In Vivo Availability of Pro-Resolving Lipid Mediators in Oxazolone Induced Dermal Inflammation in the Mouse.

Julia Homann,Jing Suo,Klaus Scholich,Nerea Ferreirós,Mike Schmidt,Natasja De Bruin,Gerd Geisslinger,Christianne Bandeira De Melo

doi:10.1371/journal.pone.0143141

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.

Highlights

Specialized pro-resolving endogenous lipid-mediators (SPM) form a new class of molecules, for which key roles in the counter-regulation of inflammation and resolution have been established in recent years [1, 2]
The results reported here reveal some new aspects of the field of resolution of dermal inflammation
We studied the role of 15-epiLXA4 in delayed type hypersensitivity and the influence of this compound in the biosynthesis of lipid mediators involved in inflammatory processes

Summary

Introduction

Specialized pro-resolving endogenous lipid-mediators (SPM) form a new class of molecules, for which key roles in the counter-regulation of inflammation and resolution have been established in recent years [1, 2]. SPM are derived from different polyunsaturated fatty acids (PUFAs) and include metabolites of arachidonic acid (AA) (e.g. LXA4 and LXB4), docosahexaenoic acid (DHA) (e.g. D-series resolvins, maresins and protectins) and PLOS ONE | DOI:10.1371/journal.pone.0143141. Pro-Resolving Mediators in Dermal Inflammation eicosapentaenoic acid (EPA) derivatives (e.g. E-series resolvins and LXA5). The biosynthesis and positive effects of the SPM have already been established for different animal disease models, such as peritonitis [10,11,12,13,14], colitis [15,16,17,18], asthma [19, 20] and atherosclerosis [21]

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Results

Conclusion