Abstract
Oxylipins modulate the behavior of immune cells in inflammation. Soluble epoxide hydrolase (sEH) converts anti-inflammatory epoxyeicosatrienoic acid (EET) to dihydroxyeicosatrienoic acid (DHET). An sEH-inhibitor, TPPU, has been demonstrated to ameliorate lipopolysaccharide (LPS)- and sepsis-induced inflammation via EETs. The immunomodulatory role of DHET is not well characterized. We hypothesized that TPPU dampens inflammation and that sEH-derived DHET alters neutrophil functionality in burn induced inflammation. Outbred mice were treated with vehicle, TPPU or 14,15-DHET and immediately subjected to either sham or dorsal scald 28% total body surface area burn injury. After 6 and 24 h, interleukin 6 (IL-6) serum levels and neutrophil activation were analyzed. For in vitro analyses, bone marrow derived neutrophil functionality and mRNA expression were examined. In vivo, 14,15-DHET and IL-6 serum concentrations were decreased after burn injury with TPPU administration. In vitro, 14,15-DHET impaired neutrophil chemotaxis, acidification, CXCR1/CXCR2 expression and reactive oxygen species (ROS) production, the latter independent from p38MAPK and PI3K signaling. We conclude that TPPU administration decreases DHET post-burn. Furthermore, DHET downregulates key neutrophil immune functions and mRNA expression. Altogether, these data reveal that TPPU not only increases anti-inflammatory and inflammation resolving EET levels, but also prevents potential impairment of neutrophils by DHET in trauma.
© 2021. The Author(s).
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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8,11,14-Eicosatrienoic Acid / analogs & derivatives*
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8,11,14-Eicosatrienoic Acid / metabolism
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Animals
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Anti-Inflammatory Agents / pharmacology
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Anti-Inflammatory Agents / therapeutic use*
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Burns / drug therapy*
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Burns / immunology
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Burns / metabolism
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Burns / pathology
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Cytokines / blood
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Epoxide Hydrolases / antagonists & inhibitors
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Female
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Lipopolysaccharides / pharmacology
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MAP Kinase Signaling System / drug effects
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Male
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Mice
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Mice, Inbred C57BL
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NADPH Oxidases / metabolism
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Neutrophils / classification
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Neutrophils / immunology*
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Neutrophils / metabolism
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Phagocytosis / drug effects
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Phenylurea Compounds / pharmacology
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Phenylurea Compounds / therapeutic use*
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Phosphatidylinositol 3-Kinases / biosynthesis
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Phosphatidylinositol 3-Kinases / genetics
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Piperidines / pharmacology
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Piperidines / therapeutic use*
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Reactive Oxygen Species / metabolism
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Receptors, Chemokine / physiology
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Respiratory Burst / drug effects
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Transcription, Genetic / drug effects
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p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors
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p38 Mitogen-Activated Protein Kinases / biosynthesis
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p38 Mitogen-Activated Protein Kinases / genetics
Substances
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1-trifluoromethoxyphenyl-3-(1-propionylpiperidine-4-yl)urea
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14,15-dihydroxyeicosatrienoic acid
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Anti-Inflammatory Agents
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Cytokines
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Lipopolysaccharides
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Phenylurea Compounds
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Piperidines
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Reactive Oxygen Species
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Receptors, Chemokine
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NADPH Oxidases
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p38 Mitogen-Activated Protein Kinases
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Epoxide Hydrolases
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8,11,14-Eicosatrienoic Acid