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Resolvin E1 Metabolome in Local Inactivation during Inflammation-Resolution¹

Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115

Resolvin E1 (RvE1; 5S,12R,18R-trihydroxy-6Z,8E,10E,14Z,16E-eicosapentaenoic acid) is a potent anti-inflammatory and proresolving mediator derived from the omega-3 eicosapentaenoic acid. In this study, we report the RvE1 metabolome, namely, the metabolic products derived from RvE1. RvE1 was converted to several novel products by human polymorphonuclear leukocytes and whole blood as well as in murine inflammatory exudates, spleen, kidney, and liver. The potential activity of each of the newly identified products was directly compared with that of RvE1. The new RvE1 products elucidated included 19-hydroxy-RvE1, 20-carboxy-RvE1, and 10,11-dihydro-RvE1. Metabolomic profiles of RvE1 were species-, tissue-, and cell type-specific. Direct comparisons of the bioactions between isolated RvE1 metabolic products indicated that 10,11-dihydro-RvE1, 18-oxo-RvE1, and 20-carboxy-RvE1 displayed reduced bioactivity in vivo. At concentrations as low as 1 nM, RvE1 enhanced macrophage phagocytosis, a proresolving activity that was reduced by metabolic inactivation. These results document novel metabolic products of RvE1 that impact its actions and that both omega-1 hydroxylation and reduction of conjugated double bonds in RvE1 are new pathways of four main routes of RvE1 metabolism in mammalian tissues. Together, these findings indicate that, during inflammation and its controlled resolution, specific tissues inactivate proresolving signals, i.e., RvE1, to permit the coordinated return to homeostasis. Moreover, the RvE1 metabolome may serve as a biomarker of these processes.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported in part by National Institutes of Health Grants DK074448 and P-50-DE-016191 (to C.N.S.).

² S.H. and T.F.P. contributed equally to this work and share first authorship.

³ Current address: Neuroscience Center, Louisiana State University Health Center, 2020 Gravier Street, Suite D, New Orleans, LA 70112.

⁴ Address correspondence and reprint requests to Dr. Charles N. Serhan, Director, Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women’s Hospital and Harvard Medical School, 75 Francis Street, Boston, MA 02115. E-mail address: cnserhan{at}zeus.bwh.harvard.edu

⁵ Abbreviations used in this paper: RvE1, resolvin E1, 5S,12R,18R-trihydroxy-6Z,8E,10E,14Z,16E-eicosapentaenoic acid; LC-UV-MS, liquid chromatography-ultraviolet-tandem mass spectrometry; LXA₄, lipoxin A₄; PMN, polymorphonuclear leukocyte; PUFA, polyunsaturated fatty acid; Resolvin, resolution phase interaction product; 18-oxo-RvE1; 18-oxo-5S,12R-dihydroxy-6Z,8E,10E,14Z,16E-eicosapentaenoic acid; EPA, eicosapentaenoic acid; RP-HPLC, reversed phase-HPLC; LTB₄, leukotriene B₄.

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