Title: Nintedanib inhibits fibroblast activation and ameliorates pulmonary and dermal fibrosis in models of systemic sclerosis (SSc)
Abstract: <b>Background:</b> Nintedanib a tyrosine kinase inhibitor for PDGFRα and β, FGFR1-3, VEGFR1-3 and Src-family kinaseshas been shown to slow disease progression in idiopathic pulmonary fibrosis (IPF) and has recently been authorized for the treatment of IPF in the US and EU. <b>Objectives:</b> To analyze the anti-fibrotic activity of nintedanib in models of pulmonary and dermal fibrosis associated with SSc. <b>Methods:</b> The effects of nintedanib on migration, proliferation, myofibroblast differentiation and release of extracellular matrix of primary human SSc fibroblasts were analyzed by MTT- and scratch assays, stress fiber staining, qPCR and SirCol assays. The anti-fibrotic effects of nintedanib were evaluated in bleomycin-induced skin fibrosis (Bleo-SF), in murine sclerodermatous chronic graft-versus host disease (GvhD), in tight-skin-1 mice (Tsk-1) and in fos-related antigen-2 transgenic (Fra2) mice. <b>Results:</b> Nintedanib delayed migration, inhibited proliferation, reduced the mRNA levels of Col 1a1, Col 1a2 and fibronectin-1, collagen protein and the basal levels of αSMA and stress fibres in SSc fibroblasts. Preventive as well as therapeutic treatment with nintedanib ameliorated dermal thickening, myofibroblast differentiation and collagen deposition in inflammation-driven models of SSc such as Bleo-SF and GvhD. In models of later, non-inflammatory stages of SSc such as Tsk-1 and Fra2 nintedanib effectively reduced pulmonary as well as dermal fibrosis. <b>Conclusions:</b> Nintedanib effectively inhibits activation of primary human fibroblasts and exerts potent anti-fibrotic effects in mouse models of SSc providing a scientific rationale for clinical trials in SSc.
Publication Year: 2015
Publication Date: 2015-09-01
Language: en
Type: article
Indexed In: ['crossref']
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Cited By Count: 1
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