Resolvins: a family of bioactive products of omega-3 fatty acid transformation circuits initiated by aspirin treatment that counter proinflammation signals.
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 (IC(50) approximately 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.
Serhan
Charles N
CN
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, USA. cnserhan@zeus.bwh.harvard.edu
Hong
Song
S
Gronert
Karsten
K
Colgan
Sean P
SP
Devchand
Pallavi R
PR
Mirick
Gudrun
G
Moussignac
Rose-Laure
RL
D000818:Animals; D001241:Aspirin / Q000494:pharmacology*; D001685:Biological Factors / Q000502:physiology*; D015525:Fatty Acids, Omega-3 / Q000494:pharmacology*; D006801:Humans; D007249:Inflammation / Q000378:metabolism*; D051379:Mice; D015398:Signal Transduction / Q000502:physiology*; D014407:Tumor Cells, Cultured
D001685:Biological Factors; D015525:Fatty Acids, Omega-3; D001241:Aspirin