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Rapid Appearance of Resolvin Precursors in Inflammatory Exudates: Novel Mechanisms in Resolution¹

Kie Kasuga^2,*, Rong Yang^2,*, Timothy F. Porter^*, Nitin Agrawal, Nicos A. Petasis, Daniel Irimia, Mehmet Toner and Charles N. Serhan^3,*

^* Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women’s Hospital, Boston, MA 02115; Department of Chemistry, University of Southern California, Los Angeles, CA 90089; and BioMEMS Resource Center, Massachusetts General Hospital, Charlestown, MA 02129, Shriners Hospital for Children, Boston, MA 02114 and Harvard Medical School, Boston, MA 02115

Resolution of inflammation is essential. Although supplementation of -3 fatty acids is widely used, their availability at sites of inflammation is not known. To this end, a multidisciplinary approach was taken to determine the relationship of circulating -3 to inflammatory exudates and the generation of resolution signals. In this study, we monitored resolvin precursors in evolving exudates, which initially paralleled increases in edema and infiltrating neutrophils. We also prepared novel microfluidic chambers to capture neutrophils from a drop of blood within minutes that permitted single-cell monitoring. In these, docosahexaenoic acid-derived resolvin D1 rapidly stopped neutrophil migration, whereas precursor docosahexaenoic acid did not. In second organ injury via ischemia-reperfusion, resolvin metabolically stable analogues were potent organ protectors reducing neutrophils. Together, these results indicate that circulating -3 fatty acids rapidly appear in inflammatory sites that require conversion to resolvins that control excessive neutrophil infiltration, protect organs, and foster resolution.

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 Grant R37-GM38765 (to C.N.S.); the Specialized Center for Oral Inflammation and Resolution, P50-DE016191 (to C.N.S. and N.A.P.); and the BioMEMS Resource Center, P41-EB002503 (to M.T. and D.I.). K.K. is the recipient of a postdoctoral fellowship award from the Arthritis Foundation.

² K.K. and R.Y. contributed equally to this study.

³ Address correspondence and reprint requests to Dr. Charles N. Serhan, Brigham and Women’s Hospital, 75 Francis Street, Boston, MA 02115.

⁴ Abbreviations used in this paper: PMN, polymorphonuclear neutrophil; d₅-DHA,4Z,7Z,10Z,13Z,16Z,19Z-docosahexaenoic-21,21,22,22,22-d₅ acid; d₅-EPA, 5Z,8Z,11Z,14Z,17Z-eicosapentaenoic-19,19,20,20,20-d₅ acid; DHA, docosahexaenoic acid; EPA, eicosapentaenoic acid; GC-MS, gas chromatography-mass spectrometry; MPO, myeloperoxidase; PDMS, poly(dimethylsiloxane); PEG, polyethylene glycol; PLA₂, phospholipase A₂; RvD1, resolvin D1; RvE1, resolvin E1.

⁵ The online version of this article contains supplemental material.