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中华损伤与修复杂志(电子版) ›› 2020, Vol. 15 ›› Issue (06) : 454 -464. doi: 10.3877/cma.j.issn.1673-9450.2020.06.006

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论著

新型高频方波电脉冲对大鼠肝癌消融治疗的影响
张冲1, 周丁华2,(), 刘智伟2, 王进2, 吕伟2, 程宇2   
  1. 1. 215006 苏州,苏州大学第六附属医院研究生培养基地
    2. 100088 北京,解放军火箭军特色医学中心肝胆外科
  • 收稿日期:2020-10-25 出版日期:2020-12-01
  • 通信作者: 周丁华
  • 基金资助:
    国家"十三五"重点研发计划(2017YFC0110401)

Influence of new high frequency square wave electric pulse in the ablation treament of liver cancer in rats

Chong Zhang1, Dinghua Zhou2,(), Zhiwei Liu2, Jin Wang2, Wei Lyu2, Yu Cheng2   

  1. 1. Postgraduate Training Base of Sixth Affiliated Hospital of Suzhou University, Suzhou 215006, China
    2. Department of Hepatobiliary Surgery, Rockets Force Characteristic Medical Center of PLA, Beijing 100088, China
  • Received:2020-10-25 Published:2020-12-01
  • Corresponding author: Dinghua Zhou
  • About author:
    Correspongding author: Zhou Dinghua, Email:
引用本文:

张冲, 周丁华, 刘智伟, 王进, 吕伟, 程宇. 新型高频方波电脉冲对大鼠肝癌消融治疗的影响[J]. 中华损伤与修复杂志(电子版), 2020, 15(06): 454-464.

Chong Zhang, Dinghua Zhou, Zhiwei Liu, Jin Wang, Wei Lyu, Yu Cheng. Influence of new high frequency square wave electric pulse in the ablation treament of liver cancer in rats[J]. Chinese Journal of Injury Repair and Wound Healing(Electronic Edition), 2020, 15(06): 454-464.

目的

探讨新型高频方波电脉冲对大鼠肝癌消融治疗的影响。

方法

肝癌McA-RH7777细胞体外培养制备肿瘤细胞悬液,清洁级SD大鼠50只经肝内注射法建立肝癌模型。建模后1周,随机选取40只肝癌模型大鼠,按照简单抽样方法分为实验组(n=26)和对照组(n=14)。实验组大鼠肝脏肿瘤在2 000 V/cm场强下接受电脉冲处理,对照组脉冲场强为0,频率均为1 Hz,脉宽为100 μs。2组大鼠术前3、1 d及术后1、7、14、21、30 d分别尾静脉采血,全自动生化分析仪监测血清生化指标[谷丙转氨酶(ALT)、谷草转氨酶(AST)、肌酐、血尿素氮、肌酸激酶(CK)、乳酸脱氢酶(LDH)]及肿瘤标志物甲胎蛋白(AFP)水平变化;分别记录2组大鼠术前1 d,术后7、14、21 d肿瘤长径变化和术后60 d生存时间改变,记录治疗过程中相关性并发症情况;术后30 d分别随机处死实验组和对照组各2只大鼠,检测2组大鼠消融靶区肿瘤组织蛋白质印迹法检测半胱氨酸天冬氨酸蛋白酶-3(Caspase-3)、B细胞淋巴瘤-2原癌基因(Bcl-2)及Bcl-2相关X蛋白(Bax)表达水平;术后30 d,切取2组肿瘤消融区域组织分别行苏木精-伊红染色、血管内皮生长因子(VEGF)免疫组织化学染色观察组织形态学改变,行KI67免疫组织化学染色、TUNEL染色分别计算肿瘤细胞增殖率及细胞凋亡率。对数据行t检验、重复测量方差分析、Kaplan-Meier曲线分析及χ2检验。

结果

实验组术前3、1 d及术后1、7、14、21、30 d,大鼠不同时相点ALT、AST、CK、LDH水平比较,差异均有统计学意义(F=41.458、39.842、33.343、52.335,P值均小于0.05),大鼠不同时相点肌酐、血尿素氮比较,差异均无统计学意义(F=0.702、2.429,P值均大于0.05);对照组术前3、1 d及术后1、7、14、21、30 d,ALT、AST比较,差异均有统计学意义(F=12.267、3.646,P值均小于0.05);大鼠不同时相点肌酐、血尿素氮、CK、LDH比较,差异均无统计学意义(F=0.885、1.100、1.773、1.338,P值均大于0.05)。术前3、1 d实验组和对照组大鼠ALT、AST、肌酐、血尿素氮、CK及LDH水平比较,差异均无统计学意义(P值均大于0.05);术后1、21、30 d,实验组和对照组ALT、AST比较,差异均有统计学意义(t=5.414、-9.993、-9.362, 4.345、-4.802、-7.159,P值均小于0.05);术后1、7、14、21、30 d,实验组和对照组肌酐、血尿素氮比较,差异均无统计学意义(t=0.651、0.322、0.045、-0.760、-0.741,4.345、0.784、-1.835、-4.802、-6.415;P值均大于0.05)。术后1、7 d,实验组和对照组CK、LDH比较,差异均有统计学意义(t=5.613、4.437,7.817、5.183,P值均小于0.05)。术前3、1 d及术后1、7、14、21、30 d,实验组肿瘤标志物AFP水平分别为(4.63±0.53)、(4.84±1.63)、(5.54±1.96)、(3.87±2.19)、(2.34±0.28)、(1.61±0.51)、(1.18±0.36) ng/L,差异有统计学意义(F=44.339,P<0.05);对照组各时相点血清AFP水平分别为(4.44±0.91)、(4.61±0.91)、(4.86±0.95)、(5.55±1.08)、(6.10±1.42)、(6.93±1.80)、(6.70±2.69) ng/L,差异有统计学意义(F=6.184,P<0.05)。术前3、1 d,实验组与对照组AFP水平比较,差异均无统计学意义(t=0.862、0.501,P=0.414、0.619);术后7、14、21、30 d,实验组与对照组比较,差异均有统计学意义(t=-2.682、-9.004、-10.809、-7.762,P值均小于0.05)。实验组术前1 d,术后7、14、21 d的肿瘤长径分别为(11.2±3.1)、(8.1±2.3)、(5.3±1.6)、(3.5±1.1) mm,而对照组各时相点的肿瘤长径分别为(9.8±2.1)、(14.1±2.7)、(17.8±3.7)、(14.4±2.7) mm;术前1 d,2组间肿瘤长径比较,差异无统计学意义(t=1.526, P=0.135);术后7、14、21 d,实验组与对照组的肝脏肿瘤长经比较,差异均有统计学意义(t=-7.330、-14.800、-18.244,P值均小于0.05)。蛋白质印迹法检测结果显示,实验组术后Caspase-3、Bax较对照组表达水平增高,Bcl-2表达水平下降。术后30 d,肿瘤组织行苏木精-伊红染色,实验组可见大量的组织坏死,有明显的细胞凋亡区,而细胞的管道结果保持完好;对照组肿瘤细胞未见明显破坏。术后30 d,肿瘤组织行VEGF免疫组织化学染色,实验组可见细胞结构排列尚清晰,未见明显细胞破坏,仅有少量棕黄色阳性染色(1+,中等染色);对照组可见细胞组织排列紊乱,大量棕黄色阳性染色(4+,强染色)。术后30 d,肿瘤组织行KI67免疫组织化学染色。实验组可见细胞结构排列完整,未见明显破坏,仅有少量棕黄色阳性染色(1+,弱染色);对照组可见组织结构紊乱,细胞可见大量棕黄色阳性染色(4+,强染色)。术后30 d,肿瘤组织行TUNEL染色。实验组可见细胞排列稍紊乱,管道结构不清晰,大量棕黄色阳性染色;对照组可见组织排列整齐,仅有少量棕黄色阳性染色。实验组与对照组的肿瘤细胞增殖率分别为(2.8±0.8)%、(43.1±3.8)%,比较差异有统计学意义(t=3.765,P<0.05)。TUNEL染色结果可见实验组强染色,而对照组呈弱染色或不染色;实验组与对照组肿瘤细胞凋亡率分别为(76.85±10.27)%、(2.56±1.67)%,比较差异有统计学意义(t=4.456,P<0.05)。

结论

新型高频方波电脉冲可有效控制大鼠肝癌的局部进展。

Objective

To explore the influence of new high frequency square wave electric pulse in the ablation treatment of liver cancer in rats.

Methods

Tumor cells suspension was prepared by in vitro culture of liver cancer McA-RH7777 cells, and 50 clean SD rats were injected intrahepatically to establish a liver cancer model. One week after modeling, 40 liver cancer model rats were randomly selected and divided into an experimental group (n=26) and a control group (n=14) according to the simple sampling method. The liver tumors of the experimental group rats were treated with electrical pulses at a field intensity of 2 000 V/cm, while the tumors of the control group rats were treated with pulses at a field intensity of 0, frequency of 1 Hz and pulse width of 100 μs. Blood samples were collected from tail vein on 3 and 1 d before operation and 1, 7, 14, 21 and 30 d after operation, and serum biochemical indexes [alanine aminotransferase (ALT), aspartate aminotransferase (AST), creatinine, urea nitrogen, creatine kinase (CK), lactate dehydrogenase (LDH)] and the tumor marker alpha-fetoprotein (AFP) were monitored. The changes of tumor length was recorded at 1 d before operation and 7, 14, and 21 d after operation in the two groups of rats, and the survival time was recorded at 60 d after operation, in the two groups of rats, respectively, and the related complications were recorded during the treatment process. Two rats in the experimental group and the control group were randomly sacrificed 30 d after operation. The expression levels of cysteine aspartic acid protease-3 (Caspase-3), B-cell lymphoma-2 proto oncogene (Bcl-2), Bcl-2 related X protein (Bax) in the tumor tissues of the target area of the ablation of the rats in the two groups were detected. Lignin-eosin staining, vascular endothelial growth factor (VEGF) immunohistochemical observation of histomorphological changes, KI67 staining, TUNEL staining, cell proliferation rate and cell apoptosis rate were calculated. Data were analyzed by t test, repeated measures, Kaplan-Meier curves and chi-square test.

Results

ALT, AST, CK, LDH level were compared at different time points in the experimental group at 3, 1 d before operation and 1, 7, 14, 21, 30 d after operation, the differences were statistically significant (F=41.458, 39.842, 33.343, 52.335; with P values above 0.05), there were no differences in creatinine and blood urea nitrogen at different time points in rats (F=0.702, 2.429; with P values above 0.05). ALT and AST were compared at 3, 1 d before operation and 1, 7, 14, 21, 30 d after operation in the control group, the differences were statistically significant (F=12.267, 3.646; with P values below 0.05), and there were no statistically significant differences in creatinine, blood urea nitrogen, CK and LDH at different time points(F=0.885, 1.100, 1.773, 1.338; with P values above 0.05). There were no statistically significant differences in the levels of ALT, AST, creatinine, blood urea nitrogen, CK, and LDH between the experimental group and the control group at 1 and 3 d before operation (with P values above 0.05). There were obvious differences in ALT and AST at 1, 21, and 30 d after operation between the experimental group and the control group and the differences were statistically significant (t=5.414, -9.993, -9.362; 4.345, -4.802, -7.159; with P values below 0.05). There were no statistically significant differences in creatinine and blood urea nitrogen at 1, 7, 14, 21, and 30 d after operation between the two groups (t=0.651, 0.322, 0.045, -0.760, -0.741; 4.345, 0.784, -1.835, -4.802, -6.415; with P values above 0.05). CK and LDH were compared between the experimental group and the control group at 1 and 7 d after operatio, the differences were statistically significant (t=5.613, 4.437, 7.817, 5.183; with P values below 0.05). The tumor marker AFP levels were (4.63±0.53), (4.84±1.63), (5.54±1.96), (3.87±2.19), (2.34±0.28), (1.61±0.51), (1.18±0.36) ng/L at 3, 1 d before operation and 1, 7, 14, 21, 30 d after operation in the experimental group, the difference was statistically significant (F=44.339, P<0.05). The tumor marker AFP levels of the control group at each time point were (4.44±0.91), (4.61±0.91), (4.86±0.95), (5.55±1.08), (6.10±1.42), (6.93±1.80), (6.70±2.686) ng/L, the difference was statistically significant (F=6.184, P<0.05). At 3 and 1 d before operation, there were no significant differences in AFP levels between the experimental group and the control group (t=0.862, 0.501; P=0.414, 0.619); at 7, 14, 21, and 30 d after operation, the difference between the experimental group and the control group were statistically significant (t=-2.682, -9.004, -10.809, -7.762; with P values below 0.05). The tumor length diameter of the experimental group were (11.2±3.1), (8.1±2.3), (5.3±1.6), (3.5±1.1) mm at 1 d before operation and 7, 14, 21 d after operation, respectively, while the tumor length diameter of the control group were (9.8±2.1), (14.1±2.7), (17.8±3.7), (14.4±2.7) mm at each time point. There was no statistically significant difference in tumor length diameter between the two groups at 1 d before operation(t=1.526, P=0.135). At 7, 14, and 21 d after operation, the differences in the length diameter between the experimental group and the control group were statistically significant (t=-7.330, -14.800, -18.244; with P values below 0.05). Compared with the control group 30 d after operation, the results of protein blotting showed that the expression levels of Caspase-3 and Bax increased and Bcl-2 decreased in the experimental group. Thirty days after surgery, hematoxylin-eosin staining was performed on tumor tissue. In the experimental group, a large number of tissue necrosis and obvious apoptotic areas were observed, while the cell duct results remained intact. No obvious destruction of tumor cells was observed in the control group. Thirty days after surgery, immunohistochemical staining of VEGF was performed on tumor tissues. In the experimental group, the cell structure arrangement was still clear, no obvious cell destruction was observed, and only a small amount of brown-yellow positive staining (1+ , moderate staining) was observed. In the control group, the arrangement of cells was disordered, with a large amount of brown-yellow positive staining (4+ , strong staining). Thirty days after surgery, the tumor tissues were stained with KI67 immunohistochemistry. In the experimental group, the cell structure arrangement was intact, no obvious damage was observed, and only a small amount of brown-yellow positive staining (1+ , weak staining) was observed. In the control group, the tissue structure was disordered, and the cells showed a large number of brown-yellow positive staining (4+ , strong staining). TUNEL staining was performed on tumor tissue 30 days after surgery. In the experimental group, the cell arrangement was slightly disordered and the structure of the pipeline was unclear. In the control group, the tissues were neatly arranged with only a small amount of brown-yellow positive staining. The tumor cell proliferation rates of the experimental group and the control group were (2.8±0.8)% and (43.1±3.8)%, respectively, and the difference was statistically significant (t=3.765, P<0.05). TUNEL staining showed strong staining in the experimental group and weak staining or no staining in the control group, the apoptosis rate of tumor cells in the experimental group and the control group were (76.85±10.27)% and (2.56±1.67)%, respectively, and the difference was statistically significant (t=4.456, P<0.05).

Conclusion

The new high-frequency square-wave electrical pulses can effectively control the local progression of liver cancer in rats.

表1 2组肝癌大鼠不同时相点ALT、AST、肌酐、血尿素氮、CK、LDH水平变化(±s)
组别 鼠数 ALT(U/L) F P
术前3 d 术前1 d 术后1 d 术后7 d 术后14 d 术后21 d 术后30 d
实验组 26 71.9±12.8 83.8±16.9 135.4±37.5 108.3±24.0 95.4±26.6 62.9±16.2 52.5±13.1 41.458 <0.05
对照组 14 77.8±9.9 85.9±10.5 92.1±11.8 117.3±26.6 111.0±28.6 126.0±23.6 128.4±28.8 12.267 <0.05
t   -1.527 -0.428 5.414 -1.091 -1.730 -9.993 -9.362    
P   0.135 0.671 <0.05 0.282 0.092 <0.05 <0.05    
组别 鼠数 AST(U/L) F P
术前3 d 术前1 d 术后1 d 术后7 d 术后14 d 术后21 d 术后30 d
实验组 26 90.0±15.3 110.3±25.2 140.4±23.9 132.5±26.3 106.3±16.1 86.6±20.4 63.7±21.8 39.842 <0.05
对照组 14 94.1±16.9 106.1±16.7 108.8±17.7 125.8±25.2 117.3±21.4 126.0±31.4 124.3±31.5 3.646 <0.05
t   -0.783 -0.560 4.345 6.784 -1.835 -4.802 -7.159    
P   0.438 0.579 <0.05 0.078 0.074 <0.05 <0.05    
组别 鼠数 肌酐(μmol/L) F P
术前3 d 术前1 d 术后1 d 术后7 d 术后14 d 术后21 d 术后30 d
实验组 26 63.7±21.8 49.7±13.3 56.5±14.7 51.0±14.7 49.9±12.3 52.0±12.2 53.3±16.7 0.702 0.649
对照组 14 52.3±11.7 48.8±11.7 53.5±12.1 49.6±10.7 49.8±10.8 55.3±14.1 57.5±18.0 0.885 0.509
t   -0.045 0.197 0.651 0.322 0.045 -0.760 -0.741    
P   0.076 0.845 0.519 0.282 0.964 0.452 0.464    
组别 鼠数 血尿素氮(mmol/L) F P
术前3 d 术前1 d 术后1 d 术后7 d 术后14 d 术后21 d 术后30 d
实验组 26 8.07±2.12 8.83±2.00 9.04±1.76 8.02±2.15 7.91±1.80 7.72±1.77 7.43±1.70 2.429 0.128
对照组 14 7.79±1,68 8.69±1.27 10.11±3.51 9.36±2.68 9.16±2.09 9.33±2.25 8.77±3.06 1.100 0.369
t   0.783 -0.560 4.345 0.784 -1.835 -4.802 -6.415    
P   0.681 0.829 0.205 0.093 0.055 0.170 0.081    
组别 鼠数 CK(U/L) F P
术前3 d 术前1 d 术后1 d 术后7 d 术后14 d 术后21 d 术后30 d
实验组 26 1 148.2±179.2 1 131.6±186.9 2 316.7±795.3 1 712.2±435.8 1 380.0±281.1 1 296.9±238.2 1 114.9±152.5 33.343 <0.05
对照组 14 1 014.5±167.8 1 045.4±141.9 1 102.1±170.0 1 166.9±191.3 1 222.3±195.9 1 161.4±239.4 1 108.6±131.3 1.773 0.113
t   1.611 7.476 5.613 4.437 1.864 1.713 0.131    
P   0.115 0.141 <0.05 <0.05 0.070 0.095 0.897    
组别 鼠数 LDH(U/L) F P
术前3 d 术前1 d 术后1 d 术后7 d 术后14 d 术后21 d 术后30 d
实验组 26 1 346.4±141.0 1 297.5±129.2 1 994.2±227.8 1 792.3±190.4 1 460.8±215.2 1 299.0±209.8 1 383.1±262.6 52.335 <0.05
对照组 14 1 290.1±185.4 1 284.8±211.3 1 330.9±303.0 1 352.9±284.8 1 409.6±243.5 1 186.5±170.8 1 264.2±168.2 1.338 0.249
t   1.077 7.173 7.817 5.183 0.686 -1.503 1.807    
P   0.288 0.814 <0.05 <0.05 0.497 0.093 0.063    
表2 2组肝癌大鼠不同时相点AFP的浓度比较(ng/L, ±s)
图1 2组肝癌大鼠方波电脉冲消融术术后60 d生存曲线
图2 术后30 d蛋白质印迹法检测实验组与对照组肝癌大鼠消融靶区肿瘤组织Caspase-3、Bcl-2、Bax的表达水平
图3 2组肝癌大鼠术后30 d消融靶区肝癌组织苏木精-伊红染色结果(10×10)
图4 2组肝癌大鼠术后30 d消融靶区肝癌组织VEGF免疫组织化学染色结果(10×10)
图5 2组肝癌大鼠术后30 d消融靶区肝癌组织KI67免疫组织化学染色结果(10×10)
图6 2组肝癌大鼠术后30 d消融靶区肝癌组织TUNEL染色结果(10×10)
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