Bioactive products formed in humans from fish oils
Resolvins, maresins, and protectins can be formed from fish oils. These specialized pro-resolving mediators (SPMs) have been implicated in the resolution of inflammation. Synthetic versions of such SPMs exert anti-inflammatory effects in vitro and when administered to animal models. However, their importance as endogenous products formed in sufficient amounts to exert anti-inflammatory actions in vivo remains speculative. We biased our ability to detect SPMs formed in healthy volunteers by supplementing fish oil in doses shown previously to influence blood pressure and platelet aggregation under placebo-controlled conditions. Additionally, we sought to determine the relative formation of SPMs during an acute inflammatory response and its resolution, evoked in healthy volunteers by bacterial lipopolysaccharide (LPS). Bioactive lipids, enzymatic epoxyeicosatrienoic acids (EETs), and free radical-catalyzed prostanoids [isoprostanes (iPs)] formed from arachidonic acid and the fish oils, served as comparators. Despite the clear shift from ω-6 to ω-3 EETs and iPs, we failed to detect a consistent signal, in most cases, of SPM formation in urine or plasma in response to fish oil, and in all cases in response to LPS on a background of fish oil. Our results question the relevance of these SPMs to the putative anti-inflammatory effects of fish oils in humans. Resolvins, maresins, and protectins can be formed from fish oils. These specialized pro-resolving mediators (SPMs) have been implicated in the resolution of inflammation. Synthetic versions of such SPMs exert anti-inflammatory effects in vitro and when administered to animal models. However, their importance as endogenous products formed in sufficient amounts to exert anti-inflammatory actions in vivo remains speculative. We biased our ability to detect SPMs formed in healthy volunteers by supplementing fish oil in doses shown previously to influence blood pressure and platelet aggregation under placebo-controlled conditions. Additionally, we sought to determine the relative formation of SPMs during an acute inflammatory response and its resolution, evoked in healthy volunteers by bacterial lipopolysaccharide (LPS). Bioactive lipids, enzymatic epoxyeicosatrienoic acids (EETs), and free radical-catalyzed prostanoids [isoprostanes (iPs)] formed from arachidonic acid and the fish oils, served as comparators. Despite the clear shift from ω-6 to ω-3 EETs and iPs, we failed to detect a consistent signal, in most cases, of SPM formation in urine or plasma in response to fish oil, and in all cases in response to LPS on a background of fish oil. Our results question the relevance of these SPMs to the putative anti-inflammatory effects of fish oils in humans. The clinical cardiovascular utility of a diet rich in fish oils, particularly EPA and DHA, has been debated over the past 50 years (1Hu F.B. Bronner L. Willett W.C. Stampfer M.J. Rexrode K.M. Albert C.M. Hunter D. Manson J.E. Fish and omega-3 fatty acid intake and risk of coronary heart disease in women.JAMA. 2002; 287: 1815-1821Crossref PubMed Scopus (873) Google Scholar, 2Amano T. Matsubara T. Uetani T. Kato M. Kato B. Yoshida T. Harada K. Kumagai S. Kunimura A. Shinbo Y. et al.Impact of omega-3 polyunsaturated fatty acids on coronary plaque instability: an integrated backscatter intravascular ultrasound study.Atherosclerosis. 2011; 218: 110-116Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar, 3de Oliveira Otto M.C. Wu J.H. Baylin A. Vaidya D. Rich S.S. Tsai M.Y. Jacobs Jr, D.R. Mozaffarian D. Circulating and dietary omega-3 and omega-6 polyunsaturated fatty acids and incidence of CVD in the Multi-Ethnic Study of Atherosclerosis.J. Am. Heart Assoc. 2013; 2: e000506Crossref PubMed Scopus (133) Google Scholar). Large clinical outcome trials, such as the open-labeled GISSI-Prevenzione (4.GISSI-Prevenzione Investigators. 1999. Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-Prevenzione trial. Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto miocardico. Lancet., 354: 447–455.Google Scholar) or JELIS (5Yokoyama M. Origasa H. Matsuzaki M. Matsuzawa Y. Saito Y. Ishikawa Y. Oikawa S. Sasaki J. Hishida H. Itakura H. et al.Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomised open-label, blinded endpoint analysis.Lancet. 2007; 369: 1090-1098Abstract Full Text Full Text PDF PubMed Scopus (1950) Google Scholar) studies, supported the notion that fish oil supplements confer therapeutic benefit on patients with cardiovascular disease. However, an overview analysis of results of more than 50 randomized controlled trials and cohort studies addressing this question yielded equivocal results (6Hooper L. Thompson R.L. Harrison R.A. Summerbell C.D. Ness A.R. Moore H.J. Worthington H.V. Durrington P.N. Higgins J.P. Capps N.E. et al.Risks and benefits of omega 3 fats for mortality, cardiovascular disease, and cancer: systematic review.BMJ. 2006; 332: 752-760Crossref PubMed Scopus (568) Google Scholar, 7Wang C. Harris W.S. Chung M. Lichtenstein A.H. Balk E.M. Kupelnick B. Jordan H.S. Lau J. n-3 Fatty acids from fish or fish-oil supplements, but not alpha-linolenic acid, benefit cardiovascular disease outcomes in primary- and secondary-prevention studies: a systematic review.Am. J. Clin. Nutr. 2006; 84: 5-17Crossref PubMed Scopus (852) Google Scholar). Consequently, the adoption of the dietary interventions with fish oil into clinical guidelines has been limited (8Hu F.B. Manson J.E. Omega-3 fatty acids and secondary prevention of cardiovascular disease-is it just a fish tale?: comment on “Efficacy of omega-3 fatty acid supplements (eicosapentaenoic acid and docosahexaenoic acid) in the secondary prevention of cardiovascular disease”.Arch. Intern. Med. 2012; 172: 694-696Crossref PubMed Scopus (23) Google Scholar). Fish oil supplementation does influence a series of cardiovascular biomarkers: it decreases blood levels of triglycerides in patients with hypertriglyceridemia, an effect primarily driven by lowering the production of triglycerides from nonesterified fatty acids (9Shearer G.C. Savinova O.V. Harris W.S. Fish oil–how does it reduce plasma triglycerides?.Biochim. Biophys. Acta. 2012; 1821: 843-851Crossref PubMed Scopus (210) Google Scholar); high doses reduce blood pressure in patients with essential hypertension (10Morris M.C. Sacks F. Rosner B. Does fish oil lower blood pressure? 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A controlled study of polyunsaturated fatty acid supplements in essential hypertension.N. Engl. J. Med. 1989; 320: 1037-1043Crossref PubMed Scopus (387) Google Scholar, H.R. Reilly I.A. Alessandrini P. FitzGerald G.A. In vivo indexes of platelet and vascular function during fish-oil administration in patients with atherosclerosis.N. Engl. J. Med. 1986; 314: PubMed Scopus Google Scholar). a we enzymatic acids and free [isoprostanes (iPs)] prostanoids formed from and the fish oils. Additionally, we sought to determine the relative formation of SPMs and these during an acute inflammatory response and its resolution, evoked in healthy volunteers by administration of Despite a clear shift from ω-6 to ω-3 EETs and iPs, we failed to detect a consistent in most cases of SPM formation in urine or plasma in response to fish oil supplementation and in all cases in response to LPS on a background of fish oil from a study the of high doses of as fish oil with on volunteers in an a for a of ω-3 of EPA and to study by the and by the and been not and from the of and as by and platelet FitzGerald G.A. platelet and formation during PubMed Scopus Google and a urine for and the and by and and the of and on of the not to major in their and to from fish to to in fish with this by or the intake of by in the and by the of in blood and by from and from a of healthy volunteers to the inflammatory response to in with lower doses of as fish to P.N. J. J. K. M. 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A for the in and as as for the The ω-6 in not by fish oil administration with doses of fish oils the formation of by with oil by by and by in by and by to LPS not in these fish oil LPS the plasma of EETs The ω-3 in urine from of and to and on and of high to and and after fish oil a ω-6 by the to The of ω-3 in healthy on an diet in a study to the ω-6 iPs, and the and in a cohort of healthy years of and of supplementation with from to to by and and of the ω-6 in urine and after supplementation with fish oil, by and and The of ω-3 to ω-6 in to the with the high supplementation The of by of from and to and by and of to and and The of in from and to and on and on fish oil to for and oil In the ω-3 to ω-6 as of the fatty acid in EPA from to after of to from to after fish oil of LPS a of and acute The in plasma of of from to LPS to from to after from to after from to after from to after from to after and from to administration of in the study of Fish in a of fish oils have been implicated in a of M. J. Resolvins, specialized and their in Full Text Full Text PDF PubMed Scopus Google the resolution of mediators for resolution PubMed Scopus Google Scholar). the therapeutic of dietary supplementation with fish oils remains (6Hooper L. Thompson R.L. Harrison R.A. Summerbell C.D. Ness A.R. Moore H.J. Worthington H.V. Durrington P.N. Higgins J.P. Capps N.E. et al.Risks and benefits of omega 3 fats for mortality, cardiovascular disease, and cancer: systematic review.BMJ. 2006; 332: 752-760Crossref PubMed Scopus (568) Google Scholar, 7Wang C. Harris W.S. Chung M. Lichtenstein A.H. Balk E.M. Kupelnick B. Jordan H.S. Lau J. n-3 Fatty acids from fish or fish-oil supplements, but not alpha-linolenic acid, benefit cardiovascular disease outcomes in primary- and secondary-prevention studies: a systematic review.Am. J. Clin. Nutr. 2006; 84: 5-17Crossref PubMed Scopus (852) Google studies have rich in fish with clinical outcomes (1Hu F.B. Bronner L. Willett W.C. Stampfer M.J. Rexrode K.M. Albert C.M. Hunter D. Manson J.E. Fish and omega-3 fatty acid intake and risk of coronary heart disease in women.JAMA. 2002; 287: 1815-1821Crossref PubMed Scopus (873) Google Scholar, J. A.R. K. P. D. Fish and the risk of myocardial Engl. J. Med. PubMed Scopus Google Scholar). this to a of dietary fatty a effect of fish oils, or with a diet rich in fish fish oils, such as EPA and DHA, for dietary a shift in formation from prostanoids to in when in vitro M. C. M. A.H. C. et and of with arachidonic eicosapentaenoic and 2007; Full Text Full Text PDF PubMed Scopus Google Scholar). In has been in the formation of lipids, such as from and mediators for resolution PubMed Scopus Google Scholar). In products formed from fish oils maresins, and have anti-inflammatory when administered in vitro or to animal T. S. A. M. vascular activation and vascular J. 2013; PubMed Scopus Google Scholar, M. and 2007; PubMed Scopus Google Scholar). such the therapeutic of their relevance as endogenous mediators of more of the by the of and the of of to with to of of formation in the the to D. A the of in plasma and PubMed Scopus Google and amounts of these in by more FitzGerald G.A. and 2011; PubMed Scopus Google Scholar). we sought for formation of in healthy volunteers a high of as fish oil to blood pressure and platelet function H.R. FitzGerald G.A. The antihypertensive effects of fish oil. A controlled study of polyunsaturated fatty acid supplements in essential hypertension.N. Engl. J. Med. 1989; 320: 1037-1043Crossref PubMed Scopus (387) Google Scholar, H.R. Reilly I.A. Alessandrini P. FitzGerald G.A. In vivo indexes of platelet and vascular function during fish-oil administration in patients with atherosclerosis.N. Engl. J. Med. 1986; 314: PubMed Scopus Google or a more in clinical trials to therapeutic D. A. S. K. effects of fatty acids on and of in heart of a Heart J. 2011; Scopus Google Scholar). In the we the response to during the evoked and during the of its In studies, supplementation with fish oils the in in a in the of EPA and to in and in the endogenous of products of the and free radical-catalyzed formation of in these by the and from for the the doses of fish oils. SPMs when in to the or doses of fish oil The inflammatory response to LPS administration by evoked SPMs not in response to LPS during the inflammatory or resolution to in these healthy In the of and in we as for their by and lower of in plasma from to for and from to for levels and from to in plasma during supplementation with and after the of supplementation on the lower of fish oils, but not during the inflammatory or resolution that formation of has to be of but by dietary supplementation or administration of our we have that of the endogenous SPMs be by the SPMs not in urine from with high supplementation of fish oils, and be in its studies have to SPM formation in response to fish oil supplementation in P. A. and mediators of resolution of in blood n-3 fatty acid 2012; PubMed Scopus Google Scholar) and have their formation during resolution of evoked in plasma levels of of and of of in a study of healthy volunteers on an diet J. S. B. et 2011; PubMed Scopus Google Scholar). a randomized and placebo-controlled supplementation of volunteers with 3 fish oil over failed to detect and in plasma C. Ness C. M. S. M. M. A. placebo-controlled with n-3 effects on and cardiovascular risk Nutr. 2013; Full Text Full Text PDF PubMed Scopus Google Scholar). However, not in a of SPM administration with Y. Y. C. P. Y. the heart J. Heart PubMed Scopus Google Scholar, H. K. M. H. H. T. K. A. et anti-inflammatory and from bacterial and acute PubMed Scopus Google Scholar, F. S. D. the response of the 2012; PubMed Scopus Google Scholar, J. S. S. M. and anti-inflammatory of in E series 2006; Full Text Full Text PDF PubMed Scopus Google Scholar, Y. H. Y. Y. et in acute PubMed Scopus Google Scholar) and effects in A. M. C. F. M. actions of of the in J. PubMed Scopus Google administration of per in plasma levels of 3 and to over the during in acute such of of the of the in this study an anti-inflammatory effect in of the of of our In we have failed to detect or in the plasma of volunteers administered fish oils or in response to an acute inflammatory after administration of and during evoked or its in to the formation of and free radical-catalyzed products of fish oils. the results of these studies question the relevance of endogenous SPMs to the putative anti-inflammatory effects of fish oils in humans. The of the of the of this and the the after the in as an in all of the in the in The to the for these clinical studies, the and the of the of as as the of the for analysis of and by and T. of clinical study by and by and the to by with arachidonic acid a epoxyeicosatrienoic acid lipopolysaccharide blood A specialized pro-resolving a