title: Resolvin D3 and Aspirin-Triggered Resolvin D3 Are Protective for Injured Epithelia.
abstract: Acute lung injury is a life-threatening condition caused by disruption of the alveolar-capillary barrier leading to edema, influx of inflammatory leukocytes, and impaired gas exchange. Specialized proresolving mediators biosynthesized from essential fatty acids, such as docosahexaenoic acid, have tissue protective effects in acute inflammation. Herein, we found that the docosahexaenoic acid-derived mediator resolvin D3 (RvD3): 4S,11R,17S-trihydroxydocosa-5Z,7E,9E,13Z,15E,19Z-hexaenoic acid was present in uninjured lungs, and increased significantly 24 to 72 hours after hydrochloric acid-initiated injury. Because of its delayed enzymatic degradation, we used aspirin-triggered (AT)-RvD3: 4S,11R,17R-trihydroxydocosa-5Z,7E,9E,13Z,15E,19Z-hexaenoic acid, a 17R-epimer of RvD3, for in vivo experiments. Histopathological correlates of acid injury (alveolar wall thickening, edema, and leukocyte infiltration) were reduced in mice receiving AT-RvD3 1 hour after injury. AT-RvD3-treated mice had significantly reduced edema, as demonstrated by lower wet/dry weight ratios, increased epithelial sodium channel γ expression, and more lymphatic vessel endothelial hyaluronan receptor 1-positive vascular endothelial growth factor receptor 3-positive lymphatic vessels. Evidence for counterregulation of NF-κB by RvD3 and AT-RvD3 was seen in vitro and by AT-RvD3 in vivo. Increases in lung epithelial cell proliferation and bronchoalveolar lavage fluid levels of keratinocyte growth factor were observed with AT-RvD3, which also promoted cutaneous re-epithelialization. Together, these data demonstrate protective actions of RvD3 and AT-RvD3 for injured mucosa that accelerated restoration of epithelial barrier and function.
authors.affiliation: Pulmonary and Critical Care Medicine Division, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Jennifer K
authors.initials: JK
authors.lastname: Colby
authors.affiliation: Pulmonary and Critical Care Medicine Division, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Raja-Elie E
authors.initials: RE
authors.lastname: Abdulnour
authors.affiliation: Pulmonary and Critical Care Medicine Division, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Ho Pan
authors.initials: HP
authors.lastname: Sham
authors.affiliation: Department of Anesthesiology, Perioperative and Pain Medicine, Center for Experimental Therapeutics and Reperfusion Injury, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Jesmond
authors.initials: J
authors.lastname: Dalli
authors.affiliation: Department of Anesthesiology, Perioperative and Pain Medicine, Center for Experimental Therapeutics and Reperfusion Injury, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Romain A
authors.initials: RA
authors.lastname: Colas
authors.affiliation: Department of Anesthesiology, Perioperative and Pain Medicine, Center for Experimental Therapeutics and Reperfusion Injury, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Jeremy W
authors.initials: JW
authors.lastname: Winkler
authors.affiliation: Department of Anesthesiology, Perioperative and Pain Medicine, Center for Experimental Therapeutics and Reperfusion Injury, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Jason
authors.initials: J
authors.lastname: Hellmann
authors.affiliation: Department of Anesthesiology, Perioperative and Pain Medicine, Center for Experimental Therapeutics and Reperfusion Injury, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Blenda
authors.initials: B
authors.lastname: Wong
authors.affiliation: Pulmonary and Critical Care Medicine Division, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Ye
authors.initials: Y
authors.lastname: Cui
authors.affiliation: Pulmonary and Critical Care Medicine Division, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Souheil
authors.initials: S
authors.lastname: El-Chemaly
authors.affiliation: Department of Chemistry, Loker Hydrocarbon Research Institute, University of Southern California, Los Angeles, California.
authors.forename: Nicos A
authors.initials: NA
authors.lastname: Petasis
authors.affiliation: Department of Anesthesiology, Perioperative and Pain Medicine, Center for Experimental Therapeutics and Reperfusion Injury, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Matthew
authors.initials: M
authors.lastname: Spite
authors.affiliation: Department of Anesthesiology, Perioperative and Pain Medicine, Center for Experimental Therapeutics and Reperfusion Injury, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Charles N
authors.initials: CN
authors.lastname: Serhan
authors.affiliation: Pulmonary and Critical Care Medicine Division, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts. Electronic address: blevy@partners.org.
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Levy
mesh_terms: D055371:Acute Lung Injury / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D001241:Aspirin / Q000494:pharmacology; D015153:Blotting, Western; D004195:Disease Models, Animal; D005231:Fatty Acids, Unsaturated / Q000378:metabolism* / Q000494:pharmacology*; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C
chemical_list: D005231:Fatty Acids, Unsaturated; C583088:resolvin D3; D001241:Aspirin