Pristane/Hypoxia (PriHx) Mouse as a Novel Model of Pulmonary Hypertension Reflecting Inflammation and Fibrosis
Pristane/Hypoxia (PriHx) Mouse as a Novel Model of Pulmonary Hypertension Reflecting Inflammation and Fibrosis
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DOI：
10.1253/circj.cj-19-1102
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发表时间：
2020-07-01
影响因子：
3.3
通讯作者：
Nakaoka, Yoshikazu
中科院分区：
文献类型：
--
作者：
Mori, Hiroyoshi;Ishibashi, Tomohiko;Nakaoka, Yoshikazu
背景：肺动脉高压(PAH)，尤其是结缔组织病相关的PAH(CTD-PAH)是一种进展性疾病，需要基于特定分子发病机制的新的治疗药物。炎症、免疫细胞异常和纤维化在CTD-PAH的发病机制中起重要作用。然而，现有的小鼠肺动脉高压(PH)模型不能充分反映这些特征。炎症与缺氧之间的关系尚不清楚。方法与结果：将昆明种矿物油Pristane与慢性缺氧相结合，建立了Pristane/Hx(Pristane/Hx)小鼠模型。血流动力学和组织学分析显示，PriHx小鼠表现出比Pristane或单纯缺氧更严重的PH表型。免疫组织化学和流式细胞术分析显示，PriHx小鼠的肺内有免疫细胞的渗透，包括含铁血黄素的巨噬细胞和活化的CD4(+)辅助T淋巴细胞。泼斯坦治疗可加重肺纤维化，并上调纤维化相关基因的表达。PriHx小鼠肺组织中炎症相关基因II6和Cxcl2表达上调，抗IL-6受体单抗MR16-1阻断IL-6改善了PriHx小鼠的PH。结论：PriHx小鼠模型是一种新的反映CTD-PAH病理特征的PH小鼠模型。
Background: Pulmonary arterial hypertension (PAH), particularly connective tissue disease-associated PAH (CTD-PAH), is a progressive disease and novel therapeutic agents based on the specific molecular pathogenesis are desired. In the pathogenesis of CTD-PAH, inflammation, immune cell abnormality, and fibrosis play important roles. However, the existing mouse pulmonary hypertension (PH) models do not reflect these features enough. The relationship between inflammation and hypoxia is still unclear.Methods and Results: Intraperitoneal administration of pristane, a kind of mineral oil, and exposure to chronic hypoxia were combined, and this model is referred to as pristane/hypoxia (PriHx) mice. Hemodynamic and histological analyses showed that the PriHx mice showed a more severe phenotype of PH than pristane or hypoxia alone. Immunohistological and flow cytometric analyses revealed infiltration of immune cells, including hemosiderin-laden macrophages and activated CD4(+) helper T lymphocytes in the lungs of PriHx mice. Pristane administration exacerbated lung fibrosis and elevated the expression of fibrosis-related genes. Inflammation-related genes such as II6 and Cxcl2 were also upregulated in the lungs of PriHx mice, and interleukin (IL)-6 blockade by monoclonal anti-IL-6 receptor antibody MR16-1 ameliorated PH of PriHx mice.Conclusions: A PriHx model, a novel mouse model of PH reflecting the pathological features of CTD-PAH, was developed through a combination of pristane administration and exposure to chronic hypoxia.