Anti-fibrotic effects of nintedanib in lung fibroblasts derived from patients with idiopathic pulmonary fibrosis

Respir Res. 2014 Dec 12;15(1):157. doi: 10.1186/s12931-014-0157-3.


Background: Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease with poor prognosis. The kinase inhibitor nintedanib specific for vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR) and fibroblast growth factor receptor (FGFR) significantly reduced the rate of decline of forced vital capacity versus placebo.

Aim: To determine the in vitro effect of nintedanib on primary human lung fibroblasts.

Methods: Fibroblasts were isolated from lungs of IPF patients and from non-fibrotic controls. We assessed the effect of VEGF, PDGF-BB and basic FGF (bFGF) ± nintedanib on: (i) expression/activation of VEGFR, PDGFR, and FGFR, (ii) cell proliferation, secretion of (iii) matrix metalloproteinases (MMP), (iv) tissue inhibitor of metalloproteinase (TIMP), and (v) collagen.

Results: IPF fibroblasts expressed higher levels of PDGFR and FGFR than controls. PDGF-BB, bFGF, and VEGF caused a pro-proliferative effect which was prevented by nintedanib. Nintedanib enhanced the expression of pro-MMP-2, and inhibited the expression of TIMP-2. Transforming growth factor-beta-induced secretion of collagens was inhibited by nintedanib.

Conclusion: Our data demonstrate a significant anti-fibrotic effect of nintedanib in IPF fibroblasts. This effect consists of the drug's anti-proliferative capacity, and on its effect on the extracellular matrix, the degradation of which seems to be enhanced.

MeSH terms

  • Becaplermin
  • Case-Control Studies
  • Cell Proliferation / drug effects
  • Cells, Cultured
  • Dose-Response Relationship, Drug
  • Enzyme Precursors / metabolism
  • Extracellular Matrix / metabolism
  • Fibroblast Growth Factor 2 / pharmacology
  • Fibroblasts / drug effects*
  • Fibroblasts / enzymology
  • Fibroblasts / pathology
  • Gelatinases / metabolism
  • Humans
  • Idiopathic Pulmonary Fibrosis / enzymology*
  • Idiopathic Pulmonary Fibrosis / pathology
  • Indoles / pharmacology*
  • Lung / drug effects*
  • Lung / enzymology
  • Lung / pathology
  • Phosphorylation
  • Protein Kinase Inhibitors / pharmacology*
  • Proto-Oncogene Proteins c-sis / pharmacology
  • Receptors, Fibroblast Growth Factor / drug effects
  • Receptors, Fibroblast Growth Factor / metabolism
  • Receptors, Platelet-Derived Growth Factor / drug effects
  • Receptors, Platelet-Derived Growth Factor / metabolism
  • Receptors, Vascular Endothelial Growth Factor / drug effects
  • Receptors, Vascular Endothelial Growth Factor / metabolism
  • Tissue Inhibitor of Metalloproteinase-2 / metabolism
  • Vascular Endothelial Growth Factor A / pharmacology


  • Enzyme Precursors
  • Indoles
  • Protein Kinase Inhibitors
  • Proto-Oncogene Proteins c-sis
  • Receptors, Fibroblast Growth Factor
  • TIMP2 protein, human
  • Vascular Endothelial Growth Factor A
  • Fibroblast Growth Factor 2
  • Tissue Inhibitor of Metalloproteinase-2
  • Becaplermin
  • Receptors, Platelet-Derived Growth Factor
  • Receptors, Vascular Endothelial Growth Factor
  • Gelatinases
  • progelatinase
  • nintedanib