TNF-α/IL-6通路在辐射旁效应诱导动脉粥样硬化中的作用研究

The radiation-induced bystander effect is the phenomenon which non-irradiated body exhibit damage effects along with irradiated body as a result of signals received from these irradiated body. The study on the irradiated crowd found that the rate of death caused by the disease of cardiovascular system based on AS remarkably increased and the blood vessel of the site without irradiation also showed injury. However, it was unclear whether the radiation-induced bystander effect played a role in the AS induced by radiation and its mechanism. In this study, we will establish the co-culture model of two cells, namely the irradiated macrophage and the smooth muscle cell without irradiation, as well as that of three cells, namely the irradiated macrophage, the endothelial cell and the smooth muscle cell without irradiation, to study the role of TNF-α/IL-6 signal pathway in the radiation-induced bystander effect mediated by the macrophage on the change of smooth muscle cell’s lipid phagocytosis, proliferation and migration. Furthermore, the animal experiment is conducted with ApoE-/- mouse and the radiation-induced bystander effect model is set up to observe the change in the cardiovascular intima change of the experimental group of ApoE-/- mouse. This project is to provide the experimental basis for the radiation protection of radiation workers, the curative effect evaluation of patients with radiotherapy and the choice of new type of prophylactic drug target.  

机体遭受电离辐射作用后，未受照射部位出现与受照射部位相似的损伤，这种现象称为辐射旁效应。对几个受照射人群的研究发现以动脉粥样硬化(atherosclerosis,AS)为基础的心血管系统疾病所致死亡率显著增加，未受照射部位的血管也会有损伤，但是辐射旁效应是否参与辐射诱发的动脉粥样硬化及其作用机制不清。本实验拟建立受照射的巨噬细胞 与未受照射平滑肌细胞两细胞共培养模型以及受照射的巨噬细胞与未受照射的内皮细胞、平滑肌细胞三细胞共培养模型，研究TNF-α/IL-6信号通路在巨噬细胞介导的辐射旁效应对平滑肌 细胞的吞噬脂质、增殖和迁移能力变化中的作用。在此基础上利用ApoE-/-小鼠进行动物实验，建立辐射旁效应模型，观察实验组ApoE-/-小鼠心血管内膜的变化。本课题的研究对于接受 局部照射的辐射工作人员的辐射防护和接受放射治疗患者的疗效评估、以及新型预防药物靶点提供实验依据。

由心血管疾病所致的死亡率成为长期存活的癌症患者除肿瘤以外致死的首要因素 。电离辐射导致的动脉粥样硬化（atherosclerosis，AS）首次报道于1959年。辐射是AS的独立危险因素之一，可与其它因素一起共同作用于动脉血管，加速AS的形成。AS是心血管疾病的基础，辐射所致的AS被认为是辐射导致心血管疾病致死的主要原因，其照射十年后发病率大大提高。肿瘤患者70%接受局部放射治疗。机体遭受电离辐射作用后，未受照射部位出现与受照射部位相似的损伤，这种现象称为辐射旁效应。对几个受照射人群的研究发现以AS为基础的心血管系统疾病所致死亡率显著增加，未受照射部位的血管也会有损伤。本实验建立受照射的巨噬细胞与未受照射原代平滑肌细胞两细胞共培养模型以及受照射的巨噬细胞与未受照射的原代内皮细胞、平滑肌细胞三细胞共培养模型，结果提示受照射巨噬细胞TNF-α表达增加导致共培养的平滑肌细胞 IL-6及MCP-1表达增加，致其增殖增加、迁移能力增强。利用ApoE-/-小鼠进行动物实验，建立辐射旁效应模型，发现实验组ApoE-/-小鼠受2Gy照射后心血管内膜第20周出现动脉粥样硬化。本课题的研究对于接受局部照射的辐射工作人员的辐射防护和接受放射治疗患者的疗效评估、以及新型预防药物靶点提供实验依据。