title: Regulation of transforming growth factor-β1-driven lung fibrosis by galectin-3.
abstract: BACKGROUND
  Idiopathic pulmonary fibrosis (IPF) is a chronic dysregulated response to alveolar epithelial injury with differentiation of epithelial cells and fibroblasts into matrix-secreting myofibroblasts resulting in lung scaring. The prognosis is poor and there are no effective therapies or reliable biomarkers. Galectin-3 is a β-galactoside binding lectin that is highly expressed in fibrotic tissue of diverse etiologies.
  
  
  OBJECTIVE
  To examine the role of galectin-3 in pulmonary fibrosis.
  
  
  METHODS
  We used genetic deletion and pharmacologic inhibition in well-characterized murine models of lung fibrosis. Further mechanistic studies were performed in vitro and on samples from patients with IPF.
  
  
  RESULTS
  Transforming growth factor (TGF)-β and bleomycin-induced lung fibrosis was dramatically reduced in mice deficient in galectin-3, manifest by reduced TGF-β1-induced EMT and myofibroblast activation and collagen production. Galectin-3 reduced phosphorylation and nuclear translocation of β-catenin but had no effect on Smad2/3 phosphorylation. A novel inhibitor of galectin-3, TD139, blocked TGF-β-induced β-catenin activation in vitro and in vivo and attenuated the late-stage progression of lung fibrosis after bleomycin. There was increased expression of galectin-3 in the bronchoalveolar lavage fluid and serum from patients with stable IPF compared with nonspecific interstitial pneumonitis and controls, which rose sharply during an acute exacerbation suggesting that galectin-3 may be a marker of active fibrosis in IPF and that strategies that block galectin-3 may be effective in treating acute fibrotic exacerbations of IPF.
  
  
  CONCLUSIONS
  This study identifies galectin-3 as an important regulator of lung fibrosis and provides a proof of principle for galectin-3 inhibition as a potential novel therapeutic strategy for IPF.
authors.affiliation: MRC Centre for Inflammation Research, The Queen's Medical Research Institute, University of Edinburgh, United Kingdom.
authors.forename: Alison C
authors.initials: AC
authors.lastname: Mackinnon
authors.forename: Michael A
authors.initials: MA
authors.lastname: Gibbons
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Farnworth
authors.forename: Hakon
authors.initials: H
authors.lastname: Leffler
authors.forename: Ulf J
authors.initials: UJ
authors.lastname: Nilsson
authors.forename: Tamara
authors.initials: T
authors.lastname: Delaine
authors.forename: A John
authors.initials: AJ
authors.lastname: Simpson
authors.forename: Stuart J
authors.initials: SJ
authors.lastname: Forbes
authors.forename: Nik
authors.initials: N
authors.lastname: Hirani
authors.forename: Jack
authors.initials: J
authors.lastname: Gauldie
authors.forename: Tariq
authors.initials: T
authors.lastname: Sethi
mesh_terms: D000818:Animals; D001761:Bleomycin / Q000633:toxicity; D003094:Collagen / Q000096:biosynthesis; D004195:Disease Models, Animal; D005347:Fibroblasts / Q000378:metabolism / Q000502:physiology; D005455:Fluorescent Antibody Technique; D037502:Galectin 3 / Q000037:antagonists & inhibitors / Q000502:physiology*; D055786:Gene Knockout Techniques; D006801:Humans; D054990:Idiopathic Pulmonary Fibrosis / Q000378:metabolism / Q000503:physiopathology*; D008168:Lung / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D015398:Signal Transduction / Q000502:physiology; D053773:Transforming Growth Factor beta1 / Q000378:metabolism / Q000502:physiology*
chemical_list: D037502:Galectin 3; D053773:Transforming Growth Factor beta1; D001761:Bleomycin; D003094:Collagen
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