title: Elucidation of novel 13-series resolvins that increase with atorvastatin and clear infections.
abstract: Endogenous mechanisms leading to host protection and resolution of infections without immunosuppression are of wide interest. Here we elucidate the structures of four new host-protective molecules produced in neutrophil-endothelial cocultures and present in human and mouse tissues after sterile inflammation or infection. The bioactive molecules contain conjugated triene and diene double bonds, carry an alcohol at C13 and are derived from n-3 docosapentaenoic acid (DPA, C22:5). These compounds, termed 13-series resolvins (RvTs), demonstrated potent protective actions increasing mice survival during Escherichia coli infections. RvTs also regulated human and mouse phagocyte responses stimulating bacterial phagocytosis and regulating inflammasome components. Their biosynthesis during neutrophil-endothelial cell interactions was initiated by endothelial cyclooxygenase-2 (COX-2), increased by atorvastatin via S-nitrosylation of COX-2 and reduced by COX-2 inhibitors. The actions of atorvastatin and RvTs were additive in E. coli infections in mice, where they accelerated resolution of inflammation and increased survival >60%. Taken together, these results document host-protective molecules in bacterial infections, namely RvTs, derived from n-3 DPA via transcellular biosynthesis and increased by atorvastatin. These molecules regulate key innate protective responses in the resolution of infectious inflammation.
authors.affiliation: Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Harvard Institutes of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Jesmond
authors.identifier: http://orcid.org/0000-0001-6328-3640
authors.initials: J
authors.lastname: Dalli
authors.affiliation: Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Harvard Institutes of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Nan
authors.initials: N
authors.lastname: Chiang
authors.affiliation: Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Harvard Institutes of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Charles N
authors.initials: CN
authors.lastname: Serhan
mesh_terms: D000818:Animals; D000069059:Atorvastatin / Q000494:pharmacology*; D004281:Docosahexaenoic Acids / Q000737:chemistry / Q000494:pharmacology*; D042783:Endothelial Cells / Q000502:physiology; D004927:Escherichia coli Infections / Q000276:immunology* / Q000401:mortality; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D007113:Immunity, Innate; D008297:Male; D051379:Mice; D009504:Neutrophils / Q000502:physiology
chemical_list: D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D004281:Docosahexaenoic Acids; D000069059:Atorvastatin