Metabolic Inactivation of Resolvin E1 and Stabilization of Its Anti-inflammatory Actions

Abstract

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...

12/15-Lipoxygenase Regulates the Inflammatory Response to Bacterial Products In Vivo

“…Our results show key differences: 1) there was no deficit in neutrophil influx, with instead a selective suppression of Mo/M migration; and 2) LXA 4 was not detected in our model even though the detection limit of our mass spectrometry assay is well below the levels previously determined using ELISAs in other studies (29 -32). A caveat is that S. epidermidis-induced inflammation is bacterial rather than fungal, and in terms of neutrophil recruitment is less severe than the zymosan model (32,33). The peak of LXA 4 reported in zymosan peritonitis occurs at 2-4 h and decreases during resolution (32).…”

Novel Lipid Mediators and Resolution Mechanisms in Acute Inflammation

“…Hence, following their actions, local tissues inactivate resolvins, permitting organs to return to homeostasis. 48,131,132 …”

“…Both RvD1 and RvE1 undergo site-specific metabolic inactivation. 131,132 Thus, the RvD1 and RvE1 analogs that display potent organ protective actions may provide new approaches to reduce organ damage characterized by excessive PMN infiltration.…”

“…131,132 Ischemia-reperfusion is an event of significant clinical importance. Reperfusion-related tissue injury often occurs during surgical procedures, particularly those involving extremities, causing both local and remote organ injury as well as increasing costs associated with prolonged postoperative recovery.…”

The Anti-inflammatory And Pro-resolving Mediator Resolvin E1 Protects Mice From Bacterial Pneumonia And Acute Lung Injury

“…Recently, a novel lipid mediator was identified in resolving inflammatory exudates that was enzymatically derived from EPA and termed resolvin E1 (RvE1) (19). This mediator decreases polymorphonuclear neutrophil (PMN) migration, production of proinflammatory cytokines, and inflammation in several disease models, including periodontitis and allergic airway inflammation (19)(20)(21)(22)(23)(24)(25). Whereas RvE1 carries potent anti-inflammatory properties in sterile airway inflammation (25), its effect on lung infection has yet to be determined.…”