• Katrin E Hostettler, Jun Zhong, Eleni Papakonstantinou, George Karakiulakis, Michael Tamm, Petra Seidel, Qingzhu Sun, Jyotshna Mandal, Didier Lardinois, Christopher Lambers, and Michael Roth.
• Pulmonary Cell Research, Department of Biomedicine, University Hospital Basel, Basel, 4031, Switzerland. katrin.hostettler@usb.ch.
• Resp Res. 2014 Jan 1;15:157.

BackgroundIdiopathic 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.AimTo determine the in vitro effect of nintedanib on primary human lung fibroblasts.MethodsFibroblasts 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.ResultsIPF 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.ConclusionOur 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.

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