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

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.

journal_name

Respir Res

journal_title

Respiratory research

authors

Hostettler KE,Zhong J,Papakonstantinou E,Karakiulakis G,Tamm M,Seidel P,Sun Q,Mandal J,Lardinois D,Lambers C,Roth M

doi

10.1186/s12931-014-0157-3

subject

Has Abstract

pub_date

2014-12-12 00:00:00

pages

157

eissn

1465-9921

issn

1465-993X

pii

s12931-014-0157-3

journal_volume

15

pub_type

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