Modulation of arachidonic and linoleic acid metabolites in myeloperoxidase-deficient mice during acute inflammation |
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Authors: | Lukas Kubala Kara R Schmelzer Anna Klinke Hana Kolarova Stephan Baldus Bruce D Hammock Jason P Eiserich |
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Institution: | 1. Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Science, Nanjing Normal University, Nanjing, China;2. Jinhu Food and Drug Administration, Jiangsu, China;3. College of Chemistry and Materials Science, Nanjing Normal University, Nanjing, China;4. Department of Medicinal Chemistry, School of Pharmacy, Soochow University, Jiangsu, China;5. Department of Pharmacology, University of Michigan, Ann Arbor, USA;1. Department of Physiology, Michigan State University, East Lansing, MI 48824, USA;2. Institute for Chemical Carcinogenesis, State Key Laboratory of Respiratory Diseases, Guangzhou Medical University, Guangzhou 510182, PR China;3. Center for Integrative Toxicology, Michigan State University, East Lansing, MI 48824, USA;1. Institute of Earth’s Crust, Siberian Branch of the Russian Academy of Science, ul. Lermontova 128, Irkutsk, 664033, Russia;2. Institute of Mineral Geology, Petrography, Mineralology, and Geochemistry, Russian Academy of Sciences, Staromonetnyi per. 35, Moscow, 190017, Russia |
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Abstract: | Acute inflammation is a common feature of many life-threatening pathologies, including septic shock. One hallmark of acute inflammation is the peroxidation of polyunsaturated fatty acids forming bioactive products that regulate inflammation. Myeloperoxidase (MPO) is an abundant phagocyte-derived hemoprotein released during phagocyte activation. Here, we investigated the role of MPO in modulating biologically active arachidonic acid (AA) and linoleic acid (LA) metabolites during acute inflammation. Wild-type and MPO-knockout (KO) mice were exposed to intraperitoneally injected endotoxin for 24 h, and plasma LA and AA oxidation products were comprehensively analyzed using a liquid chromatography–mass spectrometry method. Compared to wild-type mice, MPO-KO mice had significantly lower plasma levels of LA epoxides and corresponding LA- and AA-derived fatty acid diols. AA and LA hydroxy intermediates (hydroxyeicosatetraenoic and hydroxyoctadecadienoic acids) were also significantly lower in MPO-KO mice. Conversely, MPO-deficient mice had significantly higher plasma levels of cysteinyl-leukotrienes with well-known proinflammatory properties. In vitro experiments revealed significantly lower amounts of AA and LA epoxides, LA- and AA-derived fatty acid diols, and AA and LA hydroxy intermediates in stimulated polymorphonuclear neutrophils isolated from MPO-KO mice. Our results demonstrate that MPO modulates the balance of pro- and anti-inflammatory lipid mediators during acute inflammation and, in this way, may control acute inflammatory diseases. |
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