title: Protectin D1n-3 DPAand resolvin D5n-3 DPAare effectors of intestinal protection.
abstract: The resolution of inflammation is an active process orchestrated by specialized proresolving lipid mediators (SPM) that limit the host response within the affected tissue; failure of effective resolution may lead to tissue injury. Because persistence of inflammatory signals is a main feature of chronic inflammatory conditions, including inflammatory bowel diseases (IBDs), herein we investigate expression and functions of SPM in intestinal inflammation. Targeted liquid chromatography-tandem mass spectrometry-based metabololipidomics was used to identify SPMs from n-3 polyunsaturated fatty acids in human IBD colon biopsies, quantifying a significant up-regulation of the resolvin and protectin pathway compared with normal gut tissue. Systemic treatment with protectin (PD)1n-3 DPAor resolvin (Rv)D5n-3 DPAprotected against colitis and intestinal ischemia/reperfusion-induced inflammation in mice. Inhibition of 15-lipoxygenase activity reduced PD1n-3 DPAand augmented intestinal inflammation in experimental colitis. Intravital microscopy of mouse mesenteric venules demonstrated that PD1n-3 DPAand RvD5n-3 DPAdecreased the extent of leukocyte adhesion and emigration following ischemia-reperfusion. These data were translated by assessing human neutrophil-endothelial interactions under flow: PD1n-3 DPAand RvD5n-3 DPAreduced cell adhesion onto TNF-α-activated human endothelial monolayers. In conclusion, we propose that innovative therapies based on n-3 DPA-derived mediators could be developed to enable antiinflammatory and tissue protective effects in inflammatory pathologies of the gut.
authors.affiliation: The William Harvey Research Institute, Barts and The London School of Medicine, Queen Mary University of London, London EC1M 6BQ, United Kingdom.
authors.forename: Thomas
authors.initials: T
authors.lastname: Gobbetti
authors.affiliation: The William Harvey Research Institute, Barts and The London School of Medicine, Queen Mary University of London, London EC1M 6BQ, United Kingdom.|Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative, and Pain Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston MA 02115.
authors.forename: Jesmond
authors.initials: J
authors.lastname: Dalli
authors.affiliation: The William Harvey Research Institute, Barts and The London School of Medicine, Queen Mary University of London, London EC1M 6BQ, United Kingdom.|Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative, and Pain Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston MA 02115.
authors.forename: Romain A
authors.initials: RA
authors.lastname: Colas
authors.affiliation: The William Harvey Research Institute, Barts and The London School of Medicine, Queen Mary University of London, London EC1M 6BQ, United Kingdom.
authors.forename: Donata
authors.initials: D
authors.lastname: Federici Canova
authors.affiliation: Department of Pharmaceutical Chemistry, School of Pharmacy, University of Oslo, N-0316 Oslo, Norway.
authors.forename: Marius
authors.initials: M
authors.lastname: Aursnes
authors.affiliation: Department of Internal Medicine and Digestive Diseases, Pole Digestif, Centre Hospitalier Universitaire (CHU), 31059 Toulouse, France.
authors.forename: Delphine
authors.initials: D
authors.lastname: Bonnet
authors.affiliation: Department of Internal Medicine and Digestive Diseases, Pole Digestif, Centre Hospitalier Universitaire (CHU), 31059 Toulouse, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Alric
authors.affiliation: Institut de Recherche en Santé Digestive (IRSD), Université de Toulouse, 31300 Toulouse, France.|Unit 1220, INSERM, 31300 Toulouse, France.|Unit 1416, Institut National de la Recherche Agronomique (INRA), 31300 Toulouse, France.|École Nationale Vétérinaire de Toulouse (ENVT), 31300 Toulouse, France.|Université Paul Sabatier (UPS), 31300 Toulouse, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Vergnolle
authors.affiliation: Institut de Recherche en Santé Digestive (IRSD), Université de Toulouse, 31300 Toulouse, France.|Unit 1220, INSERM, 31300 Toulouse, France.|Unit 1416, Institut National de la Recherche Agronomique (INRA), 31300 Toulouse, France.|École Nationale Vétérinaire de Toulouse (ENVT), 31300 Toulouse, France.|Université Paul Sabatier (UPS), 31300 Toulouse, France.
authors.forename: Celine
authors.initials: C
authors.lastname: Deraison
authors.affiliation: Department of Pharmaceutical Chemistry, School of Pharmacy, University of Oslo, N-0316 Oslo, Norway.
authors.forename: Trond V
authors.initials: TV
authors.lastname: Hansen
authors.affiliation: Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative, and Pain Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston MA 02115.
authors.forename: Charles N
authors.initials: CN
authors.lastname: Serhan
authors.affiliation: The William Harvey Research Institute, Barts and The London School of Medicine, Queen Mary University of London, London EC1M 6BQ, United Kingdom; m.perretti@qmul.ac.uk.
authors.forename: Mauro
authors.identifier: 0000-0003-2068-3331
authors.initials: M
authors.lastname: Perretti
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D016022:Case-Control Studies; D003092:Colitis / Q000139:chemically induced / Q000517:prevention & control*; D004281:Docosahexaenoic Acids / Q000378:metabolism / Q000494:pharmacology*; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000187:drug effects*; D050356:Lipid Metabolism / Q000187:drug effects; D008297:Male; D008643:Mesentery / Q000098:blood supply / Q000187:drug effects; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D010538:Peritonitis / Q000139:chemically induced / Q000517:prevention & control; D015427:Reperfusion Injury / Q000517:prevention & control
chemical_list: C487679:protectin D1; C572765:resolvin D5; D004281:Docosahexaenoic Acids
keywords: inflammation resolution; intravital microscopy; neutrophils; omega-3 fatty acids; specialized proresolving mediators