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

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

Author information

1
Pulmonary Cell Research, Department of Biomedicine, University Hospital Basel, Basel, 4031, Switzerland. katrin.hostettler@usb.ch.
2
Clinics of Respiratory Medicine, University Hospital Basel, Petersgraben 4, Basel, 4031, Switzerland. katrin.hostettler@usb.ch.
3
Pulmonary Cell Research, Department of Biomedicine, University Hospital Basel, Basel, 4031, Switzerland. Jun.zhong@unibas.ch.
4
Department of Pharmacology, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki, 54124, Greece. epap@med.auth.gr.
5
Department of Pharmacology, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki, 54124, Greece. gkaraki@med.auth.gr.
6
Pulmonary Cell Research, Department of Biomedicine, University Hospital Basel, Basel, 4031, Switzerland. michael.tamm@usb.ch.
7
Clinics of Respiratory Medicine, University Hospital Basel, Petersgraben 4, Basel, 4031, Switzerland. michael.tamm@usb.ch.
8
Pulmonary Cell Research, Department of Biomedicine, University Hospital Basel, Basel, 4031, Switzerland. petra.seidel@unibas.ch.
9
Pulmonary Cell Research, Department of Biomedicine, University Hospital Basel, Basel, 4031, Switzerland. qingzhu.sun@unibas.ch.
10
Pulmonary Cell Research, Department of Biomedicine, University Hospital Basel, Basel, 4031, Switzerland. jyotshna.mandal@usb.ch.
11
Clinics of Thoracic Surgery, University Hospital Basel, Basel, 4031, Switzerland. didier.lardinois@usb.ch.
12
Department of Internal Medicine IV, University of Vienna, Vienna, 1090, Austria. clambers@gmx.de.
13
Pulmonary Cell Research, Department of Biomedicine, University Hospital Basel, Basel, 4031, Switzerland. Michael.roth@usb.ch.

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.

PMID:
25496490
PMCID:
PMC4273482
DOI:
10.1186/s12931-014-0157-3
[Indexed for MEDLINE]
Free PMC Article
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