Profibrotic role of WNT10A via TGF-β signaling in idiopathic pulmonary fibrosis

Respir Res. 2016 Apr 12;17:39. doi: 10.1186/s12931-016-0357-0.

Abstract

Background: WNT/β-catenin signaling plays an important role in the pathogenesis of idiopathic pulmonary fibrosis (IPF); however, the role of WNT10A via transforming growth factor (TGF)-β signaling remains unclear.

Methods: We evaluated the expression of WNT10A and TGF-β in bleomycin (BLM)-treated mice and the interactions between TGF-β or BLM and WNT10A in vitro. Additionally, we investigated IPF patients who underwent video-assisted thoracoscopic surgery to determine whether the WNT10A expression is related to the survival.

Results: Increased WNT10A and TGF-β expressions were noted in the BLM-treated mice. Real-time PCR and luciferase reporter assays demonstrated the levels of WNT10A and collagen in the fibroblasts cells to increase after TGF-β administration. Conversely, WNT10A siRNA treatment inhibited the synthesis of collagen in the transfected fibroblasts cells. A Kaplan-Meier survival analysis demonstrated a tendency toward a poor survival among the IPF patients with a WNT10A-positive expression compared to those with a negative expression (Hazard ratio 5.351, 95 % CI 1.703-16.82; p = 0.0041). An overexpression of WNT10A was found to be significantly predictive of an acute exacerbation of IPF (AE-IPF) (Odds ratio 13.69, 95 % CI 1.728-108.5; p = 0.013).

Conclusions: WNT10A plays an important role in the pathogenesis of IPF via TGF-β activation and it may also be a sensitive predictor for the onset of an AE-IPF.

Keywords: Acute exacerbation; Autopsy; Diffuse alveolar damage; Fibroblast; Idiopathic pulmonary fibrosis; WNT/β-catenin pathway.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bleomycin
  • Cells, Cultured
  • Fibroblasts / metabolism*
  • Fibroblasts / pathology
  • Idiopathic Pulmonary Fibrosis / chemically induced
  • Idiopathic Pulmonary Fibrosis / metabolism*
  • Idiopathic Pulmonary Fibrosis / pathology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Nerve Tissue Proteins / metabolism*
  • Survival Rate
  • Transforming Growth Factor beta / metabolism*
  • Wnt Proteins / metabolism*
  • Wnt Signaling Pathway*

Substances

  • Nerve Tissue Proteins
  • Transforming Growth Factor beta
  • Wnt Proteins
  • Wnt10a protein, mouse
  • Bleomycin