaemic brain injury in mice deficient in cytosolic phospholipase A2 , 1997, Nature.

[73]  B. Echtenacher,et al.  Critical protective role of mast cells in a model of acute septic peritonitis , 1996, Nature.

[74]  S. de Vos,et al.  Leukotriene B4 transcriptionally activates interleukin‐6 expression involving NK‐xB and NF‐IL6 , 1992, European journal of immunology.

[75]  B. Samuelsson.  Leukotrienes: mediators of immediate hypersensitivity reactions and inflammation. , 1983, Science.

[76]  G. Richards,et al.  The epidemiology of sepsis. , 1973, Clinical orthopaedics and related research.

[77]  M. McCarron,et al.  Septic Shock , 1964, International anesthesiology clinics.

[78]  M. Peters-Golden,et al.  Leukotrienes: Underappreciated Mediators of Innate Immune Responses , 2004 .

[79]  J. Arm.  Leukotriene generation and clinical implications. , 2004, Allergy and asthma proceedings.

[80]  J. Drazen.  Leukotrienes in asthma. , 2003, Advances in experimental medicine and biology.

[81]  Takao Shimizu,et al.  Discrete role for cytosolic phospholipase A(2)alpha in platelets: studies using single and double mutant mice of cytosolic and group IIA secretory phospholipase A(2). , 2002, The Journal of experimental medicine.

[82]  K. Honn,et al.  Lipoxygenase metabolites and cancer metastasis. , 1997, Advances in experimental medicine and biology.