Regulation of Transforming Growth Factor-beta 1-driven Lung Fibrosis by Galectin-3

Forskningsoutput: TidskriftsbidragArtikel i vetenskaplig tidskrift

Abstract

Rationale: 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 beta-galactoside binding lectin that is highly expressed in fibrotic tissue of diverse etiologies. Objectives: 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. Measurements and Main Results: Transforming growth factor (TGF)-beta and bleomycin-induced lung fibrosis was dramatically reduced in mice deficient in galectin-3, manifest by reduced TGF-beta 1 induced EMT and myofibroblast activation and collagen production. Galectin-3 reduced phosphorylation and nuclear translocation of beta-catenin but had no effect on Smad2/3 phosphorylation. A novel inhibitor of galectin -3, TD139, blocked TGF-beta-induced beta-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.

Detaljer

Författare
  • Alison C. MacKinnon
  • Michael A. Gibbons
  • Sarah L. Farnworth
  • Hakon Leffler
  • Ulf Nilsson
  • Tamara Delaine
  • A. John Simpson
  • Stuart J. Forbes
  • Nik Hirani
  • Jack Gauldie
  • Tariq Sethi
Enheter & grupper
Forskningsområden

Ämnesklassifikation (UKÄ) – OBLIGATORISK

  • Lungmedicin och allergi

Nyckelord

Originalspråkengelska
Sidor (från-till)537-546
TidskriftAmerican Journal of Respiratory and Critical Care Medicine
Volym185
Utgivningsnummer5
StatusPublished - 2012
PublikationskategoriForskning
Peer review utfördJa