A Hypoxia-Induced Vascular Endothelial-to-Mesenchymal Transition in Development of Radiation-Induced Pulmonary Fibrosis
A Hypoxia-Induced Vascular Endothelial-to-Mesenchymal Transition in Development of Radiation-Induced Pulmonary Fibrosis
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DOI：
10.1158/1078-0432.ccr-14-3193
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发表时间：
2015-08-15
影响因子：
11.5
通讯作者：
Lee, Yoon-Jin
中科院分区：
文献类型：
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作者：
Choi, Seo-Hyun;Hong, Zhen-Yu;Lee, Yoon-Jin
目的：放射性肺纤维化（RIPF）是胸部放疗的一种迟发性副作用。我们研究的目的是为了进一步了解RIPF.Experimental Design/Results的发展：在这里，我们观察到，照射小鼠肺诱导胶原沉积，特别是血管周围，在早期阶段的RIPF。这种沉积随后在整个受照射的组织中变得明显。伴随着胶原沉积，血管EndMT（内皮-间充质转化）在RIPF的早期阶段开始发展，在实质性纤维化阶段肺泡上皮（AE）II细胞的EMT（上皮-间充质转化）出现之前。伴随EndMT，我们检测到血管内皮细胞（EC）特异性缺氧损伤的照射肺组织。在人肺动脉内皮细胞（HPAEC）中，通过激活TGF b-R1/Smad信号传导的辐射诱导的EndMT依赖于HIF 1 α表达。一种新的HIF 1 α抑制剂，2-甲氧基乙烯（2-ME），通过下调HIF 1 α依赖的Smad信号抑制辐射诱导的EndMT。在体内，2-ME抑制血管EndMT，并减少与RIPF相关的胶原沉积。此外，HIF 1 α相关的EndMT也观察到在人类RIPF tissues.Conclusions：我们提供的第一个证据表明，EndMT发生在RIPF的发展和EndMT可以有效地抑制通过调节血管EC特异性缺氧损伤。（C）2015年AACR。
Purpose: Radiation-induced pulmonary fibrosis (RIPF) is a late side effect of thoracic radiotherapy. The purpose of our study was to gain further insight into the development of RIPF.Experimental Design/Results: Here, we observed that irradiation of mouse lungs induced collagen deposition, particularly around blood vessels, in the early phase of RIPF. Such deposition subsequently became evident throughout the irradiated tissues. Accompanied by the collagen deposition, vascular EndMT (endo-thelial-to-mesenchymal transition) began to develop in the early phase of RIPF, before the appearance of EMT (epithelial-to-mesenchymal transition) of alveolar epithelial (AE) II cells in the substantive fibrotic phase. Concomitant with the EndMT, we detected vascular endothelial cell (EC)-specific hypoxic damage in the irradiated lung tissues. In human pulmonary artery endothelial cells (HPAEC), the radiation-induced EndMT via activation of TGFb-R1/Smad signaling was dependent on HIF1 alpha expression. A novel HIF1 alpha inhibitor, 2-methoxyestradiol (2-ME), inhibited the irradiation-induced EndMT via downregulation of HIF1 alpha-dependent Smad signaling. In vivo, 2-ME inhibited the vascular EndMT, and decreased the collagen deposition associated with RIPF. Furthermore, HIF1 alpha-related EndMT was observed also in human RIPF tissues.Conclusions: We provide the first evidence that an EndMT occurs in RIPF development and that the EndMT may be effectively inhibited by modulating vascular EC-specific hypoxic damage. (C)2015 AACR.