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

Respiratory Research

Michael Roth⁵  Christopher Lambers¹  Didier Lardinois⁴  Jyotshna Mandal⁵  Qingzhu Sun⁵  Petra Seidel⁵  Michael Tamm²  George Karakiulakis³  Eleni Papakonstantinou³  Jun Zhong⁵  Katrin E Hostettler² 

[1] Department of Internal Medicine IV, University of Vienna, Vienna 1090, Austria;Clinics of Respiratory Medicine, University Hospital Basel, Petersgraben 4, Basel 4031, Switzerland;Department of Pharmacology, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki 54124, Greece;Clinics of Thoracic Surgery, University Hospital Basel, Basel 4031, Switzerland;Pulmonary Cell Research, Department of Biomedicine, University Hospital Basel, Basel 4031, Switzerland

关键词: Fibroblasts;    Lung fibrosis;    Kinase inhibitor;    In vitro model;   

Others  :  1137201
DOI  :  10.1186/s12931-014-0157-3

 received in 2014-01-24, accepted in 2014-11-25,  发布年份 2014

【 摘 要 】

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.

【 授权许可】

   
2014 Hostettler et al.; licensee BioMed Central.

【 图 表 】

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