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

ΤίτλοςAnti-fibrotic effects of nintedanib in lung fibroblasts derived from patients with idiopathic pulmonary fibrosis.
Publication TypeJournal Article
Year of Publication2014
AuthorsHostettler, K. E., Zhong J., Papakonstantinou E., Karakiulakis G., Tamm M., Seidel P., Sun Q., Mandal J., Lardinois D., Lambers C., & Roth M.
JournalRespir Res
Volume15
Pagination157
Date Published2014
ISSN1465-993X
Λέξεις κλειδιάCase-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.

DOI10.1186/s12931-014-0157-3
Alternate JournalRespir. Res.
PubMed ID25496490
PubMed Central IDPMC4273482

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