Van Hung Tran, Emoto Noriaki, Vignon-Zellweger Nicolas, Nakayama Kazuhiko, Yagi Keiko, Suzuki Yoko, Hirata Ken-ichi
Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicie, Kobe, Japan.
Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicie, Kobe, Japan; Department of Clinical Pharmacy, Kobe Pharmaceutical University, Kobe, Japan.
Life Sci. 2014 Nov 24;118(2):313-28. doi: 10.1016/j.lfs.2013.12.215. Epub 2014 Jan 8.
Severe pulmonary arterial hypertension (PAH) is an incurable disease whose exact mechanisms remain unknown. However, growing evidence highlights the role of inflammation and endothelin (ET) signaling. The lack of reliable models makes it difficult to investigate the pathophysiology of this disease. Our aim was therefore to develop a mouse model of severe PAH closely mimicking the human condition to explore the role of interleukin-6 (IL-6), and ET signaling in advanced PAH progression.
Young male SV129 mice received vascular endothelial growth factor receptor inhibitor (SU5416) three times a week and were exposed to hypoxia (10% O2) for three weeks. Molecular analysis and histological assessment were examined using real-time PCR, Western blot and immunostaining, respectively.
The developed murine model presented important characteristics of severe PAH in human: concentric neointimal wall thickening, plexogenic lesions, recruitment of macrophages, and distal arteriolar wall muscularization. We detected an increase of IL-6 production and a stronger macrophage recruitment in adventitia of remodeled arterioles developing plexogenic lesions. Moreover, ET-1 and ET receptor A were up-regulated in lung lysates and media of remodeled arterioles. Recombinant IL-6 stimulated the proliferation and regulated endothelial cells in increasing ET-1 and decreasing ET receptor B.
These data describe a murine model, which displays the most important features of human severe PAH. We assume that inflammation, particularly IL-6 regulating ET signaling, plays a crucial role in forming plexogenic lesions. This model is thus reliable and might be used for a better understanding of severe PAH progression and treatment.
重度肺动脉高压(PAH)是一种无法治愈的疾病,其确切机制尚不清楚。然而,越来越多的证据凸显了炎症和内皮素(ET)信号传导的作用。缺乏可靠的模型使得研究该疾病的病理生理学变得困难。因此,我们的目的是建立一种紧密模拟人类情况的重度PAH小鼠模型,以探讨白细胞介素-6(IL-6)和ET信号传导在晚期PAH进展中的作用。
年轻雄性SV129小鼠每周接受三次血管内皮生长因子受体抑制剂(SU5416),并暴露于低氧环境(10%氧气)三周。分别使用实时PCR、蛋白质印迹法和免疫染色进行分子分析和组织学评估。
所建立的小鼠模型呈现出人类重度PAH的重要特征:同心性内膜壁增厚、丛状病变、巨噬细胞募集以及远端小动脉壁肌化。我们检测到在发生丛状病变的重塑小动脉外膜中IL-6产生增加且巨噬细胞募集更强。此外,ET-1和ET受体A在重塑小动脉的肺裂解物和培养基中上调。重组IL-6刺激增殖并调节内皮细胞,增加ET-1并降低ET受体B。
这些数据描述了一种小鼠模型,其展现了人类重度PAH的最重要特征。我们认为炎症,特别是调节ET信号传导的IL-6,在形成丛状病变中起关键作用。因此,该模型是可靠的,可用于更好地理解重度PAH的进展和治疗。