Novel Functional Sets of Lipid-Derived Mediators with Antiinflammatory Actions Generated from Omega-3 Fatty Acids via Cyclooxygenase 2-Nonsteroidal Antiinflammatory Drugs and Transcellular Processing

doi:10.1084/jem.192.8.1197

Published online 16 October 2000.

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© The Rockefeller University Press, 0022-1007/2000/10/1197/ $5.00
The Journal of Experimental Medicine, Volume 192, Number 8, October 16, 2000 1197-1204

Brief Definitive Report

Novel Functional Sets of Lipid-Derived Mediators with Antiinflammatory Actions Generated from Omega-3 Fatty Acids via Cyclooxygenase 2–Nonsteroidal Antiinflammatory Drugs and Transcellular Processing

Charles N. Serhan^a, Clary B. Clish^a, Jessica Brannon^a, Sean P. Colgan^a, Nan Chiang^a, and Karsten Gronert^a

^a Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115
Director, Center for Experimental Therapeutics and Reperfusion Injury, Brigham and Women's Hospital, 75 Francis St., Boston, MA 02115.617-278-6957617-732-8822

Aspirin therapy inhibits prostaglandin biosynthesis withoutdirectly acting on lipoxygenases, yet via acetylation of cyclooxygenase2 (COX-2) it leads to bioactive lipoxins (LXs) epimeric at carbon15 (15-epi-LX, also termed aspirin-triggered LX [ATL]). Here,we report that inflammatory exudates from mice treated with ${omega}$ -3 polyunsaturated fatty acid and aspirin (ASA) generate a novelarray of bioactive lipid signals. Human endothelial cells withupregulated COX-2 treated with ASA converted C20:5 ${omega}$ -3 to 18R-hydroxyeicosapentaenoicacid (HEPE) and 15R-HEPE. Each was used by polymorphonuclearleukocytes to generate separate classes of novel trihydroxy-containingmediators, including 5-series 15R-LX₅ and 5,12,18R-triHEPE.These new compounds proved to be potent inhibitors of humanpolymorphonuclear leukocyte transendothelial migration and infiltrationin vivo (ATL analogue > 5,12,18R-triHEPE > 18R-HEPE).Acetaminophen and indomethacin also permitted 18R-HEPE and 15R-HEPEgeneration with recombinant COX-2 as well as ${omega}$ -5 and ${omega}$ -9 oxygenationsof other fatty acids that act on hematologic cells. These findingsestablish new transcellular routes for producing arrays of bioactivelipid mediators via COX-2–nonsteroidal antiinflammatorydrug–dependent oxygenations and cell–cell interactionsthat impact microinflammation. The generation of these and relatedcompounds provides a novel mechanism(s) for the therapeuticbenefits of ${omega}$ -3 dietary supplementation, which may be importantin inflammation, neoplasia, and vascular diseases.

Key Words: dietary PUFA • eicosanoids • leukocytes • cardiovascular disease

Presented in part at the 11th International Conference on Advancesin Prostaglandin and Leukotriene Research, plenary session June5, 2000, Florence, Italy.

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