The Journal of Experimental Medicine
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Published 21 October 2002. doi:10.1084/jem.20020760
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© Rockefeller University Press, 0022-1007/2002/10/1025 $5.00
The Journal of Experimental Medicine, Volume 196, Number 8, 1025-1037

Resolvins : A Family of Bioactive Products of Omega-3 Fatty Acid Transformation Circuits Initiated by Aspirin Treatment that Counter Proinflammation Signals



Charles N. Serhan, Song Hong, Karsten Gronert, Sean P. Colgan, Pallavi R. Devchand, Gudrun Mirick and Rose-Laure Moussignac

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

Address correspondence to Charles N. Serhan, Center for Experimental Therapeutics and Reperfusion Injury, Thorn Medical Research Bldg., 7th Floor, Brigham and Women's Hospital, Boston, MA 02115. Phone: 617-732-8822; Fax: 617-582-6141; E-mail: cnserhan{at}zeus.bwh.harvard.edu

Aspirin (ASA) is unique among current therapies because it acetylates cyclooxygenase (COX)-2 enabling the biosynthesis of R-containing precursors of endogenous antiinflammatory mediators. Here, we report that lipidomic analysis of exudates obtained in the resolution phase from mice treated with ASA and docosahexaenoic acid (DHA) (C22:6) produce a novel family of bioactive 17R-hydroxy-containing di- and tri-hydroxy-docosanoids termed resolvins. Murine brain treated with aspirin produced endogenous 17R-hydroxydocosahexaenoic acid as did human microglial cells. Human COX-2 converted DHA to 13-hydroxy-DHA that switched with ASA to 17R-HDHA that also proved a major route in hypoxic endothelial cells. Human neutrophils transformed COX-2-ASA–derived 17R-hydroxy-DHA into two sets of novel di- and trihydroxy products; one initiated via oxygenation at carbon 7 and the other at carbon 4. These compounds inhibited (IC50 ~50 pM) microglial cell cytokine expression and in vivo dermal inflammation and peritonitis at ng doses, reducing 40–80% leukocytic exudates. These results indicate that exudates, vascular, leukocytes and neural cells treated with aspirin convert DHA to novel 17R-hydroxy series of docosanoids that are potent regulators. These biosynthetic pathways utilize omega-3 DHA and EPA during multicellular events in resolution to produce a family of protective compounds, i.e., resolvins, that enhance proresolution status.

Key Words: endothelial cells • leukocytes • docosahexaenoic acid • cyclooxygenase-2 • resolution


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