Novel Eicosanoid and Docosanoid Mediators: Resolvins, Docosatrienes, and Neuroprotectins Charles N

Novel eicosanoid and docosanoid mediators: resolvins, docosatrienes, and neuroprotectins Charles N. Serhan

Purpose of review Abbreviations It is well known that arachidonic acid is the precursor to COX cyclooxygenase potent mediators. Many clinical studies suggest that DHA docosahexaenoic acid EPA eicosapentaenoic acid omega-3 polyunsaturated fatty acids such as HEPE hydroxyeicosapentaenoic acid eicosapentaenoic acid and docosahexaenoic acid have PMN polymorphonuclear neutrophils PUFA polyunsaturated fatty acids beneficial actions in human diseases. The molecular basis of these actions remains of interest. Recent findings # 2005 Lippincott Williams & Wilkins These demonstrate that eicosapentaenoic acid and 1363-1950 docosahexaenoic acid are precursors to potent (nM range) bioactive mediators that possess both anti-inflammatory Introduction and protective properties. These mediators were coined Beneficial actions of essential omega-3 polyunsaturated resolvins, docosatrienes, and protectins as general classes, fatty acids (PUFA) were noted as early as 1929 [1] and since each possesses unique chemical structures that are have been studied until the present [2–5]. In parallel, it features of the new chemical classes and are has emerged that inflammation plays a central role in biosynthesized by new pathways. Resolvins, discovered many prevalent diseases not previously known to involve first, were identified during the resolution phase of acute inflammation, including Alzheimer’s disease, cardiovas- inflammation; hence the term resolution interaction cular disease [6], and cancer [7], in addition to those well products, because they are also biosynthesized by human known to be associated with inflammation, such as arthri- cells via cell–cell interactions. Docosatrienes contain tis and periodontal disease [8,9]. The molecular mechan- conjugated triene structures generated from ism(s) underlying the many reports of the beneficial docosahexaenoic acid as a defining feature. The protectins actions of omega-3 PUFA remains an exciting and impor- comprise docosatrienes and resolvins of the D series that tant challenge for molecular medicine. Also, attributing are both neuroprotective and anti-inflammatory. Aspirin beneficial responses to these fatty acids per se may not be impacts on these new pathways by triggering formation of appropriate because pharmaceutical eicosapentaenoic their epimers (i.e. R isomers). acid (EPA) and docosahexaenoic acid (DHA) have not Summary been widely available for study. Along these lines, we In view of the many beneficial actions attributed to omega-3 recently identified novel oxygenated products generated dietary supplementation, identification of novel potent by enzymatic processes from the precursors EPA and mediators from omega-3 that are both anti-inflammatory and DHA. These new compounds possess potent actions in protective may have wide implications. the resolution of inflammatory exudates [10,11, 12 ] and have neuroprotective properties [13,14]. The terms Keywords resolvin (resolution phase interaction products) and docosa- aspirin, inflammation, polyunsaturated fatty acids, triene were introduced from initial studies, since the new resolution compounds displayed both potent anti-inflammatory and immunoregulatory properties, reducing neutrophil traffic

Curr Opin Clin Nutr Metab Care 8:115–121. # 2005 Lippincott Williams & Wilkins. and the magnitude of the inﬂammatory response [10,11]. The term neuroprotectin was introduced, given the Center for Experimental Therapeutics and Reperfusion Injury, Department of protective actions of 10,17-docosatriene in neural and Anesthesiology, Perioperative and Pain Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, USA retinal systems [14 ], as well as in stroke [13 ] and animal models of Alzheimer’s disease (N.G. Bazan, et al., unpub- Correspondence to Professor Charles N. Serhan, Director, Center for Experimental Therapeutics and Reperfusion Injury, Brigham and Women’s Hospital, 75 Francis lished data). St., Thorn Building for Medical Research, Room 724, Boston, MA 02115, USA Tel: +1 617 732 8822; fax: +1 617 582 6141; e-mail: [email protected] Unlike some of the other products characterized earlier as potentially being formed from omega-3 PUFA that are Current Opinion in Clinical Nutrition and Metabolic Care 2005, 8:115–121 similar in structure to eicosanoids but either less potent or devoid of bioactions [15,16], the resolvins, docosatrienes, and neuroprotectins evoke potent biological actions in the nanomolar or picomolar range in vitro and in vivo

115 116 Lipid metabolism and therapy

Figure 1. Essential polyunsaturated fatty acids are precursors anti-inflammation and pro-resolution. This is a sharp to bioactive lipid mediators departure from the well appreciated pro-inflammatory roles of lipid mediators in general and particularly the Prostaglandins roles of prostaglandins and leukotrienes. The recognition Pro-inflammatory Arachidonic acid Eicosanoids Leukotrienes C20:4 that resolution is an active process and that activation of EETs p450 the lipoxin biosynthetic circuit and lipoxins themselves, cell cell Anti-inflammatory as well as aspirin-triggered lipoxins and their stable Lipoxins pro-resolution analogs, are potent agonists of anti-inflammation in vivo Resolvins and in many disease models [22] has now turned our Eicosapentaenoic acid (EPA) Eicosanoids E series C20:5 attention to understanding the biochemical events that

Resolvins are activated during the resolution of local inflammatory Docosahexaenoic acid (DHA) Docosanoids D series responses. C20:6 Docosatrienes Protectins Neuroprotectins The omega-3 connection See text for details. EET, epoxyeicosatetraenoic acid. In view of the compelling results from the GISSI study, which showed improvements in >11 000 cardiovascular patients [24,25]: namely, reduction in sudden death by 45% by taking almost a gram of omega-3 per day; we [10,11,12,13,14]. This review gives a brief overview of addressed the role of omega-3 PUFA. Inspection of the the novel biosynthetic pathways from EPA that carry GISSI protocols revealed that all the patients in each arm potent biological actions, the resolvins of the E series of the study also took aspirin daily, but the contribution of (Resolvin E1 or RvE1), and those from DHA, the resolvins ongoing aspirin therapy to the beneficial outcome of of the D series (Resolvin D1 or RvD1), as well as bio- omega-3 PUFA was not accounted for in the analysis. synthesis pathways that form novel conjugated triene An abundant literature on omega-3 PUFA at doses of structures denoted as docosatrienes that are also both anti- milligrams to grams daily suggests beneficial actions in inflammatory [10,11,12] and neuroprotective [13,14], many human diseases including periodontal disease [26], termed neuroprotectins (see Ref. [14] and Fig. 1). inflammatory diseases and cancer [2,27]. The three major Chemical mediators of resolution: lipoxygenases (5-LO, 12-LO, 15-LO) can each convert recognizing that resolution is an active DHA to various monohydroxy-containing products. process However, the in-vivo functions of these products were either not apparent or they did not display bioactivity From the early studies of Bergstro¨m, Samuelsson, and [16,28,29]. Also, DHA can be non-enzymatically oxyge- colleagues, it is clear that arachidonic acid is transformed nated to isoprostane-like compounds termed neuro- into many potent bioactive compounds such as prosta- prostanes that reflect oxidative stress in the brain [30], glandins, leukotrienes, and lipoxins. The departure of or autooxidized to products that are monohydroxy fatty acids from simply playing structural roles in cell racemates [31] of the compounds that are now known membranes and/or as energy stores came largely from to be enzymatically produced during biosynthesis of the recognition of the rapid transformation of arachidonic resolvins and docosatrienes [11,12,13,14]. Despite acid to these potent eicosanoids by both cyclooxygenase the many years of research on omega-3 PUFA, it is and lipoxygenase mechanisms (see Refs [17–19]). Many noteworthy that the molecular basis and mechanisms of the classic prostaglandins and leukotriene mediators underlying their immunoprotective actions remained to are pro-inflammatory and play a decisive role in inflam- be established, and their direct connection to human mation and/or in systems such as the reproductive system, disease and treatment are still important biomedical where prostaglandins are key physiologic regulators. In challenges [32]. sharp contrast, in recent years it has become clear that counter-regulatory substances, such as the lipoxins, are generated during the resolution of acute inflammation, The impact of aspirin treatment: and that these serve as agonists for endogenous anti- discovery of the aspirin-triggered lipid inflammatory mechanisms. This constitutes the first mediators evidence that the resolution of inflammation, which Aspirin is an active ingredient in more than 60 over-the- was once thought to be a passive process [20], is actually counter remedies, making it a difficult substance to an active process that involves turning on of specific control completely in many human studies. To address pro-resolution circuits [21,22,23]. this in an experimental setting, we used murine dorsal skin pouches [10,11] that were known to spontaneously It is now clear from an abundance of emerging litera- resolve in rats [23]. We adapted them for study in mice ture that the lipoxins are potent agonists of endogenous in order to be able to look at the genetics of both species, Novel eicosanoid and docosanoid mediators Serhan 117 and to develop mediator lipidomics employing liquid Aspirin-triggered lipid mediators: chromatography-ultraviolet-tandem mass spectrometry 18R E-series resolvins and 17R D-series (LC-UV-MS-MS)-based analyses geared to evaluate resolvins whether novel lipid mediators are indeed generated The resolving exudates contain 18R-hydroxyeicosapen- during the resolution phase of inflammation [10,11]. In taenoic acid (HEPE) as well as several related bioactive this pouch (experimental contained inflammation) after compounds [10]. These novel compounds are produced 4 h, polymorphonuclear neutrophils (PMN) numbers from EPA by at least one biosynthetic pathway operative begin to drop within exudates [10,11], the cellular in human cells. This pathway, depicted in Fig. 2, involves definition of resolution. Exudates were taken at timed cell–cell interactions within the exudates; namely, intervals, focusing on the period of spontaneous resolu- vascular endothelial cells treated with aspirin convert tion’; namely, when neutrophils spontaneously are lost EPA to 18R-HEPE that is released and then rapidly from the exudate and the tissue site begins to resolve. In converted by activated human PMN to a 5(6) epoxide- this phase of the response in vivo, lipid mediator profiles containing intermediate that is converted to the bioactive were determined using tandem LC-UV-MS-MS. We 5,12,18R-trihydroxy-EPE, which we initially termed constructed lipid mediator libraries with physical proper- Resolvin, specifically Resolvin E1 (RvE1). The name ties (i.e. MS and MS/MS spectra, elution times, UV Resolvin was coined because this product (1) was identi- spectra, etc.) for matching and to assess whether known fied in the resolution phase, (2) appeared as a cell–cell and/or potential novel lipid mediators were present interaction/transcellular biosynthetic product with iso- within the exudates. When novel lipid mediators were lated human cells, and (3) most importantly proved to encountered, their structures were elucidated by carrying be a potent regulator of PMN and inflammation response out retrograde analysis for both biogenic (i.e. using in vivo. Both biogenic [10] and total organic synthesis recombinant enzymes) and total organic synthesis. This were achieved, and its complete stereochemical assign- approach permitted assessment of structure–activity ment was recently established [33] and is shown in Fig. 2. relationships as well as the scale-up required to confirm bioactions characterized for the novel compounds iden- It should also be noted that 5S,18R-diHEPE (RvE2) tified [10,11]. carries a conjugated diene structure that is separate

Figure 2. Eicosapentaenoic acid conversion to Resolvin E1

Human endothelial cells expressing cyclooxygenase- 2 (COX-2) treated with aspirin transform Vascular cells Aspirin:COX 2 O(O)H eicosapentaenoic acid EPA (EPA) by abstracting HOOC 18R-hydro(peroxy)-EPE hydrogen at C16 to give predominantly an R insertion of molecular oxygen to yield 18R-H(p)EPE. This is further O(O)H converted via sequential actions of leukocyte OH COOH 5-lipoxygenase leading to RvE2 formation of 5,12,18R- HO 5S-hydro(peroxy),18R-hydroxy-EPE triHEPE (Resolvin E1) COOH [11,33]. Reduction HO HOOC 5S ,18R-dihydroxy-EPE

OH O

5,6-epoxy,18R-hydroxy-EPE

OH Resolvin E1 OH HO (RvE1) COOH 118 Lipid metabolism and therapy

Figure 3. Docosahexaenoic acid conversion to 17S and aspirin-triggered D-series resolvins

The 17R-series resolvins are produced from HOOC Neuroprotectins docosahexaenoic acid OH (DHA) in the presence of Docosatrienes OH aspirin (lower branch). OH * 17S-resolvin D Human endothelial cells COOH expressing cyclooxygenase- Epoxidation series via LOX mechanism Resolvin D4 2 (COX-2) and treated with OH (RvD4) O aspirin transform DHA to DHA 17R-HDHA. Human PMN OH can then convert 17R- COOH HDHA to two separate LOX 4S-Hydroperoxy, 4(5)-epoxy-17S/R-HDHA OH intermediates via 5- 17S/R-HDHA lipoxygenation (LOX, Resolvin D3 modeled with the potato 5- HO (RvD3) LO) [10,11] that are each HOOC rapidly transformed into two epoxide intermediates: a 17S/R-H(p)DHA O(O)H 7(8)-epoxide (lower panel) COOH and a 4(5)-epoxide (upper OH panel). Note: the 7S-Hydroperoxy, Resolvin D2 stereochemistry is depicted Aspirin:COX 2 OH 17S/R-HDHA (RvD2) COOH in the most likely HO HO configuration, based on DHA results with recombinant Aspirin enzymes (see Refs triggered O [11,12 ] for further details). 17R-resolvin D HO COOH These two novel epoxide series Resolvin D1 7(8)-epoxy-17S/R-HDHA HO intermediates open to (RvD1) bioactive products which are denoted 17S-series OH RvD1 through RvD4, functionally redundant positional isomers generated via the actions of specific enzymes that remain to be identified. Aspirin triggers the same compound, but the chirality at carbon 17 is in the R configuration from the involvement of COX-2 when acetylated by aspirin (see text for details). and distinct from the novel triene plus diene structure was converted in vivo to a 17S series of resolvins (struc- and combined compound chromophore present within tures of RvD1 to RvD4 are depicted in Fig. 3. RvD5 and RvE1. These compounds display potent actions in vivo RvD6 are not shown) as well as docosatriene (10,17S-DT) and with isolated cells; hence the ligand-specific recep- by lipoxygenase mechanisms [12,13]. As in most struc- tors for RvE1 ligand are coined ResoER1 [33]. tural elucidation experiments, added substrates were used to confirm biosynthesis, and to isolate quantities In resolving exudates from mice given aspirin and DHA, of the novel active principle for bioassay. In this case, we found novel 17R-hydroxy-DHA (17R-HDHA) and given the large doses needed to observe effects of omega- several related bioactive compounds (Fig. 3). Hypoxic 3 PUFA in humans, experimental animals, and in-vitro human microvascular endothelial cells treated with cell culture studies (see Refs [2–5] and references aspirin generate 17R-HDHA. DHA is converted by within), we expected that these precursors needed to human recombinant cyclooxygenase-2 (COX-2), which be added in the present studies. This proved not to be the was surprising, since earlier literature indicated that DHA case. Tissues contain DHA that is available upon activa- is not a substrate of cyclooxygenase [15,34]. However, tion to produce 17S-containing docosatriene and resol- these investigations were carried out before knowledge of vins in vivo [12,13,14]. the COX-2 isoform and used organs rich in COX-1. Human recombinant COX-2 converts DHA to 13- Roles in anti-inflammation: reduced hydroxy-DHA. With aspirin, this switches to 17R-oxyge- neutrophil infiltration and pro-inflammatory nation with molecular oxygen to give epimeric aspirin- cytokine production triggered forms, also in brain [11,12], of both resolvins Microglial cells liberate cytokines in the brain, and the D- (RvD1 through RvD6) and docosatrienes (i.e. 10,17R-DT) series resolvins block tumor necrosis factor-a-induced (see Figs 3 and 4). interleukin-1b transcripts and are potent regulators of PMN infiltration in brain, skin, and peritonitis in vivo 17S D-series resolvins [12,13]. Of the docosatriene-derived family, 10,17S- Using our new mediator–lipidomic analyses, we learned DT formed in the neuroprotectin D1 pathway (shown in that without aspirin or added DHA the endogenous DHA Fig. 4) proved to be a potent regulator of PMN influx in Novel eicosanoid and docosanoid mediators Serhan 119

Figure 4. Docosatriene Neuroprotectin D1 pathway PMN inﬁltration. The Resolvin D class 17R series, triggered by aspirin, and 17S series give essentially simi- DHA lar results (DHA-derived trihydroxy resolvins), indicating that the S to R switch does not diminish their bioactions. When injected i.v. at 100 ng/mouse, they both gave 50% inhibition, and RvE1 gave 75–80% inhibition. In comparison, indomethacin at 100 ng/mouse (or 3 mg/ HOOC kg) gave roughly 25% inhibition (see Refs [11,12]).

O(O)H 17S-H(p)DHA Neuroprotection It is well appreciated that, among the essential fatty acids, DHA is concentrated in the neurons and central nervous LO system. Given the C22 structure and six unsaturated double bonds, the physical properties of DHA have led investigators to suspect that it plays a role in protection from oxidative injury as a fatty acid that can easily COOH undergo oxygenation [31]. It has also been suspected to be involved in regulating membrane fluidity, which has been demonstrated in a number of systems: fluidity O increases with the number of double bonds present in the fatty acids. DHA is well established as playing a role 16,17-Epoxy-docosatriene in the development of neuronal systems, and it is clear from a number of studies that it is also involved in (16,17-epoxy-DT) immune response. DHA can regulate ion channels present in membranes and therefore has been proposed to be a key regulator of ion fluxes required for cardiac arrhyth- mias [36]. However, the molecular mechanisms underlying each of these events remain unclear, since many HO require very large amounts of DHA. Early studies (see COOH refs [3,4] and references cited therein) demonstrated that OH DHA is transformed by enzymes present in neuronal cells; however, the products of these reactions have not been shown to possess relevant biological actions.

Bazan and colleagues [37] were the first to coin the term Neuroprotectin D1 docosanoids, products generated from DHA, in the mid- (NPD1) 1980s. The structures of these compounds were not established, but it was clear that the transformation of DHA was responsible in part for the protection of retinal The first enzymatic product 17S-H(p)docosahexaenoic acid (DHA) is converted to a 16(17)-epoxide and enzymatically converted to the pigment cells [37]. In recent studies, we have established 10,17-dihydroxy product [12] denoted as 10,17S-docosatriene that 10,17-docosatriene carries many potent actions in (DT) [13 ] and recently coined Neuroprotectin D1 based on its potent murine models. Recently, in collaborative studies with actions in vivo [13,14]. The complete stereochemistries remain to be established and are depicted in their tentative configurations based on Bazan and colleagues, we found that DHA-derived 10,17- enzymatic biosynthesis and biogenic synthesis. docosatriene is a potent local mediator that is generated during stroke in murine tissues and can limit the entry of leukocytes and prevent leukocyte-mediated damage exudates at the site where it is formed from endogenous [13]. In additional experiments with the same group, precursors [11,12], and limits stroke brain injury [13] we found that 10,17-docosatriene has a neuroprotective and retinal pigmented cellular damage [14]. Other di- action in retinal pigmented cells and can improve the hydroxy-docosanoids and isomers were substantially less sequelae associated with Alzheimer’s disease in animal active in these bioassays [12,14]. models. Hence, we introduced the term neuroprotectin D1, which is rapidly and enzymatically generated from DHA Direct comparisons of Resolvin E class versus the D released locally in these tissues [14]. classes (17R and 17S epimer series) for their ability to regulate PMN in vivo were carried out [11,12,35]. Both It now appears, in view of ongoing studies of the innate the D and E classes of resolvin are potent regulators of immune effector system as well as T helper cells, that 120 Lipid metabolism and therapy generation of the DHA-derived Resolvin D series and for example trout, also biosynthesize both Resolvin Ds 10,17-docosatriene has a much wider scope of action: it is and docosatrienes from endogenous DHA (A.F. Rowley, protective in regulating leukocyte, particularly T cell, S. Hong, C.N. Serhan, et al., manuscript in preparation). traffic (P.-L. Li, et al., unpublished data), and can play a These, together with our findings, suggest that novel role in the protection of lung-associated tissue damage in lipid mediators (e.g. resolvins, docosatrienes, and neuro- murine models of asthma (B.D. Levy, et al., unpublished protectins) are conserved in evolution as host-protective data). Hence, it appears that the release and enzymatic mediators. These pathways and their actions are the transformation of DHA to oxygenated products with subject of our current investigations. In view of the defined stereochemistry plays a much wider biological important roles of DHA and EPA in human biology role in the generation of protective local lipid mediators and medicine uncovered to date [2–5,10], the physiologic that regulate both the innate and cellular immune relevance of the resolvins and protectins is likely to response as well as regulatory events critical in neural extend well beyond our current appreciation [10,11, function and development. Future studies will no doubt 12,13,14]. These protective and anti-inflammatory focus on whether the conversion of DHA to protectins pathways may be enhanced via dietary routes that extend and resolvins of the D series is responsible and/or under- beyond the precursors EPA or DHA, and may involve lies in part the many reported beneficial actions of DHA novel intermediates (Figs 2–4) or the new compounds in human medicine. themselves, which may enter the food chain via fish and plant routes. The formation of these compounds may involve enzymes that are currently thought to be involved in the conver- Acknowledgements sion of arachidonic acid, since few studies have used The author thanks Mary Halm Small for assistance in preparing the manuscript. This work was supported in part by National Institutes of DHA with recombinant enzymes (see Refs [11,12 ,13 ] Health grant GM38675. and cf. 15,29). It is possible that, in view of the many lipoxygenases identified to date with unknown func- References and recommended reading tion(s) and or substrates, strategically positioned enzymes Papers of particular interest, published within the annual period of review, have been highlighted as: may be specifically involved in the production of these of special interest novel compounds. It follows that specific hydrolase(s), of outstanding interest synthase(s), and related enzymes specialized to act on docosanoid intermediates are likely to be involved. 1 Burr GO, Burr MM. 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