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

作者：Hostettler Katrin E^*; Zhong Jun; Papakonstantinou Eleni; Karakiulakis George; Tamm Michael; Seidel Petra; Sun Qingzhu; Mandal Jyotshna; Lardinois Didier; Lambers Christopher; Roth Michael

来源：Respiratory Research, 2014, 15(1): 157.

DOI：10.1186/s12931-014-0157-3

• In vitro model
• Kinase inhibitor
• Lung fibrosis
• Fibroblasts

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. %26lt;br%26gt;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. %26lt;br%26gt;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. %26lt;br%26gt;Conclusion: Our data demonstrate a significant anti-fibrotic effect of nintedanib in IPF fibroblasts. This effect consists of the drug%26apos;s anti-proliferative capacity, and on its effect on the extracellular matrix, the degradation of which seems to be enhanced.

• 出版日期2014-12-12