title: In Vivo Availability of Pro-Resolving Lipid Mediators in Oxazolone Induced Dermal Inflammation in the Mouse.
abstract: The activation and infiltration of polymorphonuclear neutrophils (PMN) are critical key steps in inflammation. PMN-mediated inflammation is limited by anti-inflammatory and pro-resolving mechanisms, including specialized pro-resolving lipid mediators (SPM). We examined the effects of 15-epi-LXA4 on inflammation and the biosynthesis of pro-inflammatory mediators, such as prostaglandins, leukotriene B4 and various hydroxyeicosatetraenoic acids and SPM, in an oxazolone (OXA)-induced hypersensitivity model for dermal inflammation. 15-epi-LXA4 (100 μM, 5 μL subcutaneously injected) significantly (P < 0.05) reduced inflammation in skin, 24 hours after the OXA challenge, as compared to skin treated with vehicle. No significant influence on the biosynthesis of prostaglandins or leukotriene B4 was observed, whereas the level of 15S-hydroxy-eicosatetraenoic acid was significantly (P < 0.05) lower in the skin areas treated with 15-epi-LXA4. In spite of the use of a fully validated analytical procedure, no SPM were detected in the biological samples. To investigate the reason for the lack of analytical signal, we tried to mimic the production of SPM (lipoxins, resolvins, maresin and protectin) by injecting them subcutaneously into the skin of mice and studying the in vivo availability and distribution of the compounds. All analytes showed very little lateral distribution in skin tissue and their levels were markedly decreased (> 95%) 2 hours after injection. However, docosahexaenoic acid derivatives were biologically more stable than SPM derived from arachidonic acid or eicosapentaenoic acid.
authors.affiliation: pharmazentrum frankfurt/ZAFES, Institute of Clinical Pharmacology, Goethe-University, Frankfurt, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Homann
authors.affiliation: pharmazentrum frankfurt/ZAFES, Institute of Clinical Pharmacology, Goethe-University, Frankfurt, Germany.
authors.forename: Jing
authors.initials: J
authors.lastname: Suo
authors.affiliation: Fraunhofer Institute for Molecular Biology and Applied Ecology IME, Project Group TMP, Frankfurt, Germany.
authors.forename: Mike
authors.initials: M
authors.lastname: Schmidt
authors.affiliation: Fraunhofer Institute for Molecular Biology and Applied Ecology IME, Project Group TMP, Frankfurt, Germany.
authors.forename: Natasja
authors.initials: N
authors.lastname: de Bruin
authors.affiliation: pharmazentrum frankfurt/ZAFES, Institute of Clinical Pharmacology, Goethe-University, Frankfurt, Germany.
authors.forename: Klaus
authors.initials: K
authors.lastname: Scholich
authors.affiliation: pharmazentrum frankfurt/ZAFES, Institute of Clinical Pharmacology, Goethe-University, Frankfurt, Germany.|Fraunhofer Institute for Molecular Biology and Applied Ecology IME, Project Group TMP, Frankfurt, Germany.
authors.forename: Gerd
authors.initials: G
authors.lastname: Geisslinger
authors.affiliation: pharmazentrum frankfurt/ZAFES, Institute of Clinical Pharmacology, Goethe-University, Frankfurt, Germany.
authors.forename: Nerea
authors.initials: N
authors.lastname: Ferreirós
mesh_terms: D000818:Animals; D002138:Calibration; D002853:Chromatography, Liquid; D051546:Cyclooxygenase 2 / Q000378:metabolism; D020405:Dermis / Q000187:drug effects / Q000473:pathology*; D006893:Hydroxyeicosatetraenoic Acids / Q000378:metabolism; D007249:Inflammation / Q000139:chemically induced* / Q000473:pathology*; D018836:Inflammation Mediators / Q000378:metabolism*; D007279:Injections, Subcutaneous; D007975:Leukotriene B4 / Q000378:metabolism; D008055:Lipids / Q000737:chemistry*; D044045:Lipoxins / Q000494:pharmacology; D008163:Luminescent Measurements; D013058:Mass Spectrometry; D008810:Mice, Inbred C57BL; D010081:Oxazolone; D019696:Peptidylprolyl Isomerase / Q000378:metabolism; D015203:Reproducibility of Results; D012269:Ribosomal Proteins / Q000378:metabolism
chemical_list: D006893:Hydroxyeicosatetraenoic Acids; D018836:Inflammation Mediators; D008055:Lipids; D044045:Lipoxins; D012269:Ribosomal Proteins; C520792:Rpl13a protein, mouse; C040527:lipoxin A4; D010081:Oxazolone; D007975:Leukotriene B4; D051546:Cyclooxygenase 2; D019696:Peptidylprolyl Isomerase