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1895年,德国物理学家伦琴发现X射线后,开启了癌症治疗的新时代。1896年,X射线即被用于癌症治疗,仅1年后便出现了对放疗引起的肠道损伤这种不良反应的报道[1]。放射引起的胃肠道损伤也一直是放疗过程中面临的挑战之一[2]。
肠道充斥在所有的腹腔、腹膜后和盆腔肿瘤的治疗区域中。放射性肠病被定义为在照射骨盆、腹部后出现的一种渐进的局部缺血以及纤维化(促纤维化)进程。临床研究中将放疗期间或放疗后任何进展的新胃肠道综合征定义为胃肠道毒性。胃肠道毒性是一个多因素的问题,不仅仅与电离辐射的方式和剂量有关,还与组织和细胞损伤的内在进程有关。
在科学研究中,放射引起的肠损伤的复杂性,导致放射性肠损伤模型和研究评价指标也多种多样,笔者综述了近年来的放射性肠损伤模型和对放射性肠损伤的评价标准和研究方案,为今后的科学研究提供可靠的参考依据。
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在体外实验中,实验对象较为单一,常用正常的肠道细胞,如人源正常小肠FHs 74 Int细胞、大鼠正常肠上皮IEC-6细胞作为模型。除了正常的肠上皮细胞外,还采用可永生化的人类结肠癌Caco-2细胞,通过在培养皿中构建致密的单层细胞模型来模拟肠道上皮细胞屏障,以观察受照后的影响。
在体内实验中,由于存在照射野、照射源和动物种类的差异,不同的放射性损伤动物模型亦存在差异,表 1对部分放射引起的肠道损伤模型进行了总结。
年龄或体重 模式动物 照射条件 剂量/Gy 剂量率 照射源 照射后取样时间 主要研究内容 存活率或致死率 参考文献 20周龄、体重25g 雌性B6D2F1/J小鼠 全身照射 8.5-10.0 0.4 Gy/min 60Co 1、2、3、7d 炎症 LD50/30=9.65 Gy [3] 10周龄 雄性BALB/C小鼠 全身照射 3-7 1.05 Gy/min 137Cs 1~42 d 炎症与细菌转移 7Gy 照射后存活率为10% [4] 6~8周龄 雄性 C57BL/6小鼠 全身照射 14 0.8 Gy/min 137Cs 1、3.5、7d 肠干细胞 14Gy照射后平均存活 5~6 d [5] 8~10周龄 雄性 C57BL/6小鼠 腹部部照射,暴露骨髓5% 15.69 1.47Gy/min 137Cs 3.5、4.5 d DNA 损伤与细胞凋亡 LD70/30=15.69 Gy [6] 8~10周龄 雄性 C57BL/6小鼠 局部照射,暴露骨髓40% 14 70 cGy/min X射线 4、10 d 肠道功能及肠隐窝细胞的存活情况 肠存率70% [7] 8~10周龄 雄性 C57BL/6小鼠 腹部部照射,暴露骨髓 5% 16 79.5 cGy/min X射线 10 d 存活率 致死剂量为16 Gy,照射寸后10d,无存活 [7] 10~12周龄 雄性 C57BL/6小鼠 全身照射 15 3.8 Gy/min 137Cs 3.5 d 肠隐窝细胞的存活和增殖 无数据 [8] 6~7 、体重 22-25 g 雄性 C57BL/6小鼠 全身照射 8~10 1.35 Gy/min 137Cs 4、6、8、10 d 肠道完整性 LD50/10=9.44 Gy [9] 未提及 雄性C57BL/6小鼠 全身照射 2.0~10.4 236 cGy/min 137Cs 6 h,1、3、5、10、20、25 d 肝脏、血浆标志物 无数据 [10] 6~8周龄 雄性CD2F1小鼠 全身照射 11 0.6 Gy/min 60Co 1、2、4、24 h DNA损伤、细胞凋亡和增殖 无数据 [11] 6~7周龄、体重22~25 g 雄性CD2F1小鼠 全身照射 9 1.35 Gy/min 137Cs 3.5、7、14 d 肠道完整性 LD50/30=9Gy [12] 6~8周龄 雄性CD2F1小鼠 全身照射 11 0.6 Gy/min 60Co 3、13、14、17 d 细菌分类 LD50/30=9.2Gy [13] 12~14周龄 雄性CD2F1小鼠 全身照射 10~12 0.6 Gy/min 60Co 12、24 h,3.5、10、11 d 炎症、凋亡、菌群易位 致死剂量为10.5 Gy,10 Gy照射后存活30% [14] 12~13周龄 雄性ICR小鼠 全身照射 9 458 cGy/min 137Cs 2、5、9 d 凋亡、增殖、肠干细胞特性 致死剂量为9 Gy,照射后20 d,无存活 [15] 6~12周龄 ICR nu/nu小鼠 腹腔中移除肠 30 1.9 Gy/min X射线 13、27 d 溃疡和纤维化 无数据 [16] 未提及 NIH nu/nu 全身照射 10 7 Gy/min 137Cs 3 d 凋亡、增殖和抗氧化 无数据 [17] 体重140~180 g 雄性Wistar大鼠 全身照射 6 0.46 Gy/min 137Cs 2、5 d 肠道完整性 无数据 [18] 8~12周龄、体重200~230 g 雄性Wistar大鼠 全腹照射 20 2.01 Gy/min X射线 14 d 菌群易位 无数据 [19] 体重280~350 g SD大鼠 全腹照射 14 300 cGy/min X射线 1、3、5、7、14 d 炎症 无数据 [20] 体重400~450 g SD大鼠 局部照射,剑突下5 cm×5 cm 15 1.75 Gy/min X射线 3、10、21 d 纤维化、肠干细胞 致死剂量为15 Gy,照射后16 d,无存活 [21] 4.0~6.2年龄、体重4~7 kg 恒河猴 全身照射 6.7~7.4 60 cGy/min 60Co 4、7、12 d 肠上皮紧密连接 无数据 [22] 注:表中,ICR:美国癌症研究所;NIH:美国国立卫生研究院;LD50/30、LD70/30、LD50/10分别表示30 d内半数致死剂量、30 d内70%致死剂量、10 d内半数致死剂量。 表 1 放射引起的肠道损伤动物模型建立方法
Table 1. Establishing methods of radiation-induced intestinal injuries animal model
放射性肠损伤模型及其评价研究进展
Progress on the evaluating and establishing methods of radiation-induced intestinal injuries animal model
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摘要: 辐射诱导的肠损伤是放疗造成的严重不良影响之一,可导致肠道局部缺血、纤维化、溃疡、肠狭窄和下消化道出血等。放疗引起的肠损伤的复杂性导致放射性肠损伤模型和研究评价指标也多种多样。笔者综述了近年来的放射性肠损伤模型及对放射性肠损伤的评价标准和研究方案,为今后的科学研究提供可靠的参考依据。Abstract: Radiation-induced intestinal injuries, a devastating adverse effect of radiation therapy, can lead to local ischemia and fibrosis with the development of ulcers, strictures and lower gastrointestinal bleeding. As the complex causes of radiation-induced intestinal injuries, diverse evaluating methods and animal model had been established. In this context, the present review will focus on the evaluating and establishing methods of radiation-induced intestinal injuries animal model, what would provide ideas for related basic research.
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Key words:
- Intestines /
- Radiation injuries /
- Models,animal /
- Evaluation studies
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表 1 放射引起的肠道损伤动物模型建立方法
Table 1. Establishing methods of radiation-induced intestinal injuries animal model
年龄或体重 模式动物 照射条件 剂量/Gy 剂量率 照射源 照射后取样时间 主要研究内容 存活率或致死率 参考文献 20周龄、体重25g 雌性B6D2F1/J小鼠 全身照射 8.5-10.0 0.4 Gy/min 60Co 1、2、3、7d 炎症 LD50/30=9.65 Gy [3] 10周龄 雄性BALB/C小鼠 全身照射 3-7 1.05 Gy/min 137Cs 1~42 d 炎症与细菌转移 7Gy 照射后存活率为10% [4] 6~8周龄 雄性 C57BL/6小鼠 全身照射 14 0.8 Gy/min 137Cs 1、3.5、7d 肠干细胞 14Gy照射后平均存活 5~6 d [5] 8~10周龄 雄性 C57BL/6小鼠 腹部部照射,暴露骨髓5% 15.69 1.47Gy/min 137Cs 3.5、4.5 d DNA 损伤与细胞凋亡 LD70/30=15.69 Gy [6] 8~10周龄 雄性 C57BL/6小鼠 局部照射,暴露骨髓40% 14 70 cGy/min X射线 4、10 d 肠道功能及肠隐窝细胞的存活情况 肠存率70% [7] 8~10周龄 雄性 C57BL/6小鼠 腹部部照射,暴露骨髓 5% 16 79.5 cGy/min X射线 10 d 存活率 致死剂量为16 Gy,照射寸后10d,无存活 [7] 10~12周龄 雄性 C57BL/6小鼠 全身照射 15 3.8 Gy/min 137Cs 3.5 d 肠隐窝细胞的存活和增殖 无数据 [8] 6~7 、体重 22-25 g 雄性 C57BL/6小鼠 全身照射 8~10 1.35 Gy/min 137Cs 4、6、8、10 d 肠道完整性 LD50/10=9.44 Gy [9] 未提及 雄性C57BL/6小鼠 全身照射 2.0~10.4 236 cGy/min 137Cs 6 h,1、3、5、10、20、25 d 肝脏、血浆标志物 无数据 [10] 6~8周龄 雄性CD2F1小鼠 全身照射 11 0.6 Gy/min 60Co 1、2、4、24 h DNA损伤、细胞凋亡和增殖 无数据 [11] 6~7周龄、体重22~25 g 雄性CD2F1小鼠 全身照射 9 1.35 Gy/min 137Cs 3.5、7、14 d 肠道完整性 LD50/30=9Gy [12] 6~8周龄 雄性CD2F1小鼠 全身照射 11 0.6 Gy/min 60Co 3、13、14、17 d 细菌分类 LD50/30=9.2Gy [13] 12~14周龄 雄性CD2F1小鼠 全身照射 10~12 0.6 Gy/min 60Co 12、24 h,3.5、10、11 d 炎症、凋亡、菌群易位 致死剂量为10.5 Gy,10 Gy照射后存活30% [14] 12~13周龄 雄性ICR小鼠 全身照射 9 458 cGy/min 137Cs 2、5、9 d 凋亡、增殖、肠干细胞特性 致死剂量为9 Gy,照射后20 d,无存活 [15] 6~12周龄 ICR nu/nu小鼠 腹腔中移除肠 30 1.9 Gy/min X射线 13、27 d 溃疡和纤维化 无数据 [16] 未提及 NIH nu/nu 全身照射 10 7 Gy/min 137Cs 3 d 凋亡、增殖和抗氧化 无数据 [17] 体重140~180 g 雄性Wistar大鼠 全身照射 6 0.46 Gy/min 137Cs 2、5 d 肠道完整性 无数据 [18] 8~12周龄、体重200~230 g 雄性Wistar大鼠 全腹照射 20 2.01 Gy/min X射线 14 d 菌群易位 无数据 [19] 体重280~350 g SD大鼠 全腹照射 14 300 cGy/min X射线 1、3、5、7、14 d 炎症 无数据 [20] 体重400~450 g SD大鼠 局部照射,剑突下5 cm×5 cm 15 1.75 Gy/min X射线 3、10、21 d 纤维化、肠干细胞 致死剂量为15 Gy,照射后16 d,无存活 [21] 4.0~6.2年龄、体重4~7 kg 恒河猴 全身照射 6.7~7.4 60 cGy/min 60Co 4、7、12 d 肠上皮紧密连接 无数据 [22] 注:表中,ICR:美国癌症研究所;NIH:美国国立卫生研究院;LD50/30、LD70/30、LD50/10分别表示30 d内半数致死剂量、30 d内70%致死剂量、10 d内半数致死剂量。 -
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