Identification of specialized pro-resolving mediator clusters from healthy adults after intravenous low-dose endotoxin and omega-3 supplementation: a methodological validation

• Published in: Scientific reports Vol. 8; no. 1; pp. 18050 - 13
• Main Authors: Norris, Paul C., Skulas-Ray, Ann C., Riley, Ian, Richter, Chesney K., Kris-Etherton, Penny M., Jensen, Gordon L., Serhan, Charles N., Maddipati, Krishna Rao
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 21.12.2018; Nature Publishing Group
• Subjects: 692/420/256/2516; 692/420/2780/262; Administration, Intravenous; Adult; Chromatography, Liquid; Dietary Supplements; Docosahexaenoic acid; Docosahexaenoic Acids - administration & dosage; Dose-Response Relationship, Drug; Eicosapentaenoic acid; Eicosapentaenoic Acid - administration & dosage; Eicosapentaenoic Acid - analogs & derivatives; Endotoxins; Endotoxins - administration & dosage; Endotoxins - adverse effects; Esters; Fatty Acids, Omega-3 - administration & dosage; Female; Healthy Volunteers; Humanities and Social Sciences; Humans; Inflammation; Inflammation - chemically induced; Inflammation - diet therapy; Intravenous administration; Laboratories; Lipid Metabolism - drug effects; Lipopolysaccharides; Lipoxin A4; Male; Metabolome - drug effects; Metabolomics - methods; multidisciplinary; Plasma; Polyunsaturated fatty acids; Prostaglandins; Research Design - standards; Science; Science (multidisciplinary); Tandem Mass Spectrometry; Young Adult
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-018-36679-4

Specialized pro-resolving mediator(s) (SPMs) are produced from the endogenous ω-3 polyunsaturated fatty acids (PUFA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), and accelerate resolution of acute inflammation. We identified specific clusters of SPM in human plasma and serum using LC-MS/MS based lipid mediator (LM) metabololipidomics in two separate laboratories for inter-laboratory validation. The human plasma cluster consisted of resolvin (Rv)E1, RvD1, lipoxin (LX)B 4 , 18-HEPE, and 17-HDHA, and the human serum cluster consisted of RvE1, RvD1, AT-LXA 4 , 18-HEPE, and 17-HDHA. Human plasma and serum SPM clusters were increased after ω-3 supplementation (triglyceride dietary supplements or prescription ethyl esters) and low dose intravenous lipopolysaccharide (LPS) challenge. These results were corroborated by parallel determinations with the same coded samples in a second, separate laboratory using essentially identical metabololipidomic operational parameters. In these healthy subjects, two ω-3 supplementation protocols (Study A and Study B) temporally increased the SPM cluster throughout the endotoxin-challenge time course. Study A and Study B were randomized and Study B also had a crossover design with placebo and endotoxin challenge. Endotoxin challenge temporally regulated lipid mediator production in human serum, where pro-inflammatory eicosanoid (prostaglandins and thromboxane) concentrations peaked by 8 hours post-endotoxin and SPMs such as resolvins and lipoxins initially decreased by 2 h and were then elevated at 24 hours. In healthy adults given ω-3 supplementation, the plasma concentration of the SPM cluster (RvE1, RvD1, LXB 4 , 18-HEPE, and 17-HDHA) peaked at two hours post endotoxin challenge. These results from two separate laboratories with the same samples provide evidence for temporal production of specific pro-resolving mediators with ω-3 supplementation that together support the role of SPM in vivo in inflammation-resolution in humans.