Recombinant Human Interferon Alpha 2b Prevents and Reverses Experimental Pulmonary Hypertension
Recombinant Human Interferon Alpha 2b Prevents and Reverses Experimental Pulmonary Hypertension
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DOI：
10.1371/journal.pone.0096720
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发表时间：
2014-05-16
期刊：
影响因子：
3.7
通讯作者：
Bauer, Philip M.
中科院分区：
文献类型：
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作者：
Bauer, Eileen M.;Zheng, Han;Bauer, Philip M.
肺动脉高压（PH）是一种进行性、致命性的疾病，无法治愈。 PH 中的血管重塑涉及内皮细胞和平滑肌细胞的管腔内生长，导致闭塞性血管病变。这些病变中的细胞生长是准肿瘤性的，有单克隆性、细胞凋亡抗性和癌症样代谢紊乱的证据。在此，我们在大鼠 SU5416/缺氧 (SUH) 模型和小鼠缺氧模型中测试了多效细胞因子和抗癌治疗剂人干扰素 α 2b (IFN α) 对 PH 发生和进展的影响。在这两种模型中，通过测量右心室收缩压和右心室肥厚评估，IFN α 均减弱了 PH 的发展并逆转了已建立的 PH。 IFN α 的作用取决于 I 型干扰素受体 (IFNAR)，因为缺乏 IFNAR 亚基的小鼠不受 IFN α 的保护。对缺氧小鼠或 SUH 大鼠肺小动脉的形态计量学分析表明，IFN α 抑制两种模型中的肺血管重塑，并且 IFN α 逆转已患有疾病的 SUH 大鼠中的肺血管重塑。免疫组织化学染色显示，IFN α 减少了肺小动脉壁中 PCNA 和 Tunel 阳性细胞的数量。在体外，IFNα抑制人肺动脉平滑肌细胞的增殖以及人肺动脉内皮细胞的增殖和凋亡。这些发现共同表明，IFN α 可逆转已建立的实验性 PH，并为进一步探索 IFN α 和其他免疫疗法在 PH 中的应用提供了理论依据。
Pulmonary hypertension (PH) is a progressive and fatal disease with no cure. Vascular remodeling in PH involves intraluminal growth of endothelial and smooth muscle cells, leading to obliterative vascular lesions. Cell growth in these lesions is quasi-neoplastic, with evidence of monoclonality, apoptosis resistance and cancer-like metabolic derangements. Herein we tested the effect of human interferon alpha 2b (IFN alpha), a pleiotropic cytokine and anti-cancer therapeutic, on the development and progression of PH in the rat SU5416/hypoxia (SUH) model and mouse hypoxia model of the disease. In both models IFN alpha attenuated the development of PH and reversed established PH as assessed by measuring right ventricular systolic pressure and right ventricular hypertrophy. The effect of IFN alpha was dependent on the type I interferon receptor (IFNAR) since mice lacking a subunit of the IFNAR were not protected by IFN alpha. Morphometric analysis of pulmonary aterioles from hypoxic mice or SUH rats showed that IFN alpha inhibited pulmonary vascular remodeling in both models and that IFN alpha reversed remodeling in SUH rats with established disease. Immunohistochemical staining revealed that IFN alpha decreased the number of PCNA and Tunel positive cells in the wall of pulmonary arterioles. In vitro, IFN alpha inhibited proliferation of human pulmonary artery smooth muscle cells and as well as human pulmonary artery endothelial cell proliferation and apoptosis. Together these findings demonstrate that IFN alpha reverses established experimental PH and provide a rationale for further exploration of the use of IFN alpha and other immunotherpies in PH.