Title: TPPU treatment of burned mice dampens inflammation and generation of bioactive DHET which impairs neutrophil function.
Authors: Bergmann, Christian B; Hammock, Bruce D; Wan, Debin; Gogolla, Falk; Goetzman, Holly; Caldwell, Charles C; Supp, Dorothy M
Published In Sci Rep, (2021 08 16)
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.
PubMed ID: 34400718
MeSH Terms: 8,11,14-Eicosatrienoic Acid/analogs & derivatives*; 8,11,14-Eicosatrienoic Acid/metabolism; Animals; Anti-Inflammatory Agents/pharmacology; Anti-Inflammatory Agents/therapeutic use*; Burns/drug therapy*; Burns/immunology; Burns/metabolism; Burns/pathology; Cytokines/blood; Epoxide Hydrolases/antagonists & inhibitors; Female; Lipopolysaccharides/pharmacology; MAP Kinase Signaling System/drug effects; Male; Mice; Mice, Inbred C57BL; NADPH Oxidases/metabolism; Neutrophils/classification; Neutrophils/immunology*; Neutrophils/metabolism; Phagocytosis/drug effects; Phenylurea Compounds/pharmacology; Phenylurea Compounds/therapeutic use*; Phosphatidylinositol 3-Kinases/biosynthesis; Phosphatidylinositol 3-Kinases/genetics; Piperidines/pharmacology; Piperidines/therapeutic use*; Reactive Oxygen Species/metabolism; Receptors, Chemokine/physiology; Respiratory Burst/drug effects; Transcription, Genetic/drug effects; p38 Mitogen-Activated Protein Kinases/antagonists & inhibitors; p38 Mitogen-Activated Protein Kinases/biosynthesis; p38 Mitogen-Activated Protein Kinases/genetics