Regulation of transforming growth factor-β1-driven lung fibrosis by galectin-3

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 β-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)-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.