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J. Biol. Chem., Vol. 282, Issue 13, 9323-9334, March 30, 2007

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Resolvin D1 and Its Aspirin-triggered 17R Epimer

STEREOCHEMICAL ASSIGNMENTS, ANTI-INFLAMMATORY PROPERTIES, AND ENZYMATIC INACTIVATION^*

Yee-Ping Sun, Sungwhan F. Oh, Jasim Uddin, Rong Yang, Katherine Gotlinger^¶, Eric Campbell, Sean P. Colgan, Nicos A. Petasis, and Charles N. Serhan^¶1

From the Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital and ^¶Department of Oral Medicine, Infection and Immunity, Harvard School of Dental Medicine and Harvard Medical School, Boston, Massachusetts 02115 and the Department of Chemistry, Loker Hydrocarbon Institute, University of Southern California, Los Angeles, California 90089

We recently uncovered two new families of potent docosahexaenoic acid-derived mediators, termed D series resolvins (Rv; resolution phase interaction products) and protectins. Here, we assign the stereochemistry of the conjugated double bonds and chirality of alcohols present in resolvin D1 (RvD1) and its aspirin-triggered 17R epimer (AT-RvD1) with compounds prepared by total organic synthesis. In addition, docosahexaenoic acid was converted by a single lipoxygenase in a "one-pot" reaction to RvD1 in vitro. The synthetic compounds matched the physical and biological properties of those enzymatically generated. RvD1 proved to be 7S,8R,17S-trihydroxy-4Z,9E,11E,13Z,15E,19Z-docosahexaenoic acid, AT-RvD1 matched 7S,8R,17R-trihydroxy-4Z,9E,11E,13Z,15E,19Z-docosahexaenoic acid, and they both stopped transendothelial migration of human neutrophils (EC₅₀ 30 nM). In murine peritonitis in vivo, RvD1 and AT-RvD1 proved equipotent (at nanogram dosages), limiting polymorphonuclear leukocyte infiltration in a dose-dependent fashion. RvD1 was converted by eicosanoid oxidoreductase to novel 8-oxo- and 17-oxo-RvD1 that gave dramatically reduced bioactivity, whereas enzymatic conversion of AT-RvD1 was sharply reduced. These results establish the complete stereochemistry and actions of RvD1 and AT-RvD1 as well as demonstrate the stereoselective basis for their enzymatic inactivation. RvD1 regulates human polymorphonuclear leukocyte transendothelial migration and is anti-inflammatory. When its carbon 17S alcohol is enzymatically converted to 17-oxo-RvD1, it is essentially inactive, whereas the 17R alcohol configuration in its aspirin-triggered form (AT-RvD1) resists rapid inactivation. These results may contribute to the beneficial actions of aspirin and -3 fish oils in humans.

Received for publication, September 28, 2006 , and in revised form, December 22, 2006.

^* This work was supported by National Institutes of Health Grants GM38765, DK074448, and P50-DE016191. 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 To whom correspondence should be addressed: Center for Experimental Therapeutics and Reperfusion Injury, Dept. of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, 75 Francis St., Boston, MA 02115. Tel.: 617-732-8822; Fax: 617-582-6141; E-mail: cnserhan{at}zeus.bwh.harvard.edu.

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