Review
Resolvins, docosatrienes, and neuroprotectins, novel omega-3-derived mediators, and their aspirin-triggered endogenous epimers: an overview of their protective roles in catabasis

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Abstract

The molecular basis for the beneficial impact of essential omega-3 fatty acids is of considerable interest. Recently, novel mediators generated from eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) that displayed potent bioactions were first identified in resolving inflammatory exudates [J. Exp. Med. 192 (2000) 1197; J. Exp. Med. 196 (2002) 1025] and in tissues enriched with DHA [J. Exp. Med. 196 (2002) 1025; J. Biol. Chem. 278 (2003) 14677]. The trivial names Resolvin (resolution phase interaction products) and docosatrienes were introduced for the bioactive compounds belonging to these novel series because they demonstrate potent anti-inflammatory and immunoregulatory actions. The compounds derived from eicosapentaenoic acid carrying potent biological actions (i.e., 1–10 nM range) are designated E series, given their EPA precursor, and denoted as Resolvins of the E series (Resolvin E1 or RvE1), and those biosynthesized from the precursor docosahexaenoic acid are Resolvins of the D series (Resolvin D1 or RvD1). Bioactive members from DHA with conjugated triene structures are docosatrienes (DT) that are immunoregulatory [J. Exp. Med. 196 (2002) 1025; J. Biol. Chem. 278 (2003) 14677], and neuroprotective [J. Biol. Chem., 278 (2003) 43807; Proc. Natl. Acad. Sci. U.S.A. [submitted for publication]] and are termed neuroprotectins. The specific receptors for these novel bioactive products from omega-3 EPA and DHA are abbreviated Resolvin D receptors (i.e., ResoDR1), Resolvin E receptor (ResoER1; RER1), and neuroprotectin D receptors (NPDR), respectively, in recognition of their respective cognate ligands. Aspirin treatment impacts biosynthesis of these compounds and a related series by triggering endogenous formation of the 17R-D series Resolvins and docosatrienes. These novel epimers are denoted as aspirin-triggered (AT)-RvDs and -DTs, and possess potent anti-inflammatory actions in vivo essentially equivalent to their 17S series pathway products. Here, we provide a syntomy overview of the formation and actions of these newly uncovered pathways and products as well as highlight their role(s) as endogenous protective mediators generated in anti-inflammation and catabasis.

Introduction

The potential beneficial impact of essential omega-3 fatty acids was suspected as early as 1929 from the studies of Burr and Burr [6] and for several decades [7], [8], [9], [10]. Inflammation has emerged as playing a central role in many prevalent diseases not previously believed to involve inflammation, including Alzheimer’s disease, cardiovascular disease [11], and cancer [12], [13], in addition to those well known to be associated with inflammation, such as arthritis and periodontal disease [14], [15]. Novel oxygenated products generated from precursors eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) that possessed potent bioactions were identified in resolving inflammatory exudates [1], [2], and similar structures were elucidated in tissues rich in docosahexaenoic acid [2], [3]. Hence, the terms Resolvin (resolution phase interaction products) and docosatrienes were introduced in initial studies because they displayed potent anti-inflammatory and immunoregulatory properties.

Unlike other products identified earlier from omega-3 fatty acids that are similar in structure to eicosanoids but less potent or devoid of bioactions, the Resolvins, docosatrienes, and neuroprotectins evoke potent biological actions in vitro and in vivo [1], [2], [3], [4], [5]. In this minireview, we provide a brief overview of the novel compounds and biosynthetic pathways from EPA that carry potent biological actions (i.e., 1–10 nM range), Resolvins of the E series (Resolvin E1 or RvE1), and those from DHA, namely, Resolvins of the D series (Resolvin D1 or RvD1). Bioactive members from these biosynthesis pathways carrying conjugated triene structures are denoted as docosatrienes (DT) and are both anti-inflammatory [2], [3] and neuroprotective [4], [5]. Also, specific dihydroxy acid-containing docosatrienes (e.g., 10,17S-DT) were recently termed neuroprotectins (NPD1) (see Ref. [5]).

Specific receptors for these novel omega-3 bioactive products are abbreviated Reso(E or D) receptors to designate the precursor origin and a numerical index (i.e., ResoER1) in recognition of their respective cognate ligands. In addition, traditional anti-inflammatory therapies, such as aspirin treatment, impact biosynthesis of these and related compounds by triggering the formation of the respective 17R series Resolvin Ds and 17R series DT. These novel bioactive epimers are denoted as aspirin-triggered (AT)-RvDs and AT-DTs. Here, we provide an overview of the salient structural features and corresponding bioactions that define these novel pathways and compounds as well as emphasize the origins of the systematic trivial names for their biosynthetic pathways. At this juncture, their biosynthesis and in vivo production provide evidence for a new overarching concept regarding the role of lipid mediators in the general inflammatory response, namely, novel host protective roles of lipid mediators, and underscore the importance of appreciating that not all lipid mediators are proinflammatory “bad guys” (Fig. 1).

Section snippets

Novel lipid mediators and aspirin-triggered epimers identified during resolution of acute inflammation: a new face of PMN inflammation

It is often questioned whether other essential fatty acids, such as the omega-3 EPA or DHA, are converted to potent lipid mediators or, in other words, “Is arachidonic acid, of the many naturally occurring fatty acids, the only precursor to potent bioactive molecules?” In short, no. Both DHA and EPA are important precursors. We now appreciate that intimate cell–cell interactions within vessel walls, i.e., adherent platelets that are studded with PMN, converge on the endothelium and can be

The link to omega-3 polyunsaturated fatty acids (PUFA)

We addressed a potential role of omega-3 PUFA recently in view of the compelling results from the GISSI study, which showed improvements in >11,000 cardiovascular patients [39], [40]: namely, reduction in sudden death by ∼45% by taking almost a gram of omega-3 per day. Inspection of their methods indicated that all the patients also took daily ASA that was unaccounted for in their analysis. Despite very large doses (milligram to gram daily), an abundant literature with omega-3 (n − 3) PUFA

Experiments with aspirin open new directions

ASA is an active ingredient in >60 over-the-counter remedies, making it a difficult substance to control for in some human studies. What is the molecular basis for omega-3’s protective action, and is there an overlap in these actions? To address this question in laboratory experimental settings, we used murine dorsal skin pouches [1], [2] that spontaneously resolve in rats [49] and adapted them for mice in order to include both genetics and to set up lipidomics employing LC-UV-MS-MS-based

Aspirin-triggered endogenous mediators, 18R-E series Resolvins

Resolving exudates in mice contain 18R-HEPE as well as several related bioactive compounds [1]. These novel compounds are produced from EPA by at least one biosynthetic pathway operative in human cells. This pathway is shown in Fig. 4; namely, vascular endothelial cells treated with aspirin convert EPA to 18R-HEPE that is released and rapidly converted by activated human PMN to a 5(6)-epoxide-containing intermediate that is converted to the bioactive 5,12,18R-trihydroxy-EPE, which we initially

17R-D series Resolvins

In resolving exudates from mice given aspirin and DHA, we found novel 17R-hydroxy-docosahexaenoic acid (17R-HDHA; see Table 1) and several related bioactive compounds (Fig. 5). Human microvascular endothelial cells, also ASA treated in hypoxia, generate 17R-HDHA. DHA is converted by human recombinant COX-2, which was surprising, since earlier literature indicated that DHA is not a substrate of cyclooxygenase [52], [53]. However, these investigations were before knowledge of the COX-2 isoform

17S-D series Resolvins

Are these types of bioactive compounds generated without aspirin or omega-3 supplements? In short, yes. Using our new lipidomic analyses, we learned that without ASA or added DHA the endogenous DHA was converted in vivo to a 17S series of Resolvins (RvD1 through RvD6) as well as docosatriene (10,17S-DT) [3], [4]. As in most structural elucidation experiments, added substrates were used to confirm biosynthesis, and to isolate quantities of the novel active principle for bioassay. In this case,

Anti-inflammatory actions

With microglial cells that liberate cytokines in the brain, the D class Resolvins block TNFα-induced IL-1β transcripts and are potent regulators of PMN infiltration in brain, skin, and peritonitis in vivo [3], [4]. Of the docosatriene-derived family, 10,17S-DT, the neuroprotectin D1 pathway shown in Fig. 6, proved a potent regulator of PMN influx in exudates at site where it is formed from endogenous precursors [2], [3] and limits stroke brain injury [4] and retinal pigmented cellular damage [5]

The main bioactive products and their respective series

Fig. 7 shows the main bioactive Resolvins and docosatrienes as representative members. These include five distinct series: (I) 18R Resolvins from EPA (i.e., RvE1); (II) 17R series (AT) Resolvins from DHA (RvD1 through RvD6); (III) 17S series Resolvins from DHA (RvD1 through RvD6); (IV) Docosatrienes (DT) from DHA; and (V) their AT form 17R series DT. Additional members are given in Table 1. The formation of these compounds may involve enzymes that are also involved in the conversion of

Acknowledgements

We thank Mary Halm Small for assistance in preparing the manuscript. This work was supported in part by National Institutes of Health Grants GM38675 and P01-DE13499.

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