title: A novel anti-inflammatory and pro-resolving role for resolvin D1 in acute cigarette smoke-induced lung inflammation.
abstract: BACKGROUND
  Cigarette smoke is a profound pro-inflammatory stimulus that contributes to acute lung injuries and to chronic lung disease including COPD (emphysema and chronic bronchitis). Until recently, it was assumed that resolution of inflammation was a passive process that occurred once the inflammatory stimulus was removed. It is now recognized that resolution of inflammation is a bioactive process, mediated by specialized lipid mediators, and that normal homeostasis is maintained by a balance between pro-inflammatory and pro-resolving pathways. These novel small lipid mediators, including the resolvins, protectins and maresins, are bioactive products mainly derived from dietary omega-3 and omega-6 polyunsaturated fatty acids (PUFA). We hypothesize that resolvin D1 (RvD1) has potent anti-inflammatory and pro-resolving effects in a model of cigarette smoke-induced lung inflammation.
  
  
  METHODS
  Primary human lung fibroblasts, small airway epithelial cells and blood monocytes were treated with IL-1β or cigarette smoke extract in combination with RvD1 in vitro, production of pro-inflammatory mediators was measured. Mice were exposed to dilute mainstream cigarette smoke and treated with RvD1 either concurrently with smoke or after smoking cessation. The effects on lung inflammation and lung macrophage populations were assessed.
  
  
  RESULTS
  RvD1 suppressed production of pro-inflammatory mediators by primary human cells in a dose-dependent manner. Treatment of mice with RvD1 concurrently with cigarette smoke exposure significantly reduced neutrophilic lung inflammation and production of pro-inflammatory cytokines, while upregulating the anti-inflammatory cytokine IL-10. RvD1 promoted differentiation of alternatively activated (M2) macrophages and neutrophil efferocytosis. RvD1 also accelerated the resolution of lung inflammation when given after the final smoke exposure.
  
  
  CONCLUSIONS
  RvD1 has potent anti-inflammatory and pro-resolving effects in cells and mice exposed to cigarette smoke. Resolvins have strong potential as a novel therapeutic approach to resolve lung injury caused by smoke and pulmonary toxicants.
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Rochester, Rochester, New York, USA.
authors.forename: Hsi-Min
authors.initials: HM
authors.lastname: Hsiao
authors.forename: Ramil E
authors.initials: RE
authors.lastname: Sapinoro
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Thatcher
authors.forename: Amanda
authors.initials: A
authors.lastname: Croasdell
authors.forename: Elizabeth P
authors.initials: EP
authors.lastname: Levy
authors.forename: Robert A
authors.initials: RA
authors.lastname: Fulton
authors.forename: Keith C
authors.initials: KC
authors.lastname: Olsen
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Pollock
authors.forename: Charles N
authors.initials: CN
authors.lastname: Serhan
authors.forename: Richard P
authors.initials: RP
authors.lastname: Phipps
authors.forename: Patricia J
authors.initials: PJ
authors.lastname: Sime
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid; D018925:Chemokines / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D017931:DNA Primers / Q000235:genetics; D004281:Docosahexaenoic Acids / Q000378:metabolism*; D005260:Female; D005347:Fibroblasts; D006706:Homeostasis / Q000502:physiology; D006801:Humans; D008168:Lung / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D010587:Phagocytosis / Q000502:physiology; D011014:Pneumonia / Q000188:drug therapy* / Q000209:etiology* / Q000378:metabolism*; D012907:Smoking / Q000009:adverse effects*
chemical_list: D018925:Chemokines; D016207:Cytokines; D017931:DNA Primers; C518399:resolvin D1; D004281:Docosahexaenoic Acids