Department of Internal Medicine 3 and Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany.
Rheumaklinik, University Hospital Zurich, Zurich, Switzerland.
Ann Rheum Dis. 2017 Nov;76(11):1941-1948. doi: 10.1136/annrheumdis-2016-210823. Epub 2017 Aug 16.
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).
The 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.
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.
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.
尼达尼布是一种针对血小板衍生生长因子受体、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，最近已被批准用于治疗特发性肺纤维化。本研究旨在分析尼达尼布在富丝氨酸抗原-2（Fra2）系统性硬化症（SSc）小鼠模型中的作用。
分析尼达尼布对肺动脉高压伴肺血管平滑肌细胞（PVSMCs）增殖和管腔闭塞、微血管病变伴微血管内皮细胞（MVECs）凋亡和纤维化伴肌成纤维细胞分化和细胞外基质积累的影响。我们还研究了尼达尼布对 SSc 发病机制中关键介质水平的影响和巨噬细胞极化。
尼达尼布抑制 PVSMCs 的增殖，防止血管壁增厚和肺动脉管腔闭塞。尼达尼布治疗还抑制 MVECs 的凋亡，并减轻 Fra2 转基因小鼠的毛细血管稀疏。这些作用与尼达尼布治疗后 Fra2 小鼠血清血管内皮生长因子水平的正常化有关。尼达尼布还能有效阻止肌成纤维细胞分化，减少 Fra2 转基因小鼠的肺、皮肤和心肌纤维化。尼达尼布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。
尼达尼布靶向 Fra2 转基因小鼠的 SSc 核心特征，并改善肺动脉高压、破坏性微血管病和肺及皮肤纤维化的组织学特征。这些数据可能对尼达尼布在 SSc 相关间质性肺病的 III 期临床试验有直接影响。
