Resolvin D1 and Its Aspirin-triggered 17R Epimer

Abstract

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 (EC(50) approximately 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 omega-3 fish oils in humans.

Formation of Highly Reactive Cyclopentenone Isoprostane Compounds (A3/J3-Isoprostanes) in Vivo from Eicosapentaenoic Acid

“…Thus, compounds derived from EPA are thought to exert less inflammatory activity. Further, Serhan and co-workers have described a specific group of polyoxygenated EPA derivatives termed resolvins that are produced enzymatically in various tissues; these molecules have been shown to inhibit cytokine expression and other inflammatory responses (7,(43)(44)(45)(46)(47).…”

Identification of Novel Autoxidation Products of the ω-3 Fatty Acid Eicosapentaenoic Acid in Vitro and in Vivo

“…EPA not only can replace arachidonic acid in phospholipid bilayers but is also a competitive inhibitor of COX, reducing the production of 2-series PGs and thromboxane, in addition to the 4-series leukotrienes (11,12). Recent studies have also shown that 3-and 5-series eicosanoids derived from EPA are either less biologically active or inactive compared with the former products and are thus considered to exert effects that are less inflammatory (10,13,39,40). Furthermore, Serhan (14,15,39,41,42) and co-workers have described a group of polyoxygenated DHA and EPA derivatives termed Resolvins that are produced enzymatically in various tissues.…”

“…Recent studies have also shown that 3-and 5-series eicosanoids derived from EPA are either less biologically active or inactive compared with the former products and are thus considered to exert effects that are less inflammatory (10,13,39,40). Furthermore, Serhan (14,15,39,41,42) and co-workers have described a group of polyoxygenated DHA and EPA derivatives termed Resolvins that are produced enzymatically in various tissues. These compounds inhibit cytokine expression and other inflammatory responses in microglia, skin cells, and other cell types.…”

Anti-Inflammatory and Proresolving Lipid Mediators

“…Following assessment of potential bioactions, the complete stereochemistry of the bioactive and related isomers and compounds was confirmed using total organic synthesis as outlined in Fig. 8 (8,80,81).…”