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  • 顾静,刘润,刘凯,张学燕,李海龙,吴红彦*.放射性心脏“炎性-纤维化”损伤大鼠模型的建立与评估[J].第二军医大学学报,2019,40(10):1069-1077    [点击复制]
  • GU Jing,LIU Run,LIU Kai,ZHANG Xue-yan,LI Hai-long,WU Hong-yan*.Establishment and evaluation of radiation-induced “inflammatory-fibrosis” heart damage model in rats[J].Acad J Sec Mil Med Univ,2019,40(10):1069-1077   [点击复制]
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放射性心脏“炎性-纤维化”损伤大鼠模型的建立与评估
顾静,刘润,刘凯,张学燕,李海龙,吴红彦*
0
(甘肃中医药大学中西医结合学院, 兰州 730000
*通信作者)
摘要:
目的 从炎性-纤维化病理损伤角度出发筛选优化造模条件,构建放射性心脏损伤(RIHD)动物模型。方法 通过X线单次全身照射大鼠获得最大耐受剂量,以该剂量为依据进行心脏局部性单次照射,筛选能引起大鼠心脏显著炎性-纤维化病理损伤的最小X线剂量。以筛选得到的X线剂量进行大鼠心脏局部单次照射,构建RIHD大鼠模型。于照射后1 d、1周、2周、4周、6周取材,检测大鼠心脏病理损伤评分、Masson染色心肌胶原容积分数(CVF)、血浆心肌酶水平、心肌组织炎性因子和纤维化因子的表达,评价动物模型。结果 大鼠全身照射耐受剂量低于16 Gy;大鼠心脏局部照射剂量不低于25 Gy时能引起显著的炎性-纤维化病理损伤,是RIHD大鼠模型的构建条件。以25 Gy心脏局部单次X线照射剂量构建大鼠RIHD模型,照射后大鼠心脏病理损伤评分、心肌CVF增高,血浆肌酸激酶同工酶MB(CK-MB)、心肌肌钙蛋白(cTn)水平增高;心肌组织核因子κB(NF-κB)p65、NF-κB p50和肿瘤坏死因子α(TNF-α)等炎性因子在X线照射后第1天开始出现高表达,并持续至第4周;心肌组织转化生长因子β1(TGF-β1)、Ⅰ型胶原蛋白(ColⅠ)和Ⅲ型胶原蛋白(ColⅢ)等纤维化分子表达呈渐进性升高的趋势,第4周达峰值。结论 采用25 Gy X线心脏局部单次照射可构建稳定的炎性-纤维化RIHD模型。病理观察和CVF能动态反映RIHD模型大鼠早期炎性病理变化和随时间渐进性的纤维化病理进程,炎性因子NF-κB p65、NF-κB p50、TNF-α的早期持续高表达及纤维化因子TGF-β1、ColⅠ、Col Ⅲ的渐进性升高可评价RIHD动物模型的急性炎性损伤和纤维化迟发效应。
关键词:  实验性辐射损伤  放射性心脏损伤  动物疾病模型  炎症反应  纤维化
DOI:10.16781/j.0258-879x.2019.10.1069
投稿时间:2019-01-22修订日期:2019-07-16
基金项目:国家自然科学基金(81660742),中国博士后科学基金(2017M620477),甘肃省中医药管理局科研课题(GZK-2015-43).
Establishment and evaluation of radiation-induced “inflammatory-fibrosis” heart damage model in rats
GU Jing,LIU Run,LIU Kai,ZHANG Xue-yan,LI Hai-long,WU Hong-yan*
(Institute of Integrated Traditional Chinese and Western Medicine, Gansu University of Traditional Chinese Medicine, Lanzhou 730000, Gansu, China
*Corresponding author)
Abstract:
Objective To screen and optimize the modeling condition for radiation-induced heart damage (RIHD) models characterized by inflammatory-fibrosis pathological injury. Methods The rats were irradiated with single whole-body X-ray to screen the maximal tolerated dose. Based on the screened whole-body dose, single local heart irradiation doses were used to screen the minimal X-ray dose which could induce the significant cardiac damage. And the RIHD rat model was established by exposure to the screened dose of X-ray. Tissue samples were harvested 1 day, 1 week, 2 weeks, 4 weeks and 6 weeks after irradiation. The cardiac pathological injury score, collagen volume fraction (CVF) in myocardial tissues by Masson staining, plasma myocardial enzyme level, and the expression of inflammatory and fibrosis factors in myocardial tissues were examined for evaluating the animal model. Results The tolerance dose of whole-body irradiation was lower than 16 Gy for rats. Local irradiation dose at least 25 Gy could induce RIHD in rats. The pathological injury score of myocardial tissues, CVF in myocardial tissues and creatine kinase isoenzyme MB (CK-MB) and cardiac troponin (cTn) in plasma were increased in the RIHD model rats. Inflammatory factors including nuclear factor (NF)-κB p65, NF-κB p50 and tumor necrosis factor α (TNF-α) in myocardial tissues were increased 1 day after irradiation in the RIHD rats and maintained high to the fourth week. The expression levels of fibrotic molecules transforming growth factor β1 (TGF-β1), collagen type Ⅰ (ColⅠ) and ColⅢ in myocardial tissues were increased gradually, and reached the peaks at week 4 after irradiation. Conclusion Stable RIHD rat model can be established by irradiating the precardiac region with 25 Gy X-ray. Pathological observation and CVF can dynamically reflect the early inflammatory changes and the progression of fibrosis in RIHD rats. The sustained high expression of NF-κB p65, NF-κB p50 and TNF-α at early stage and the progressive increases of TGF-β1, ColⅠand ColⅢ can be used to evaluate the acute inflammatory injury and delayed fibrosis in the RIHD inflammatory-fibrosis model.
Key words:  experimental radiation injuries  radiation-induced heart damage  animal disease models  inflammatory reaction  fibrosis