Resolvins

Abstract

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.

Success of prostaglandin E 2 in structure–function is a challenge for structure-based therapeutics

“…15-epi-lipoxins, and resolvins (29)(30)(31). In the absence of mPGES-1, paw edema formation and leukocyte accumulation are reduced in delayed-type hypersensitivity.…”

“…Although there is evidence for an in vivo link between COX-2 and mPGES1, it does not preclude the formation of other COX-2-derived products, such as the 15-epi-lipoxins or resolvins that display antiinflammatory and proresolving properties (31). In addition to disruption of these proresolving biosynthetic circuits for ATL (33) and resolvins (31), inhibition of COX-2 is associated with several adverse effects, including impaired renal and cardiac function as well as increased thrombogenesis (34,35).…”

Targeting the D Series Resolvin Receptor System for the Treatment of Osteoarthritis Pain

“…Resolvins are endogenous specialized pro‐resolution lipid mediators derived from docosahexaenoic acid (DHA [D series resolvins]) and eicosapentaenoic acid (EPA [E series resolvins]), which exhibit potent antiinflammatory and pro‐resolution properties 7, 8. Four resolvin receptors have been identified: ALX (also known as N ‐formyl peptide receptor 2), G protein–coupled receptor 32 (GPR32) 9, 10, 11, chemokine‐like receptor 1 (ChemR23) 12, and leukotriene B 4 receptor (BLT‐1) 13.…”

14S,21R-Dihydroxydocosahexaenoic Acid Remedies Impaired Healing and Mesenchymal Stem Cell Functions in Diabetic Wounds

“…DHA ameliorates complications of diabetes (3) and significantly promotes wound healing (4). Resolvins, neuroprotectins/protectins, and maresins are lipid mediators (LMs) that are generated naturally from essential -3 fatty acids, DHA, and eicosapentaenoic acid, during acute inflammation and have potent anti-inflammatory functions (5)(6)(7)(8)(9). Their discovery established a new avenue toward unraveling the mechanisms behind the beneficial effects of DHA.…”