Anti-fibrotic effects of nintedanib in lung fibroblasts derived from patients with idiopathic pulmonary fibrosis.
Title | Anti-fibrotic effects of nintedanib in lung fibroblasts derived from patients with idiopathic pulmonary fibrosis. |
Publication Type | Journal Article |
Year of Publication | 2014 |
Authors | Hostettler, K. E., Zhong J., Papakonstantinou E., Karakiulakis G., Tamm M., Seidel P., Sun Q., Mandal J., Lardinois D., Lambers C., & Roth M. |
Journal | Respir Res |
Volume | 15 |
Pagination | 157 |
Date Published | 2014 |
ISSN | 1465-993X |
Keywords | Case-Control Studies, Cell Proliferation, Cells, Cultured, Dose-Response Relationship, Drug, Enzyme Precursors, Extracellular Matrix, Fibroblast Growth Factor 2, Fibroblasts, Gelatinases, Humans, Idiopathic Pulmonary Fibrosis, Indoles, Lung, Phosphorylation, Protein Kinase Inhibitors, Proto-Oncogene Proteins c-sis, Receptors, Fibroblast Growth Factor, Receptors, Platelet-Derived Growth Factor, Receptors, Vascular Endothelial Growth Factor, Tissue Inhibitor of Metalloproteinase-2, Vascular Endothelial Growth Factor A |
Abstract | 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. |
DOI | 10.1186/s12931-014-0157-3 |
Alternate Journal | Respir. Res. |
PubMed ID | 25496490 |
PubMed Central ID | PMC4273482 |