Nintedanib inhibits fibroblast activation and ameliorates fibrosis in preclinical models of systemic sclerosis
Nintedanib inhibits fibroblast activation and ameliorates fibrosis in preclinical models of systemic sclerosis
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DOI：
10.1136/annrheumdis-2014-207109
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发表时间：
2016-05-01
影响因子：
27.4
通讯作者：
Distler, Joerg H. W.
中科院分区：
文献类型：
--
作者：
Huang, Jingang;Beyer, Christian;Distler, Joerg H. W.
尼达尼布是一种酪氨酸激酶抑制剂，最近在两项重复的III期临床试验中被证明可以减缓特发性肺纤维化的疾病进展。本研究的目的是分析尼达尼布在系统性硬化症（SSc）临床前模型中的抗纤维化作用，并为SSc的临床试验提供科学背景。方法采用四氮唑微滴法、刮痕法、应力纤维染色法、qPCR法和SirCol法分析尼达尼布对真皮成纤维细胞迁移、增殖、肌成纤维细胞分化和细胞外基质释放的影响。在博莱霉素诱导的皮肤纤维化、小鼠慢性移植物抗宿主病模型和紧致皮肤1型小鼠中评估了尼达尼布的抗纤维化作用。尼达尼布剂量依赖性地减少血小板衍生生长因子诱导和转化生长因子诱导的增殖和迁移，以及肌成纤维细胞分化和皮肤成纤维细胞的胶原蛋白释放。尼达尼布还能抑制SSc成纤维细胞的内源性活化。尼达尼布以剂量依赖的方式预防博来霉素诱导的皮肤纤维化，并且在治疗已建立的纤维化方面也有效。此外，在耐受性良好的剂量下，尼达尼布治疗可改善慢性移植物抗宿主病模型和紧皮肤1小鼠的纤维化。结论尼达尼布可有效抑制内源性和细胞因子诱导的SSc成纤维细胞活化，并在不同的SSc互补小鼠模型中发挥有效的抗纤维化作用。这些数据对尼达尼布治疗SSc的临床试验具有直接的转化意义。
Background Nintedanib is a tyrosine kinase inhibitor that has recently been shown to slow disease progression in idiopathic pulmonary fibrosis in two replicate phase III clinical trials. The aim of this study was to analyse the antifibrotic effects of nintedanib in preclinical models of systemic sclerosis (SSc) and to provide a scientific background for clinical trials in SSc.Methods The effects of nintedanib on migration, proliferation, myofibroblast differentiation and release of extracellular matrix of dermal fibroblasts were analysed by microtitre tetrazolium and scratch assays, stress fibre staining, qPCR and SirCol assays. The antifibrotic effects of nintedanib were evaluated in bleomycin-induced skin fibrosis, in a murine sclerodermatous chronic graft-versus-host disease model and in tight-skin-1 mice.Results Nintedanib dose-dependently reduced platelet-derived growth factor-induced and transforming growth factor--induced proliferation and migration as well as myofibroblast differentiation and collagen release of dermal fibroblasts from patients with and healthy individuals. Nintedanib also inhibited the endogenous activation of SSc fibroblasts. Nintedanib prevented bleomycin-induced skin fibrosis in a dose-dependent manner and was also effective in the treatment of established fibrosis. Moreover, treatment with nintedanib ameliorated fibrosis in the chronic graft-versus-host disease model and in tight-skin-1 mice in well-tolerated doses.Conclusions We demonstrate that nintedanib effectively inhibits the endogenous as well as cytokine-induced activation of SSc fibroblasts and exerts potent antifibrotic effects in different complementary mouse models of SSc. These data have direct translational implications for clinical trials with nintedanib in SSc.