Metabolic Inactivation of Resolvin E1 and Stabilization of Its Anti-inflammatory Actions
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. 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 (1Majno G. Joris I. Cells, Tissues, and Disease.Principles of General Pathology. Oxford University Press, New York2004Google Scholar), 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. 2Serhan C.N. Savill J. Nat. Immunol. 2005; 6: 1191-1197Crossref PubMed Scopus (1776) Google Scholar and 3Gilroy D.W. Lawrence T. Perretti M. Rossi A.G. Nat. Rev. Drug Discov. 2004; 3: 401-416Crossref PubMed Scopus (640) Google Scholar). 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 (2Serhan C.N. Savill J. Nat. Immunol. 2005; 6: 1191-1197Crossref PubMed Scopus (1776) Google Scholar). 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 (4Bannenberg G.L. Chiang N. Ariel A. Arita M. Tjonahen E. Gotlinger K.H. Hong S. Serhan C.N. J. Immunol. 2005; 174: 4345-4355Crossref PubMed Scopus (0) Google Scholar, 5Tai H.-H. Ensor C.M. Tong M. Zhou H. Yan F. Prostaglandins Other Lipid Mediat. 2002; 68 (483-493): 68-69Google Scholar, 6Clish C.B. Levy B.D. Chiang N. Tai H.-H. Serhan C.N. J. Biol. Chem. 2000; 275: 25372-25380Abstract Full Text Full Text PDF PubMed Scopus (160) Google Scholar). 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 (4Bannenberg G.L. Chiang N. Ariel A. Arita M. Tjonahen E. Gotlinger K.H. Hong S. Serhan C.N. J. Immunol. 2005; 174: 4345-4355Crossref PubMed Scopus (0) Google Scholar). 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) 2The abbreviations used are: PMN, polymorphonuclear leukocyte; resolvin, resolution phase interaction product; RvE1, resolvin E1; PGDH, prostaglandin dehydrogenase; MS/MS, tandem mass spectrometry; IL, interleukin; ESI, electrospray ionization; LC, liquid chromatography; GC, gas chromatography; LXA4, lipoxin A4; ATLa, 15-epi-16-(p-fluorophenoxy)-LXA4 methyl ester (LXA4 analog); LTB4, leukotriene B4; PBS, phosphate-buffered saline; HPLC, high pressure liquid chromatography; RANTES, regulated on activation normal T cell expressed and secreted.2The abbreviations used are: PMN, polymorphonuclear leukocyte; resolvin, resolution phase interaction product; RvE1, resolvin E1; PGDH, prostaglandin dehydrogenase; MS/MS, tandem mass spectrometry; IL, interleukin; ESI, electrospray ionization; LC, liquid chromatography; GC, gas chromatography; LXA4, lipoxin A4; ATLa, 15-epi-16-(p-fluorophenoxy)-LXA4 methyl ester (LXA4 analog); LTB4, leukotriene B4; PBS, phosphate-buffered saline; HPLC, high pressure liquid chromatography; RANTES, regulated on activation normal T cell expressed and secreted. infiltration and promote resolution (for recent reviews, see Refs. 2Serhan C.N. Savill J. Nat. Immunol. 2005; 6: 1191-1197Crossref PubMed Scopus (1776) Google Scholar and 3Gilroy D.W. Lawrence T. Perretti M. Rossi A.G. Nat. Rev. Drug Discov. 2004; 3: 401-416Crossref PubMed Scopus (640) Google Scholar, and references therein). They are generated during multicellular responses such as inflammation and microbial infections, a unique pathway that involve cell-cell interactions and transcellular biosynthetic routes. When aspirin is given during inflammation, resolvin E1 (RvE1) is formed from eicosapentaenoic acid via cell-cell interactions involving cells bearing cyclooxygenase-2 that has been acetylated at Ser516 by aspirin and cells that possess 5-lipoxygenase (7Serhan C.N. Clish C.B. Brannon J. Colgan S.P. Chiang N. Gronert K. J. Exp. Med. 2000; 192: 1197-1204Crossref PubMed Scopus (933) Google Scholar, 8Arita M. Bianchini F. Aliberti J. Sher A. Chiang N. Hong S. Yang R. Petasis N.A. Serhan C.N. J. Exp. Med. 2005; 201: 713-722Crossref PubMed Scopus (749) Google Scholar). These newly produced resolvins may be responsible for some of the beneficial effects of taking omega-3 eicosapentaenoic acid and aspirin (9Arita M. Yoshida M. Hong S. Tjonahen E. Glickman J.N. Petasis N.A. Blumberg R.S. Serhan C.N. Proc. Natl. Acad. Sci. U. S. A. 2005; 102: 7671-7676Crossref PubMed Scopus (507) Google Scholar, 10GISSI-Prevenzione InvestigatorsLancet. 1999; 354: 447-455Abstract Full Text Full Text PDF PubMed Scopus (3720) Google Scholar). RvE1 is also formed by microbial cytochrome P450 monooxygenase in an aspirin-independent manner (11Arita M. Clish C.B. Serhan C.N. Biochem. Biophys. Res. Commun. 2005; 338: 149-157Crossref PubMed Scopus (108) Google Scholar), which can contribute to its production in vivo that is enhanced with aspirin treatment in both human (8Arita M. Bianchini F. Aliberti J. Sher A. Chiang N. Hong S. Yang R. Petasis N.A. Serhan C.N. J. Exp. Med. 2005; 201: 713-722Crossref PubMed Scopus (749) Google Scholar) and mouse (9Arita M. Yoshida M. Hong S. Tjonahen E. Glickman J.N. Petasis N.A. Blumberg R.S. Serhan C.N. Proc. Natl. Acad. Sci. U. S. A. 2005; 102: 7671-7676Crossref PubMed Scopus (507) Google Scholar). The complete stereochemistry of bioactive RvE1 was established and demonstrated to be (5S,12R,18R)-trihydroxy-6Z,8E,10E,14Z,16E-eicosapentaenoic acid (8Arita M. Bianchini F. Aliberti J. Sher A. Chiang N. Hong S. Yang R. Petasis N.A. Serhan C.N. J. Exp. Med. 2005; 201: 713-722Crossref PubMed Scopus (749) Google Scholar). RvE1 is active in both in vitro and in vivo systems, where it displays potent counterregulatory and tissue-protective roles. RvE1, for example, reduces neutrophil transendothelial migration in vitro in the nanomolar concentration range (7Serhan C.N. Clish C.B. Brannon J. Colgan S.P. Chiang N. Gronert K. J. Exp. Med. 2000; 192: 1197-1204Crossref PubMed Scopus (933) Google Scholar). These anti-inflammatory actions are also demonstrable in vivo, where RvE1 blocks PMN infiltration both in peritonitis (8Arita M. Bianchini F. Aliberti J. Sher A. Chiang N. Hong S. Yang R. Petasis N.A. Serhan C.N. J. Exp. Med. 2005; 201: 713-722Crossref PubMed Scopus (749) Google Scholar) and in inflamed colon tissues during colitis (9Arita M. Yoshida M. Hong S. Tjonahen E. Glickman J.N. Petasis N.A. Blumberg R.S. Serhan C.N. Proc. Natl. Acad. Sci. U. S. A. 2005; 102: 7671-7676Crossref PubMed Scopus (507) Google Scholar). RvE1 also attenuates antigen-presenting cell functions such as dendritic cell migration and interleukin (IL)-12 production in vivo (8Arita M. Bianchini F. Aliberti J. Sher A. Chiang N. Hong S. Yang R. Petasis N.A. Serhan C.N. J. Exp. Med. 2005; 201: 713-722Crossref PubMed Scopus (749) Google Scholar). Here, we report that enzymatic conversion of RvE1 specifically generates 18-oxo-RvE1 resulting in its inactivation. An RvE1 stable analog was designed that resisted rapid conversion by dehydrogenation and retained biological activity that reduced both PMN infiltration and pro-inflammatory cytokines and chemokines in vivo. Materials—Synthetic RvE1 was prepared by total organic synthesis and matched with the published criteria (8Arita M. Bianchini F. Aliberti J. Sher A. Chiang N. Hong S. Yang R. Petasis N.A. Serhan C.N. J. Exp. Med. 2005; 201: 713-722Crossref PubMed Scopus (749) Google Scholar). The RvE1 analog (19-(p-fluorophenoxy)-RvE1 methyl ester) was prepared in a stereochemically pure form by total organic synthesis (structure and olefinic region NMR spectrum is shown in Fig. 6A). Female C57BL/6J mice (7-8 weeks old) were from The Jackson Laboratory (Bar Harbor, ME). Recombinant human 15-PGDH was isolated as described previously (6Clish C.B. Levy B.D. Chiang N. Tai H.-H. Serhan C.N. J. Biol. Chem. 2000; 275: 25372-25380Abstract Full Text Full Text PDF PubMed Scopus (160) Google Scholar). NAD+, diethyl ether, and methoxamine hydrochloride were from Sigma. N,O-Bis(trimethylsilyl)trifluoroacetamide was from Fisher. LC-UV-MS/MS Analysis—Liquid chromatography-ultraviolet-tandem mass spectrometry (LC-UV-MS/MS) results were acquired with the LCQ (Thermo Finnigan) quadrupole ion trap mass spectrometer system equipped with an electrospray ionization probe. RvE1 and its enzymatic products were suspended in mobile phase and injected into the HPLC component with a LUNA C18-2 (100 × 2 mm × 5 μm) column and a UV diode array detector. The column was eluted with methanol/water/acetic acid (58/42/0.01 (v/v/v)) at 0.2 ml/min. GC-MS Analysis—Carboxylic acid was methylated with excess ethereal diazomethane for 1 h at room temperature. The RvE1 metabolic product was derivatized with hydromethoxamine in pyridine to form methoxime for 2 h at room temperature, and hydroxyl groups were derivatized by N,O-bis(trimethylsilyl)trifluoroacetamide to form O-trimethylsilyl ether (12Powell W.S. Anal. Biochem. 1983; 128: 93-103Crossref PubMed Scopus (23) Google Scholar). GC-MS analysis was performed with a Hewlett-Packard 5971A mass selective detector quadropole equipped with a HPG1030A work station and GC 5890. The column was a HP-5MS (5% diphenyl-95% dimethylpolysiloxane). The temperature program was initiated at 150 °C for 2 min, reaching 230 °C at 10 min and then 280 °C at 20 min. Reference saturated fatty acid methyl esters carbons C16-C24 gave the following retention times (min): C16, 8.80; C18, 10.64; C20, 12.54; C22, 14.70; C24, 17.06; these were used to calculate C-values. Enzymatic Conversion of RvE1—RvE1 (5 μg) was incubated with recombinant human 15-PGDH (1 μg) and NAD+ (1 mm) in 100 μl of Tris-HCl buffer (50 mm, pH 9.0) at 37 °C. Increments in absorption at 340 nm were recorded, and reaction rates were calculated via first order regression curves computer-fitted to the change in absorption as a function of time. The product of this reaction was purified by solid extraction (Sep-Pak C18) and further purified by reverse-phase HPLC with a LUNA C18-2 (100 × 2 mm x 5 μm) column eluted with methanol/water/acetic acid (58/42/0.01 (v/v/v)) at 0.2 ml/min. RvE1 Metabolism in Cells and Tissues—Female C57BL/6J mice at 7-8 weeks were euthanized by isofluorane, and lungs (150-200 mg) were isolated and washed with ice-cold phosphate buffered saline (PBS). Dissected organs were freeze-thawed three times and then suspended in 200 μl of PBS (pH 7.4) and 1 mm NAD+. Incubations were initiated by adding 1 μg of RvE1 at 37 °C, and after 2 h, 2 volumes of ice-cold methanol was added to terminate the reactions. Human PMN were isolated from healthy volunteers (Brigham and Women's Hospital by as described previously (7Serhan C.N. Clish C.B. Brannon J. Colgan S.P. Chiang N. Gronert K. J. Exp. Med. 2000; 192: 1197-1204Crossref PubMed Scopus (933) Google Scholar). isolated were suspended at × cells in of PBS, incubated with 1 μg of RvE1 for 20 min at 37 °C, and the reaction was with 2 volumes of ice-cold peritonitis was as described previously M. in Press, Scholar), and 100 of RvE1 18-oxo-RvE1 was injected into the by 1 of (1 injected into the with the RvE1 analog, RvE1 methyl ester methyl ester was given at were at 2 h, and cells were leukocyte 100 μl of the cells were added to 100 μl of and at for min a The were to and cells were and were determined from a mouse array Enzymatic Conversion of were to whether 15-PGDH could catalyze the conversion of RvE1 to oxo RvE1 eluted from the system at min and gave a of mass which was rapidly and to a product of recombinant human 15-PGDH and NAD+. The main product derived from RvE1 gave a retention of min and a of mass The in mass of 2 mass to the of that could with the of of the groups within RvE1 to to an oxo The UV absorption spectrum of RvE1 a at and nm with the (8Arita M. Bianchini F. Aliberti J. Sher A. Chiang N. Hong S. Yang R. Petasis N.A. Serhan C.N. J. Exp. Med. 2005; 201: 713-722Crossref PubMed Scopus (749) Google Scholar), of the of both and Conversion of an of RvE1 to an oxo group also the from to a in with the of the in and and the absorption was from to nm for the structure and the carbon the product ion mass spectrum was of and to the product and and of the to to and to The product ion derived from of the that the oxo group was at the carbon 18 position the carbon position the 5 further the oxo group at the carbon 18 the isolated was with diazomethane by to form the methoxime and ion at of 18-oxo-RvE1 methyl ester in the of 2 ether and 1 identified a at min of The spectrum of the methoxime product gave as and in Fig. 2 the structure of RvE1 conversion product was as RvE1. the of RvE1 conversion to 18-oxo-RvE1 by the dehydrogenase was by the formation of from NAD+ as in at 340 nm The initial conversion for RvE1 was of of reaction prostaglandin was at a of of of In conversion was the of RvE1 these results the for the dehydrogenase RvE1 Metabolism in Cells and whether of the group at carbon 18 position represents a major pathway of RvE1 metabolism in cells we performed RvE1 with isolated mouse and human PMN shown in Fig. gave a component a of at min on a unique UV with a at nm and with the prepared 18-oxo-RvE1 by the recombinant 15-PGDH as described spectrum at further the of the product as 18-oxo-RvE1 with the at and at and of the added RvE1 was to and other were at that to These results that 18-oxo-RvE1 is the major initial product of RvE1 in the the other RvE1 with isolated human PMN gave a major component a of at min with UV at and an product and in the and The tandem mass spectrum of the this at an product structure with at and as as at and RvE1 metabolism was and in that at the carbon 18 position was the major initial metabolism in the lung, and to form was the major pathway in human of whether 18-oxo-RvE1 retained the bioactivities of RvE1 (8Arita M. Bianchini F. Aliberti J. Sher A. Chiang N. Hong S. Yang R. Petasis N.A. Serhan C.N. J. Exp. Med. 2005; 201: 713-722Crossref PubMed Scopus (749) Google Scholar), the isolated was assessed for its to leukocyte infiltration in vivo the zymosan-induced of RvE1 at 100 reduced total leukocyte by in the inflamed PMN infiltration by 18-oxo-RvE1 at the was devoid of anti-inflammatory activity These results that the conversion of RvE1 to its represents a mode of RvE1 inactivation. Conversion of RvE1 RvE1 conversion to 18-oxo-RvE1 by dehydrogenation at carbon 18 represents biological inactivation an analog was designed with to the 18 position on the of the to both and carbon 18 position namely methyl ester 6A). RvE1 analog was designed an and to that used for ATLa, a stable analog structure of lipoxin T. Clish C.B. Gronert K. Petasis N.A. Serhan C.N. J. PubMed Scopus Google Scholar, K. Colgan S.P. J. J. Immunol. 2002; PubMed Scopus Google Scholar). Here, a group at carbon was used in of the carbons at the 6A). novel RvE1 analog was to rapid by the recombinant human dehydrogenase and whether the designed RvE1 retained the anti-inflammatory activity of RvE1, we this analog with the actions of RvE1 in vivo. RvE1 analog, methyl proved to be as potent as RvE1 in total leukocyte infiltration and specifically PMN infiltration into murine the cytokines and chemokines with and inflammation were At 2 h, both RvE1 and its analog pro-inflammatory RANTES, and these results that the RvE1 analog in Fig. retained the of and RvE1 stable analog stop PMN infiltration in vivo RvE1 methyl ester and methyl ester were injected at 1 by 1 of (1 into the 2 h, total and PMN were from of in in in in in in a new and RvE1 stable analog cytokine/chemokine in vivo from murine were as in 1 and of chemokines and cytokines were by inflammatory from RvE1 from in a new The results are the first to that RvE1 is further via dehydrogenation that is at carbon 18 to 18-oxo-RvE1. In the lung, dehydrogenation of the hydroxyl group at carbon 18 to form 18-oxo-RvE1 represented the major initial metabolic route for RvE1. The 18-oxo-RvE1 was devoid of the potent anti-inflammatory actions of its RvE1 in vivo. RvE1 analog, namely methyl was prepared that proved to retain the anti-inflammatory actions of RvE1 to PMN infiltration and pro-inflammatory cytokine/chemokine in vivo. RvE1 has potent actions both in vitro and in vivo within the nanomolar range to stop leukocyte migration and tissues from (8Arita M. Bianchini F. Aliberti J. Sher A. Chiang N. Hong S. Yang R. Petasis N.A. Serhan C.N. J. Exp. Med. 2005; 201: 713-722Crossref PubMed Scopus (749) Google Scholar, M. Yoshida M. Hong S. Tjonahen E. Glickman J.N. Petasis N.A. Blumberg R.S. Serhan C.N. Proc. Natl. Acad. Sci. U. S. A. 2005; 102: 7671-7676Crossref PubMed Scopus (507) Google Scholar). In such as and are generated from their at J. D.W. S. Serhan C.N. T. T. Rev. PubMed Scopus Google Scholar), and are rapidly inactivated via local enzymatic in pathways are described that are in metabolism via of the main and/or H.-H. Ensor C.M. Tong M. Zhou H. Yan F. Prostaglandins Other Lipid Mediat. 2002; 68 (483-493): 68-69Google Scholar). for example, is by in human PMN by a cytochrome P450 S. J. Biol. Chem. Full Text PDF PubMed Google Scholar) by dehydrogenation at the group to form in T. T. T. T. F. F. T. J. Biol. Chem. Full Text PDF PubMed Google Scholar). is by dehydrogenation and in by 15-PGDH and (6Clish C.B. Levy B.D. Chiang N. Tai H.-H. Serhan C.N. J. Biol. Chem. 2000; 275: 25372-25380Abstract Full Text Full Text PDF PubMed Scopus (160) Google Scholar). 15-PGDH activity is in high in lung, and cells and is in the metabolic inactivation of and and H.-H. Ensor C.M. Tong M. Zhou H. Yan F. Prostaglandins Other Lipid Mediat. 2002; 68 (483-493): 68-69Google Scholar, A. H. Tai Med. Chem. 2005; PubMed Scopus Google Scholar). Here, we that RvE1 initial metabolic pathways that are and/or in that of group at the carbon 18 position was the major route in the lung, and to form was a major route in human Moreover, in to the i.e. hydroxyl dehydrogenase we report that 15-PGDH also as hydroxyl dehydrogenase for RvE1 to form which results in inactivation of RvE1. The inflammatory response of the a of and and/or by recruitment of inflammatory cells the and resolution of inflammation, which to return to homeostasis (1Majno G. Joris I. Cells, Tissues, and Disease.Principles of General Pathology. Oxford University Press, New York2004Google Scholar). inflammatory processes are self-limiting and systems, the existence of endogenous anti-inflammatory and/or pro-resolution mediators that are operative during the of inflammation (7Serhan C.N. Clish C.B. Brannon J. Colgan S.P. Chiang N. Gronert K. J. Exp. Med. 2000; 192: 1197-1204Crossref PubMed Scopus (933) Google Scholar). RvE1 is a potent anti-inflammatory lipid derived from eicosapentaenoic acid, which is generated during the spontaneous resolution phase of inflammation where cell-cell interactions (7Serhan C.N. Clish C.B. Brannon J. Colgan S.P. Chiang N. Gronert K. J. Exp. Med. 2000; 192: 1197-1204Crossref PubMed Scopus (933) Google Scholar, 8Arita M. Bianchini F. Aliberti J. Sher A. Chiang N. Hong S. Yang R. Petasis N.A. Serhan C.N. J. Exp. Med. 2005; 201: 713-722Crossref PubMed Scopus (749) Google Scholar). we described that the counterregulatory activity of RvE1 on leukocyte migration is to enzymatic inactivation. system may contribute in to the return of inflamed to homeostasis with a temporal of the families of lipid mediators generated during the of inflammation and resolution (2Serhan C.N. Savill J. Nat. Immunol. 2005; 6: 1191-1197Crossref PubMed Scopus (1776) Google Scholar, G.L. Chiang N. Ariel A. Arita M. Tjonahen E. Gotlinger K.H. Hong S. Serhan C.N. J. 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PubMed Scopus Google Scholar, J. PubMed Google Scholar, N. J. Med. PubMed Scopus Google Scholar). In the a RvE1 analog, namely methyl ester was designed to from both and/or rapid dehydrogenation at carbon 18 and was to be to RvE1 in vivo in leukocyte infiltration and reducing pro-inflammatory cytokine/chemokine production in RvE1 at the carbon 5 hydroxyl group is also and been shown to in some cells T. T. T. T. F. F. T. J. Biol. Chem. Full Text PDF PubMed Google Scholar, W.S. J. Lipid Res. 2005; PubMed Scopus Google Scholar), were in the resolvin that further can be useful in vivo to evaluate the and actions of resolvins and their for new treatment of human with We M. H. for Gotlinger for with and Yang for the structure of the RvE1 analog in Fig.