The resolvins (Rv) are lipid mediators derived from omega-3 polyunsaturated fatty acids that act within a local inflammatory milieu to stop leukocyte recruitment and promote resolution. Resolvin E1 (RvE1; (5S,12R,18R)-trihydroxy-6Z,8E,10E,14Z,16E-eicosapentaenoic acid) is an oxygenase product derived from omega-3 eicosapentaenoic acid that displays potent anti-inflammation/pro-resolution actions in vivo. Here, we determined whether oxidoreductase enzymes catalyze the conversion of RvE1 and assessed the biological activity of the RvE1 metabolite. With NAD ؉ as a cofactor, recombinant 15-hydroxyprostaglandin dehydrogenase acted as an 18-hydroxyl dehydrogenase to form 18-oxo-RvE1. In the murine lung, dehydrogenation of the hydroxyl group at carbon 18 position to form 18-oxo-RvE1 represented the major initial metabolic route for RvE1. At a concentration where RvE1 potently reduced polymorphonuclear leukocyte (PMN) recruitment in zymosan-induced peritonitis, 18-oxo-RvE1 was devoid of activity. In human neutrophils, carbon 20 hydroxylation of RvE1 was the main route of conversion. An RvE1 analog, i.e. 19-(p-fluorophenoxy)-RvE1, was synthesized that resisted rapid metabolic inactivation and proved to retain biological activity reducing PMN infiltration and pro-inflammatory cytokine/chemokine production in vivo. These results established the structure of a novel RvE1 initial metabolite, indicating that conversion of RvE1 to the oxo product represents a mode of RvE1 inactivation. Moreover, the designed RvE1 analog, which resisted further metabolism/inactivation, could be a useful tool to evaluate the actions of RvE1 in complex disease models.Most inflammatory processes are self-limiting (1), implicating the existence of endogenous circuits for anti-inflammation and/or pro-resolution mediators that are operative during the temporal events of host defense and inflammation (recently reviewed in Refs. 2 and 3). We identified and characterized lipid mediators that are generated during spontaneous resolution phase and that possess anti-inflammatory and/or pro-resolving properties; these include lipoxins, resolvins, and protectins (2). Like other autacoids, these lipid mediators are generated in response to stimuli, act locally, and may be rapidly inactivated by further metabolism via enzymatic pathways (4 -6). Resolution of inflammation is an active process governed by timely and spatially regulated formation and inactivation of local lipid mediators and termination of pro-resolving signals, so that tissues can return to homeostasis (4). Thus, it is important to identify the further metabolic products of these pro-resolving lipid mediators and evaluate their bioactivities in vivo.The resolvins and protectins are new families of lipid mediators derived from omega-3 polyunsaturated fatty acids, namely eicosapentaenoic acid and docosahexaenoic acid, that are generated and act locally at sites of inflammation, where they counterregulate polymorphonuclear leukocyte (PMN) 2 infiltration and promote resolution (for recent reviews, se...
