title: Resolvins attenuate inflammation and promote resolution in cigarette smoke-exposed human macrophages.
abstract: Inflammation is a protective response to injury, but it can become chronic, leading to tissue damage and disease. Cigarette smoke causes multiple inflammatory diseases, which account for thousands of deaths and cost billions of dollars annually. Cigarette smoke disrupts the function of immune cells, such as macrophages, by prolonging inflammatory signaling, promoting oxidative stress, and impairing phagocytosis, contributing to increased incidence of infections. Recently, new families of lipid-derived mediators, "specialized proresolving mediators" (SPMs), were identified. SPMs play a critical role in the active resolution of inflammation by counterregulating proinflammatory signaling and promoting resolution pathways. We have identified dysregulated concentrations of lipid mediators in exhaled breath condensate, bronchoalveolar lavage fluid, and serum from patients with chronic obstructive pulmonary disease (COPD). In human alveolar macrophages from COPD and non-COPD patients, D-series resolvins decreased inflammatory cytokines and enhanced phagocytosis. To further investigate the actions of resolvins on human cells, macrophages were differentiated from human blood monocytes and treated with D-series resolvins and then exposed to cigarette smoke extract. Resolvins significantly suppressed macrophage production of proinflammatory cytokines, enzymes, and lipid mediators. Resolvins also increased anti-inflammatory cytokines, promoted an M2 macrophage phenotype, and restored cigarette smoke-induced defects in phagocytosis, highlighting the proresolving functions of these molecules. These actions were receptor-dependent and involved modulation of canonical and noncanonical NF-κB expression, with the first evidence for SPM action on alternative NF-κB signaling. These data show that resolvins act on human macrophages to attenuate cigarette smoke-induced inflammatory effects through proresolving mechanisms and provide new evidence of the therapeutic potential of SPMs.
authors: Department of Environmental Medicine, University of Rochester School of Medicine and Dentistry, Rochester, New York; Lung Biology and Disease Program, University of Rochester School of Medicine and Dentistry, Rochester, New York;
authors: Amanda
authors: A
authors: Croasdell
authors: Lung Biology and Disease Program, University of Rochester School of Medicine and Dentistry, Rochester, New York; Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, New York; and.
authors: Thomas H
authors: http://orcid.org/0000-0001-7177-3041
authors: TH
authors: Thatcher
authors: Lung Biology and Disease Program, University of Rochester School of Medicine and Dentistry, Rochester, New York; Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, New York; and.
authors: R Matthew
authors: RM
authors: Kottmann
authors: Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Brigham and Women's Hospital, Boston, Massachusetts.
authors: Romain A
authors: RA
authors: Colas
authors: Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Brigham and Women's Hospital, Boston, Massachusetts.
authors: Jesmond
authors: J
authors: Dalli
authors: Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Brigham and Women's Hospital, Boston, Massachusetts.
authors: Charles N
authors: CN
authors: Serhan
authors: Department of Environmental Medicine, University of Rochester School of Medicine and Dentistry, Rochester, New York; Lung Biology and Disease Program, University of Rochester School of Medicine and Dentistry, Rochester, New York; Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, New York; and.
authors: Patricia J
authors: PJ
authors: Sime
authors: Department of Environmental Medicine, University of Rochester School of Medicine and Dentistry, Rochester, New York; Lung Biology and Disease Program, University of Rochester School of Medicine and Dentistry, Rochester, New York; Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, New York; and richard_phipps@urmc.rochester.edu.
authors: Richard P
authors: RP
authors: Phipps
mesh_terms: D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis; D004281:Docosahexaenoic Acids / Q000494:pharmacology*; D006801:Humans; D007249:Inflammation / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D018836:Inflammation Mediators / Q000378:metabolism; D050356:Lipid Metabolism / Q000187:drug effects; D016676:Macrophages, Alveolar / Q000187:drug effects* / Q000473:pathology / Q000502:physiology; D018384:Oxidative Stress / Q000187:drug effects; D010587:Phagocytosis / Q000187:drug effects; D029424:Pulmonary Disease, Chronic Obstructive / Q000473:pathology / Q000503:physiopathology; D015398:Signal Transduction / Q000187:drug effects; D012906:Smoke / Q000009:adverse effects; D012907:Smoking / Q000009:adverse effects*
chemical_list: D016207:Cytokines; D018836:Inflammation Mediators; D012906:Smoke; C518399:resolvin D1; D004281:Docosahexaenoic Acids
keywords: chronic obstructive pulmonary disease; cigarette smoke; macrophage; resolvin; specialized proresolving mediators