Abstract
Introduction: Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease with poor prognosis. Nintedanib (BIBF 1120) is a tyrosine kinase inhibitor specific for platelet-derived growth factor receptor, fibroblast growth factor receptor and vascular endothelial growth factor receptor. Its effect on IPF disease progression measured by lung function decline has been investigated in two replicate Phase III clinical trials (INPULSIS-1 and INPULSI-2) in patients with IPF. Scant information is available on the in-vitro effect of nintedanib on transforming growth factor-beta (TGF-β) – induced pro-fibrotic effects.
Aim: To determine the in vitro effect of nintedanib on TGF-β1-stimulated primary human lung myofibroblasts.
Methods: Primary human lung myofibroblasts were isolated and propagated from lung parenchyma derived from patients with IPF and from non-fibrotic control lungs. After incubation with nintedanib (0.001 - 1µM) and stimulation with or without TGF-β1, the expression of matrix metalloproteinases (MMP) was assessed in the culture medium by gelatin zymography, collagen secretion was quantitated by the Sircol assay, and cell proliferation was assessed by automatic cell counting.
Results: In IPF myofibroblasts nintedanib prevented 1) the TGF-β1-induced reduction of pro-MMP2 expression, 2) the TGF-β1-induced enhanced secretion of collagen and 3) the pro-proliferative effect induced by TGF-β1.
Conclusion: Our data demonstrate that nintedanib significantly counteracts TGF-β-induced pro-fibrotic effects, and thus provide new insight into the mechanisms underlying the drug's clinically documented beneficial activity.
- © 2014 ERS