[1]胡蝶,杨陟华,王易龙,等.TGF-β3通过抑制上皮间质转化拮抗放射性肺纤维化[J].国际放射医学核医学杂志,2018,(2):129-134.[doi:10.3760/cma.j.issn.1673-4114.2018.02.006]
　Hu Die,Yang Zhihua,Wang Yilong,et al.TGF-β3-ameliorated radiation-induced pulmonary fibrosis by inhibiting epithelial-mesenchymal transition[J].International Journal of Radiation Medicine and Nuclear Medicine,2018,(2):129-134.[doi:10.3760/cma.j.issn.1673-4114.2018.02.006]
点击复制

TGF-β3通过抑制上皮间质转化拮抗放射性肺纤维化(/HTML)
分享到：

《国际放射医学核医学杂志》[ISSN:1673-4114/CN:12-1381/R]

卷:
期数:
2018年第2期
页码:
129-134
栏目:
基础研究
出版日期:
2018-05-09

文章信息/Info

Title:
TGF-β3-ameliorated radiation-induced pulmonary fibrosis by inhibiting epithelial-mesenchymal transition
作者:
胡蝶1; 2;  杨陟华2;  王易龙2;  罗祥智1;  潘秀颉2;  姚振江1;  徐龙2;  顾永清2;  朱茂祥2
1. 510006 广州, 广东药科大学公共卫生学院;
2. 100850 北京, 军事科学院军事医学研究院辐射医学研究所
Author(s):
Hu Die1; 2;  Yang Zhihua2;  Wang Yilong2;  Luo Xiangzhi1;  Pan Xiujie2;  Yao Zhenjiang1;  Xu Long2;  Gu Yongqing2;  Zhu Maoxiang2
1. School Public Health, Guang Dong Pharmaceutical University, Guangzhou 510006, China;
2. Institute of Radiation Medicine, Academy of Military Medical Sciences, Academy of Military Sciences, Beijing 100850, China
关键词:
特发性肺纤维化; 辐射损伤; 实验性; 转化生长因子β3; 上皮间质转化
Keywords:
Idiopathic pulmonary fibrosis; Radiation injuries;  experimental; Transforming growth factor beta 3; Epithelial mesenchymal transition
DOI:
10.3760/cma.j.issn.1673-4114.2018.02.006
摘要:
目的 检测分析放射性肺纤维化过程中上皮间质转化（EMT）情况，探索转化生长因子β3（TGF-β3）是否通过EMT途径抑制放射性肺纤维化的发生。方法 将180只C57BL/6雌性小鼠按体重完全随机分为对照组、单纯照射组（简称照射组）和照射+TGF-β3组（简称TGF-β3组），照射组和TGF-β3组经20 Gy 60Co γ射线单次胸部照射后，分别腹腔注射0.5 mL 0.9%的生理盐水和TGF-β3（1 μg/kg），每周1次，于照射后1、3和6个月活杀，用苏木素-伊红（HE）染色、Masson三色染色后观察肺组织病理学改变，用免疫组化法检测肺组织EMT相关的上皮标志物紧密连接蛋白（ZO-1）和间质标志物N-钙粘蛋白（N-cadherin）的表达，用Mann-Whitney U秩和检验和Fisher确切概率法对结果进行统计分析。结果 HE和Masson染色结果显示，照射能够引起小鼠肺泡壁增厚、肺泡间隔明显增宽、肺泡结构严重破坏、胶原纤维大量沉积等典型纤维化病理改变；照射后3和6个月，与照射组比较，TGF-β3组小鼠肺纤维化病变明显减轻，差异有统计学意义（Z=-2.562、-2.807，均P<0.05），胶原沉积显著减少，差异有统计学意义（Z=2.442、2.529，均P<0.05）。免疫组化结果显示，与对照组比较，照射后1、3和6个月，小鼠肺组织ZO-1的表达量明显减少，差异有统计学意义（Z=4.492、5.831、6.064，均P<0.05），N-cadherin的表达量显著增高，差异有统计学意义（Z=-3.269、-5.520、-6.063，均P<0.05）；与照射组比较，TGF-β3组ZO-1表达量显著增高，差异有统计学意义（Z=-2.881、-4.220、-5.695，均P<0.05），而N-cadherin表达量显著减少，差异有统计学意义（Z=4.546、3.560、4.919，均P<0.05）。结论 TGF-β3可通过抑制EMT拮抗放射性肺纤维化。
Abstract:
Objective To detect and analyze the influence of epithelial-mesenchymal transition (EMT) on radiation-induced pulmonary fibrosis and explore whether the anti-fibrosis effect of transforming growth factor-β3 (TGF-β3) is mediated by EMT. Methods C57BL/6 female mice were randomly divided into three groups:control group, irradiation group only (irradiated group), and irradiation and TGF-β3 group (TGF-β3 group). The irradiation group received intraperitoneal injections of 0.5 ml saline, and the TGF-β3 group received intraperitoneal injections of 1 μg/kg human recombinant TGF-β3 every week after single dose of 20 Gy irradiation to their thoraxes. The mice in each group were sacrificed for 1, 3, and 6 months after irradiation. The mouse lung pathological changes were evaluated by hematoxylin-eosin and Masson trichrome. The expression of EMT epithelium-marked protein zonula occludens-1(ZO-1) and interstitial-marked protei N-cadherin were measured by immunohistochemistry. The results were analyzed using Mann-Whitney U test and Fisher’s exact probability. Results Alveolar walls thickened, collagen fibers were deposited, and other typical fibrosis changed after irradiation. Unlike those in the irradiation group, pulmonary fibrosis lesions were significantly reduced (Z=-2.562, -2.807, both P<0.05) and collagen deposition was obviously decreased (Z=2.442, 2.529, both P<0.05) in the TGF-β3 group. The expression of ZO-1 was markedly decreased (Z=4.492, 5.831, 6.064, all P<0.05) and the expression of N-cadherin was significantly increased (Z=-3.269, -5.520, -6.063, all P<0.05) in the lung tissues of mice at 1, 3, and 6 months after irradiation. Unlike the irradiation group, the expression of ZO-1 was increased (Z=-2.881, -4.220, -5.695, all P<0.05) and the expression of N-cadherin was decreased (Z=4.546, 3.560, 4.919, all P<0.05) in the TGF-β3 group. The differences were significant. Conclusion TGF-β3 may antagonize radiation-induced pulmonary fibrosis by inhibiting EMT.

参考文献/References:

[1] Straub JM, New J, Hamilton CD, et al. Radiation-induced fibrosis:mechanisms and implications for therapy[J]. J Cancer Res Clin Oncol, 2015, 141(11):1985-1994. DOI:10.1007/s00432-015-1974-6.
[2] 郑啓盛, 刘培勋. 放射性肺纤维化的分子机制及其防治药物综述[J]. 辐射研究与辐射工艺学报, 2016, 34(1):1-10. DOI:10.11889/j.1000-3436.2016.rrj.34.010101. Zheng QS, Liu PX. Review on molecular mechanisms and protective drugs research on radiation-induced lung fibrosis[J]. J Radiat Res Radiat Process, 2016, 34(1):1-10.
[3] 朱玉凤. 肺纤维化细胞因子机制研究进展[J]. 当代医药论丛, 2015, 13(5):157-157, 158. Zhu YF. Progress of cytokine mechanism in pulmonary fibrosis[J]. Contemporary Med Forum, 2015, 13(5):157-157, 158.
[4] 王司仪, 原铭贞, 刘笑玎, 等. 细胞因子与肺纤维化相关性的研究进展[J]. 吉林大学学报(医学版), 2014, 40(6):1325-1329. DOI:10.13481/j.1671-587x.20140641. Wang SY, Yuan MZ, Liu XD, et al. Advance research on relationship between cytokines and pulmonary fibrosis[J]. J Jilin Univ Med Edit, 2014, 40(6):1325-1329.
[5] Leask A, Abraham DJ. TGF-beta signaling and the fibrotic response[J]. FASEB J, 2004, 18(7):816-827. DOI:10.1096/fj.03-1273rev.
[6] Hall BE, Wankhade UD, Konkel JE, et al. Transforming growth factor-β3(TGF-β3) knock-in ameliorates inflammation due to TGF-β1 deficiency while promoting glucose tolerance[J]. J Biol Chem, 2013, 288(44):32074-32092. DOI:10.1074/jbc.M113. 480764.
[7] Ask K, Bonniaud P, Maass K, et al. Progressive pulmonary fibrosis is mediated by TGF-β isoform 1 but not TGF-β3[J]. Int J Biochem Cell Biol, 2008, 40(3):484-495. DOI:10.1016/j.biocel.2007. 08. 016.
[8] Xu L, Xiong S, Guo R, et al. Transforming growth factor β3 attenuates the development of radiation-induced pulmonary fibrosis in mice by decreasing fibrocyte recruitment and regulating IFN-γ/IL-4 balance[J]. Immunol Lett, 2014, 162(1 Pt A):27-33. DOI:10.1016/j.imlet.2014.06.010.
[9] Horowitz JC, Thannickal VJ. Epithelial-mesenchymal interactions in pulmonary fibrosis[J]. Semin Respir Crit Care Med, 2006, 27(6):600-612. DOI:10.1055/s-2006-957332.
[10] 杜雪梅, 柳晓兰, 崔玉芳, 等. 放射性肺损伤小鼠动物模型的建立及其病变规律[J]. 中国体视学与图像分析, 2003, 8(4):203-206. DOI:10.3969/j.issn.1007-1482.2003.04.003. Du XM, Liu XL, Cui YF, et al. ESTABLISHMENT OF IRRADIA-TION-INDUCED LUNG INJURY MOUSE MODEL AND ITS PATHOLOGICAL CHANGES REGULARITY[J]. CHIN J STERE-OL IMAGE ANALYSIS, 2003, 8(4):203-206.
[11] 杨燕光, 王金云, 张珏, 等. 局部晚期非小细胞肺癌调强放疗与三维适形放疗的剂量学及临床疗效分析[J]. 中国肿瘤, 2014, 23(10):873-877. DOI:10.11735/j.issn.1004-0242.2014.10.A017. Yang YG, Wang JY, Zhang J, et al. An Analysis of Dosimetric and Clinical Effect of Intensity Modulated Radiotherapy and Three-dimensional Conformal Radiotherapy for Locally Advanced Non-small Cell Lung Cancer[J]. China Cancer, 2014, 23(10):873-877.
[12] Xiong SS, Guo RF, Yang ZH, et al. Regulatory T Cells Promote β-Catenin-Mediated Epithelium-to-Mesenchyme Transition During Radiation-Induced Pulmonary Fibrosis[J]. Int J Radiat Oncol Biol Phys, 2015, 93(2):425-435. DOI:10.1016/j.ijrobp.2015.05.043.
[13] 陈忠杰, 王莉, 方银善, 等. 放射线剂量和剂量率对小鼠肺纤维化的影响[J]. 中华结核和呼吸杂志, 2016, 39(2):117-121. DOI:10.3760/cma.j.issn.1001-0939.2016.02.010. Chen ZJ, Wang L, Fang YS, et al. Effect of radiation dose and dose rate on pulmonary fibrosis in mice[J]. Chin J Tubere Respir Dis, 2016, 39(2):117-121.
[14] 赵利强. 沙百润肺颗粒干预大鼠放射性肺纤维化的实验研究[D]. 太原:山西省中医药研究院, 2016:1-46. Zhao LQ. The experimental study of Shabai Moistening Lung particles intervening in radiation-induced pulmonary fibrosis in rats[D]. Taiyuan:Shanxi Traditional Chinese Medicine Institute, 2016:1-46.
[15] Reilkoff RA, Bucala R, Herzog EL. Fibrocytes:emerging effector cells in chronic inflammation[J]. Nat Rev Immunol, 2011, 11(6):427-435. DOI:10.1038/nri2990.
[16] 熊珊珊. 调节性T淋巴细胞在放射性肺纤维化中的作用及机制研究[D]. 北京:军事医学科学院, 2015:1-135. Xiong SS. The roles and mechanisms of Regulatory T cells (Tregs) in radiation-induced pulmonary fibrosis[D]. Beijing:Academy of Military Medical Sciences, 2015:1-135.
[17] Hay ED. The mesenchymal cell, its role in the embryo, and the remarkable signaling mechanisms that create it[J]. Dev Dyn, 2005, 233(3):706-720. DOI:10.1002/dvdy.20345.
[18] 徐龙. 转化生长因子-β3调控循环纤维细胞在放射性肺纤维化中的作用研究[D]. 北京:军事医学科学院, 2015:1-101. Xu L. Study on the role of transforming growth factor-β3 by regulating fibrocytes in radiation-induced pulmonary fibrosis[D]. Beijing:Academy of Military Medical Sciences, 2015:1-101.

相似文献/References:

[1]包明月,刘玉龙.应用间充质干细胞治疗急性辐射损伤的研究现状与进展[J].国际放射医学核医学杂志,2016,40(1):65.[doi:10.3760/cma.j.issn.1673-4114.2016.01.013]
　Bao Mingyue,Liu Yulong.Recent advances in the application of mesenchymal stem cells for treatment of acute radiation injury[J].International Journal of Radiation Medicine and Nuclear Medicine,2016,40(2):65.[doi:10.3760/cma.j.issn.1673-4114.2016.01.013]
[2]贺欣,储小飞,罗丹,等.穿心莲药物对辐射损伤效应影响的初步研究[J].国际放射医学核医学杂志,2015,39(5):375.[doi:10. 3760 / cma. j. issn. 1673-4114. 2015. 05. 005]
　he xin,chu xiaofei,luo dan,et al.exploration of andrographolide effects on radiation injury[J].International Journal of Radiation Medicine and Nuclear Medicine,2015,39(2):375.[doi:10. 3760 / cma. j. issn. 1673-4114. 2015. 05. 005]
[3]路璐,张俊伶,李德冠,等.6 gy 137cs γ射线照射对小鼠造血功能损伤的动态观察研究[J].国际放射医学核医学杂志,2015,39(5):393.[doi:10. 3760 / cma. j. issn. 1673-4114. 2015. 05. 009]
　lu lu*,zhang junling,li deguan,et al.effects of 6 gy 137cs γ-irradiattion on the hematopoietic system of mice[J].International Journal of Radiation Medicine and Nuclear Medicine,2015,39(2):393.[doi:10. 3760 / cma. j. issn. 1673-4114. 2015. 05. 009]
[4]刘惠惠,李险峰.放射性心脏损伤诊断和防治的临床研究进展[J].国际放射医学核医学杂志,2016,40(5):374.[doi:10.3760/cma.j.issn.1673-4114.2016.05.008]
　Liu Huihui,Li Xianfeng.Clinical research progress in diagnosis,prevention and treatment of radiation-induced heart disease[J].International Journal of Radiation Medicine and Nuclear Medicine,2016,40(2):374.[doi:10.3760/cma.j.issn.1673-4114.2016.05.008]
[5]张倩如,李海涛,田红旗.小分子辐射防护药物的研究进展[J].国际放射医学核医学杂志,2016,40(5):394.[doi:10.3760/cma.j.issn.1673-4114.2016.05.012]
　Zhang Qianru,Li Haitao,Tian Hongqi.Small molecule compounds against radiation:research advances[J].International Journal of Radiation Medicine and Nuclear Medicine,2016,40(2):394.[doi:10.3760/cma.j.issn.1673-4114.2016.05.012]
[6]张莹莹,王振光,武凤玉,等.特发性肺间质纤维化HRCT病变区与非病变区18F-FDG PET/CT表现分析[J].国际放射医学核医学杂志,2016,40(6):414.[doi:10.3760/cma.j.issn.1673-4114.2016.06.003]
　Zhang Yingying,Wang Zhenguang,Wu Fengyu,et al.18F-FDG PET/CT imaging analysis of regions with abnormal and normal pulmonary parenchyma on high resolution CT in idiopathic pulmonary fibrosis patients[J].International Journal of Radiation Medicine and Nuclear Medicine,2016,40(2):414.[doi:10.3760/cma.j.issn.1673-4114.2016.06.003]
[7]王浩,沈秀,靳瑾,等.“四物汤”对辐射危害的辅助保护作用研究[J].国际放射医学核医学杂志,2015,39(2):121.[doi:10.3760/cma.j.issn.1673-4114.2015.02.004]
　Wang Hao,Shen Xiu,Jin Jin,et al.Protective activity of Siwu Decoction against radiation hazards[J].International Journal of Radiation Medicine and Nuclear Medicine,2015,39(2):121.[doi:10.3760/cma.j.issn.1673-4114.2015.02.004]
[8]曹婉婷,李浣洋,陈雪英,等.正常组织在放射治疗中并发的迟发性损伤[J].国际放射医学核医学杂志,2015,39(3):260.[doi:10.3760/cma.j.issn.1673-4114.2015.03.016]
　Cao Wanting,Li Huanyang,Chen Xueying,et al.Late effects of radiotherapy on normal tissue[J].International Journal of Radiation Medicine and Nuclear Medicine,2015,39(2):260.[doi:10.3760/cma.j.issn.1673-4114.2015.03.016]
[9]陈雪梅,周树云,范源,等.表没食子儿茶素没食子酸酯对131I辐射损伤所致甲减大鼠模型抗氧化体系的保护作用[J].国际放射医学核医学杂志,2015,39(4):311.[doi:10.3760/cma.j.issn.1673-4114.2015.04.009]
　Chen Xuemei,Zhou Shuyun,Fan Yuan,et al.Protection of antioxidant system of EGCG on the thyroid in rat model from 131I radiation damage[J].International Journal of Radiation Medicine and Nuclear Medicine,2015,39(2):311.[doi:10.3760/cma.j.issn.1673-4114.2015.04.009]
[10]李德冠,路璐,吴红英,等.G-CSF联合SB203580对4Gy照射小鼠免疫系统的作用[J].国际放射医学核医学杂志,2014,38(4):216.[doi:10.3760/cma.j.issn.1673-4114.2014.04.002]
　Li Deguan,Lu Lu,Wu Hongying,et al.The effects of G-CSF combined with SB203580 on the immune system of mice received 4 Gy total body irradiation[J].International Journal of Radiation Medicine and Nuclear Medicine,2014,38(2):216.[doi:10.3760/cma.j.issn.1673-4114.2014.04.002]

备注/Memo

备注/Memo:
收稿日期:2018-01-12。
基金项目:国家自然科学基金（81472910）
通讯作者:朱茂祥,Email:zhumx@nic.bmi.ac.cn
更新日期/Last Update: 2018-05-09