title: Aspirin-triggered resolvin D1 is produced during self-resolving gram-negative bacterial pneumonia and regulates host immune responses for the resolution of lung inflammation.
abstract: Bacterial pneumonia is a leading cause of morbidity and mortality worldwide. Host responses to contain infection and mitigate pathogen-mediated lung inflammation are critical for pneumonia resolution. Aspirin-triggered resolvin D1 (AT-RvD1; 7S,8R,17R-trihydroxy-4Z,9E,11E,13Z,15E,19Z-docosahexaenoic acid) is a lipid mediator (LM) that displays organ-protective actions in sterile lung inflammation, and regulates pathogen-initiated cellular responses. Here, in a self-resolving murine model of Escherichia coli pneumonia, LM metabololipidomics performed on lungs obtained at baseline, 24, and 72 h after infection uncovered temporal regulation of endogenous AT-RvD1 production. Early treatment with exogenous AT-RvD1 (1 h post infection) enhanced clearance of E. coli and Pseudomonas aeruginosa in vivo, and lung macrophage phagocytosis of fluorescent bacterial particles ex vivo. Characterization of macrophage subsets in the alveolar compartment during pneumonia identified efferocytosis by infiltrating macrophages (CD11b(Hi) CD11c(Low)) and exudative macrophages (CD11b(Hi) CD11c(Hi)). AT-RvD1 increased efferocytosis by these cells ex vivo, and accelerated neutrophil clearance during pneumonia in vivo. These anti-bacterial and pro-resolving actions of AT-RvD1 were additive to antibiotic therapy. Taken together, these findings suggest that the pro-resolving actions of AT-RvD1 during pneumonia represent a novel host-directed therapeutic strategy to complement the current antibiotic-centered approach for combatting infections.
authors.affiliation: Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: R E
authors.initials: RE
authors.lastname: Abdulnour
authors.affiliation: Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: H P
authors.initials: HP
authors.lastname: Sham
authors.affiliation: Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: D N
authors.initials: DN
authors.lastname: Douda
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, Massachusetts, USA.
authors.forename: R A
authors.initials: RA
authors.lastname: Colas
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, Massachusetts, USA.
authors.forename: J
authors.initials: J
authors.lastname: Dalli
authors.affiliation: Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Bai
authors.affiliation: Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: X
authors.initials: X
authors.lastname: Ai
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, Massachusetts, USA.
authors.forename: C N
authors.initials: CN
authors.lastname: Serhan
authors.affiliation: Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.|Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: B D
authors.initials: BD
authors.lastname: Levy
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000276:immunology / Q000493:pharmacokinetics*; D001241:Aspirin / Q000008:administration & dosage / Q000276:immunology / Q000493:pharmacokinetics*; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology; D004281:Docosahexaenoic Acids / Q000096:biosynthesis* / Q000276:immunology; D004926:Escherichia coli / Q000254:growth & development / Q000276:immunology; D004927:Escherichia coli Infections / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology; D015870:Gene Expression; D050356:Lipid Metabolism / Q000187:drug effects; D008055:Lipids / Q000032:analysis / Q000276:immunology; D000071068:Lipocalin-2 / Q000235:genetics / Q000276:immunology; D008168:Lung / Q000187:drug effects / Q000276:immunology / Q000382:microbiology; D016676:Macrophages, Alveolar / Q000187:drug effects / Q000276:immunology / Q000382:microbiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009504:Neutrophils / Q000276:immunology / Q000473:pathology; D010587:Phagocytosis / Q000187:drug effects; D018410:Pneumonia, Bacterial / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology; D011552:Pseudomonas Infections / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology; D011550:Pseudomonas aeruginosa / Q000254:growth & development / Q000276:immunology
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D008055:Lipids; D000071068:Lipocalin-2; C518399:resolvin D1; C071332:Lcn2 protein, mouse; D004281:Docosahexaenoic Acids; D001241:Aspirin