title: Ly6Chi monocytes direct alternatively activated profibrotic macrophage regulation of lung fibrosis.
abstract: BACKGROUND
  Idiopathic pulmonary fibrosis (IPF) is a devastating disease. Antiinflammatory therapies, including corticosteroids, are of no benefit. The role of monocytes and macrophages is therefore controversial.
  
  
  OBJECTIVE
  To define the role of monocytes and macrophages during lung fibrogenesis and resolution, and explore the phenotype of the cells involved.
  
  
  METHODS
  We used multiple in vivo depletional strategies, backed up by adoptive transfer techniques. Further studies were performed on samples from patients with IPF.
  
  
  RESULTS
  Depletion of lung macrophages during fibrogenesis reduced pulmonary fibrosis as measured by lung collagen (P = 0.0079); fibrosis score (P = 0.0051); and quantitative polymerase chain reaction for surrogate markers of fibrosis Col1 (P = 0.0083) and a-smooth muscle actin (P = 0.0349). There was an associated reduction in markers of the profibrotic alternative macrophage activation phenotype, Ym1 (P = 0.0179), and Arginase 1. The alternative macrophage marker CD163 was expressed on lung macrophages from patients with IPF. Depletion of Ly6Chi circulating monocytes reduced pulmonary fibrosis (P = 0.0052) and the number of Ym1- positive alternatively activated lung macrophages (P = 0.0310). Their adoptive transfer during fibrogenesis exacerbated fibrosis (P = 0.0304); however, adoptively transferred CD45.1 Ly6Chi cells were not found in the lungs of recipient CD45.2 mice.
  
  
  CONCLUSIONS
  We demonstrate the importance of circulating monocytes and lung macrophages during pulmonary fibrosis, and emphasize the importance of the alternatively activated macrophage phenotype. We show that Ly6Chi monocytes facilitate the progression of pulmonary fibrosis, but are not obviously engrafted into lungs thereafter. Finally, we provide empirical data to suggest that macrophages may have a resolution-promoting role during the reversible phase of bleomycin-induced pulmonary fibrosis.
authors.affiliation: Medical Research Council/University of Edinburgh Centre for Inflammation Research, Queen's Medical Research Institute, Edinburgh, United Kingdom.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Gibbons
authors.forename: Alison C
authors.initials: AC
authors.lastname: MacKinnon
authors.forename: Prakash
authors.initials: P
authors.lastname: Ramachandran
authors.forename: Kevin
authors.initials: K
authors.lastname: Dhaliwal
authors.forename: Rodger
authors.initials: R
authors.lastname: Duffin
authors.forename: Alexander T
authors.initials: AT
authors.lastname: Phythian-Adams
authors.forename: Nico
authors.initials: N
authors.lastname: van Rooijen
authors.forename: Christopher
authors.initials: C
authors.lastname: Haslett
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Howie
authors.forename: A John
authors.initials: AJ
authors.lastname: Simpson
authors.forename: Nikhil
authors.initials: N
authors.lastname: Hirani
authors.forename: Jack
authors.initials: J
authors.lastname: Gauldie
authors.forename: John P
authors.initials: JP
authors.lastname: Iredale
authors.forename: Tariq
authors.initials: T
authors.lastname: Sethi
authors.forename: Stuart J
authors.initials: SJ
authors.lastname: Forbes
mesh_terms: D000818:Animals; D001761:Bleomycin / Q000633:toxicity; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D006801:Humans; D007111:Immunity, Cellular; D008262:Macrophage Activation / Q000235:genetics / Q000276:immunology*; D016676:Macrophages, Alveolar / Q000276:immunology* / Q000473:pathology; D051379:Mice; D009000:Monocytes / Q000502:physiology*; D010641:Phenotype; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000209:etiology* / Q000473:pathology
chemical_list: D001761:Bleomycin