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

In English

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
Visa allt

Summary, in English

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.

Publiceringsår

2012

Språk

Engelska

Sidor

537-546

Publikation/Tidskrift/Serie

American Journal of Respiratory and Critical Care Medicine

Volym

185

Issue

5

Dokumenttyp

Artikel i tidskrift

Förlag

American Thoracic Society

Ämne

  • Respiratory Medicine and Allergy

Nyckelord

  • fibrosis
  • epithelial cells
  • fibroblasts

Status

Published

ISBN/ISSN/Övrigt

  • ISSN: 1535-4970