Nintedanib inhibits macrophage activation and ameliorates vascular and fibrotic manifestations in the Fra2 mouse model of systemic sclerosis
Nintedanib inhibits macrophage activation and ameliorates vascular and fibrotic manifestations in the Fra2 mouse model of systemic sclerosis
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DOI：
10.1136/annrheumdis-2016-210823
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发表时间：
2017-11-01
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;Maier, Christiane;Distler, Joerg H. W.
研究背景：NATRA是一种靶向血小板源性生长因子受体、成纤维细胞生长因子受体和血管内皮生长因子受体酪氨酸激酶的抑制剂，最近被批准用于治疗特发性肺纤维化。本研究的目的是分析尼达尼布在系统性硬化症（SSc）的fos相关抗原-2（Fra 2）小鼠模型中的作用。方法观察尼达尼布对肺动脉高压伴肺血管平滑肌细胞（PVSMCs）增殖和管腔阻塞的影响，微血管内皮细胞凋亡的微血管疾病并分析了成纤维细胞活化与肌成纤维细胞分化和细胞外基质积累的关系。我们还研究了尼达尼布对参与SSc发病机制的关键介质水平和巨噬细胞polarisation.Results的影响，抑制PVSMCs的增殖，防止血管壁增厚和肺动脉管腔闭塞。尼达尼布给药还可抑制MVEC凋亡，并减弱Fra 2转基因小鼠的毛细血管稀疏。这些效应与尼达尼布治疗后Fra 2小鼠血清血管内皮生长因子水平恢复正常有关。在Fra 2转基因小鼠中，Naphthalene还有效地阻断了肌成纤维细胞分化，并减少了肺、皮肤和心肌纤维化。nintedanib的抗纤维化作用与单核细胞M2极化受损和M2巨噬细胞数量减少有关。结论Nintedanib靶向Fra 2转基因小鼠SSc的核心特征，并改善肺动脉高压、破坏性微血管病以及肺和皮肤纤维化的组织学特征。这些数据可能对正在进行的尼达尼布治疗SSC相关间质性肺病的III期临床试验有直接影响。
Background Nintedanib is an inhibitor targeting platelet-derived growth factor receptor, fibroblast growth factor receptor and vascular endothelial growth factor receptor tyrosine kinases that has recently been approved for the treatment of idiopathic pulmonary fibrosis. The aim of this study was to analyse the effects of nintedanib in the fos-related antigen-2 (Fra2) mouse model of systemic sclerosis (SSc).Methods T he effects of nintedanib on pulmonary arterial hypertension with proliferation of pulmonary vascular smooth muscle cells (PVSMCs) and luminal occlusion, on microvascular disease with apoptosis of microvascular endothelial cells (MVECs) and on fibroblast activation with myofibroblast differentiation and accumulation of extracellular matrix were analysed. We also studied the effects of nintedanib on the levels of key mediators involved in the pathogenesis of SSc and on macrophage polarisation.Results Nintedanib inhibited proliferation of PVSMCs and prevented thickening of the vessel walls and luminal occlusion of pulmonary arteries. Treatment with nintedanib also inhibited apoptosis of MVECs and blunted the capillary rarefaction in Fra2-transgenic mice. These effects were associated with a normalisation of the serum levels of vascular endothelial growth factor in Fra2 mice on treatment with nintedanib. Nintedanib also effectively blocked myofibroblast differentiation and reduced pulmonary, dermal and myocardial fibrosis in Fra2-transgenic mice. The antifibrotic effects of nintedanib were associated with impaired M2 polarisation of monocytes and reduced numbers of M2 macrophages.Conclusion Nintedanib targets core features of SSc in Fra2-transgenic mice and ameliorates histological features of pulmonary arterial hypertension, destructive microangiopathy and pulmonary and dermal fibrosis. These data might have direct implications for the ongoing phase III clinical trial with nintedanib in SSc-associated interstitial lung disease.