title: Novel proresolving aspirin-triggered DHA pathway.
abstract: Endogenous mechanisms in the resolution of acute inflammation are of interest because excessive inflammation underlies many pathologic abnormalities. We report an aspirin-triggered DHA metabolome that biosynthesizes a potent product in inflammatory exudates and human leukocytes, namely aspirin-triggered Neuroprotectin D1/Protectin D1 [AT-(NPD1/PD1)]. The complete stereochemistry of AT-(NPD1/PD1) proved to be 10R,17R-dihydroxydocosa-4Z,7Z,11E,13E,15Z,19Z-hexaenoic acid. The chirality of hydroxyl groups and geometry of the conjugated triene system essential for bioactivity were established by matching biological materials with stereochemically pure isomers prepared by organic synthesis. AT-(NPD1/PD1) reduced neutrophil (PMN) recruitment in murine peritonitis in a dose-dependent fashion whereby neither a Δ(15)-trans-isomer nor DHA was effective. With human cells, AT-(NPD1/PD1) decreased transendothelial PMN migration as well as enhanced efferocytosis of apoptotic human PMN by macrophages. These results indicate that AT-(NPD1/PD1) is a potent anti-inflammatory proresolving molecule.
authors.affiliation: Center for Experimental Therapeutics and Reperfusion Injury, Harvard Institutes of Medicine, Department of Anesthesiology, Perioperative, and Pain Medicine, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA 02115, USA. cnserhan@zeus.bwh.harvard.edu
authors.forename: Charles N
authors.initials: CN
authors.lastname: Serhan
authors.forename: Gabrielle
authors.initials: G
authors.lastname: Fredman
authors.forename: Rong
authors.initials: R
authors.lastname: Yang
authors.forename: Sergey
authors.initials: S
authors.lastname: Karamnov
authors.forename: Ludmila S
authors.initials: LS
authors.lastname: Belayev
authors.forename: Nicolas G
authors.initials: NG
authors.lastname: Bazan
authors.forename: Min
authors.initials: M
authors.lastname: Zhu
authors.forename: Jeremy W
authors.initials: JW
authors.lastname: Winkler
authors.forename: Nicos A
authors.initials: NA
authors.lastname: Petasis
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000276:immunology / Q000494:pharmacology*; D001241:Aspirin / Q000276:immunology / Q000494:pharmacology*; D053898:Biosynthetic Pathways / Q000187:drug effects*; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects; D004281:Docosahexaenoic Acids / Q000737:chemistry / Q000276:immunology*; D006801:Humans; D007536:Isomerism; D008264:Macrophages / Q000166:cytology / Q000187:drug effects; D051379:Mice; D009504:Neutrophils / Q000166:cytology / Q000187:drug effects; D010538:Peritonitis / Q000188:drug therapy / Q000276:immunology
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; C487679:protectin D1; D004281:Docosahexaenoic Acids; D001241:Aspirin