Resolvins: a family of bioactive products of omega-3 fatty acid transformation circuits initiated by aspirin treatment that counter proinflammation signals

CN Serhan, S Hong, K Gronert, SP Colgan… - The Journal of …, 2002 - rupress.org
CN Serhan, S Hong, K Gronert, SP Colgan, PR Devchand, G Mirick, RL Moussignac
The Journal of experimental medicine, 2002rupress.org
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 17 R-hydroxy-containing di-and tri-hydroxy-docosanoids
termed resolvins. Murine brain treated with aspirin produced endogenous 17 R …
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.
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