四组复方中药对实验性肝损伤大鼠肝纤维化状态的影响比较
王育强, 蒋书勤, 武警医学院附属医院传染科 天津市 300162
李茹, 武警医学院基础部 天津市 300162
武警医学院资助课题, No.9646
项目负责人: 王育强, 300162, 天津市, 天津武警医学院附属医院传染科. wangyuqiang12356@sohu.com
电话: 022-60578766
收稿日期: 2002-10-07 接受日期: 2002-10-18
摘要
目的: 观查4组复方中药对四氯化碳 (CCl4) 所致肝损伤大鼠肝病理状态的影响.
方法: 40%CCl4油溶液注射于大鼠皮下对其肝脏进行损害，中药灌服，观查中药对大鼠的肝保护作用.
结果: 各组中药对大鼠肝病理状态均有影响，与模型组比较，均能在一定程度上减轻肝损害，减轻肝纤维化程度，但各组间在在护肝效果上有差异. 另外，与模型组比较，中药对转氨酶ALT降低的影响不明显，但对AST有一定降低作用.
结论: 中药多种组方，均能达一定程度的减轻肝纤维化效果，阻止肝组织进一步损害.但应进一步研究各组中药对肝脏保护差异的原因.
王育强, 蒋书勤, 李茹. 四组复方中药对实验性肝损伤大鼠肝纤维化状态的影响比较. 世界华人消化杂志 2004;12(1):217-220
0 引言为观察按不同中医机制和不同药物组方的4组复方中药对CCl4所致肝损伤大鼠的肝保护作用，比较药物疗效，为临床合理选药提供借鉴，我们观察了按中医“活血化瘀，养血柔肝”组方的两组药物“人参四物汤”、“桃红四物汤”和一组按“清热解毒，行气散结”理论组方的药物“复方鳖甲四黄丸”、及市售治肝中药“益肝草”对CCl4所致肝损伤大鼠肝纤维化状态的影响，现报告如下:
1 材料和方法
1.1 材料 药物组成: 方1人参四物汤含 白人参、丹参 熟地 当归、赤芍 川芎; 方2 含桃仁 红花、熟地 当归、赤芍 川芎; 方3 含麝香、当归、鳖甲、黄芩、枝子、神曲、龙胆草、黄连、大黄、柴胡、砂仁、青黛、芦荟、丹皮、黄柏、由大枣、生姜、核仁、黑豆等调其性味; 方4市售中成药 益肝草 贵洲特色药业有限责任公司生产 批号: 960815. 动物分组: SD大鼠56只，随机分为4组，模型组8只; 正常对照组8只; 实验1组10只; 实验2组10只; 实验3组10只; 实验4组10只; 药物配制: 方1和方2药物每10付水煮，制成600 mL浓缩药液，冰箱贮藏. 方3中 麝香、鳖甲研成细粉，余药温火熬制，去渣，将药溶合制成3:1药液，即20 g溶质配成60 mL药液.方4按说明每袋5 g加水10 mL配成药液应用.
1.2 方法 大鼠分组后，除正常对照组外，其余动物给40% CC14油溶液皮下注射2次/wk，注射CC14时精确计算剂量. 同时实验各组均分别灌服各自药物，即1 mL原液/100 g体重.每3 d根据鼠体重变化调整1次给予CC14的量和灌服药物的剂量. 8 wk后处死动物，测定肝功能，剖取大鼠肝脏做病理检查.
2 结果2.1 40%CC14油溶液皮下注射8 wk后各组动物之间肝功能的比较(表1)
表1 实验各组动物8 wk时肝功能指标与正常对照的比较(mean±s)
aP <0.01 vs 对照组; bP <0.05 vs 模型组.
2.2 40%CC14油溶液皮下注射8wk后各组动物与正常对照组的肝病理状态比较，见表2.
表2 各组动物肝脏外观及镜下病理状态比较
图1正常对照低倍镜肝切片.
图2正常对照中倍镜肝切片.
图3模型组低倍镜肝病理.
图4模型组中倍镜肝病理.
图5 服方1药物的大鼠中倍镜肝病理.
图6 服方2药物的大鼠中倍镜肝病理.
图7 服方3药物的大鼠中倍镜肝病理.
图8 服方3药物的大鼠高倍镜肝病理.
3 讨论近些年，中药治疗肝纤维化的研究较多[1-29]，CC14动物肝纤维化模型的建立较简便，病变典型，被广泛应用.本文所述的4组药物，前2组为古方药，第3组为中医经验方，第4组是随机选取的1个成药. 4组药物均曾在临床上用于病毒性肝损害患者，各家报道认为有减轻肝损害作用. 本次实验显示，各实验组动物在用中药予以保护后转氨酶仍很高，这可能是CC14对肝脏的破坏作用较强而呈急性损害，中药难以逆转CC14造成的肝细胞破坏，但AST较模型组降低，也在一定程度上说明中药对阻止肝细胞进一步损害有作用. 模型组大鼠肝脏有广泛的纤维组织增生甚至部分或全部的肝小叶结构被破坏，有假小叶形成或形成趋势，说明造模成功.用中药的各治疗组大鼠肝脏多数仅见肝细胞的中心性脂肪变性及轻度的肝坏死，纤维组织增生较模型组明显减轻，肝脏未见假小叶形成. 这提示，中药对阻断肝损伤动物的肝脏纤维化有一定作用. 但从病理切片看各组中药组方的合理与否对动物肝保护作用还是有较大差别.因此，选择有效的方剂，进行长期观察和改进，并就其机制进行分析是以后中药治疗肝病的一项任务.
4 参考文献1 程明亮, 刘三都. 肝纤维化基础研究与临床. 第1版. 北京: 人民卫生出版社, 1996:228-271
2 Liu P, Hu YY, Liu C, Zhu DY, Xue HM, Xu ZQ, Xu LM, Liu CH, Gu HT, Zhang ZQ. Clinical observation of salvianolic acid B
in treatment of liver fibrosis in chronic hepatitis B. World J Gastroenterol 2002;8:679-685
3 Liu P, Liu CH, Wang HN, HuYY, Liu C. Effect of salvianolic acid B on collagen production and mitogen-activated protein
kinase activity in rat hepatic stellate cells. Acta Pharmacol Sin 2002;23:733-738
4 Liu P, Hu Y, Liu C, Liu C, Zhu D. Effects of salviainolic acid A (SA-A) on liver injury: SA-A action on hepatic peroxidation.
Liver 2001;21:384-390
5 Yao L, Yao ZM, Yu T. Influence of BOL on hyaluronic acid, laminin and hyperplasia in hepatofibrotic rats. World J
Gastroenterol 2001;7:872-875
6 Liu CH, Hu YY, Wang XL, Liu P, Xu LM. Effects of salvianolic acid-A on NIH/3T3 fibroblast proliferation, collagen
synthesis and gene expression. World J Gastroenterol 2000;6:361-364
7 Liu P, Liu C, Xu LM, HuYY, Xue HM, Liu CH, Zhang ZQ. Effects of Fuzheng Huayu 319 recipe on liver fibrosis in chronic
hepatitis B. World J Gastroenterol 1998;4:348-353
8 Cai DY, Zhao G, Chen JC, Ye GM, BingFH, Fan BW. Therapeutic effect of Zijin capsule in liver fibrosis in rats. World J
Gastroenterol 1998;4:260-263
9 Huang Z, Li Q, Wang Z. Observation on dynamic changes of serum procollagen III, hyaluronic acid and laminin in rats
with hepatic fibrosis treated with Hujin pill. Zhongguo Zhongxiyi Jiehe Zazhi 2000;20:447-449
10 Wu J, Zhang L. Study on essence of syndrome of traditional Chinese medicine in liver cirrhotic patients. Zhongguo
Zhongxiyi Jiehe Zazhi 1999;19:279-281
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dimethylnitrosamine and drugs intervention. Zhonghua Ganzangbing Zazhi 2001;9(Suppl):18-20
12 Liu CH, Liu P, Hu YY, Xu LM, Tan YZ, Wang ZN, Liu C. Effects of salvianolic acid-A on rat hepatic stellate cell
proliferation and collagen production in culture. Acta Pharmacol Sin 2000;21:721-726
13 Yang H, Chen Y, Xu R, Shen W, Chen G. Clinical observation on the long-term therapeutic effects of traditional Chinese
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14 Hu Y, Wang R, Zhang X, Liu C, Liu C, Liu P, Zhu D. Effects of carbon tetrachloride-injured hepatocytes on hepatic stellate
cell activation and salvianolic acid A preventive action in vitro. Zhonghua Ganzangbing Zazhi 2000;8:299-301
15 Chen JC, Tsai CC, Chen LD, Chen HH, Wang WC. Therapeutic effect of gypenoside on chronic liver injury and fibrosis
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traditional Chinese medicine in liver-cirrhosis patients. Zhongguo Zhongxiyi Jiehe Zazhi 1994;14:148-149
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Western medicine. Zhongguo Zhongxiyi Jiehe Zazhi 1992;12:381-384
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differentiated by traditional Chinese medicine. Chin Med J (Engl) 1990;103:939-944
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29 Wang QM. The relation between blood rheology and the differential diagnosis of chronic hepatitis and liver cirrhosis in
Chinese medicine. Zhongguo Zhongxiyi Jiehe Zazhi 1984;4:528-532, http://www.100md.com( 王育强, 蒋书勤,李 茹)
李茹, 武警医学院基础部 天津市 300162
武警医学院资助课题, No.9646
项目负责人: 王育强, 300162, 天津市, 天津武警医学院附属医院传染科. wangyuqiang12356@sohu.com
电话: 022-60578766
收稿日期: 2002-10-07 接受日期: 2002-10-18
摘要
目的: 观查4组复方中药对四氯化碳 (CCl4) 所致肝损伤大鼠肝病理状态的影响.
方法: 40%CCl4油溶液注射于大鼠皮下对其肝脏进行损害，中药灌服，观查中药对大鼠的肝保护作用.
结果: 各组中药对大鼠肝病理状态均有影响，与模型组比较，均能在一定程度上减轻肝损害，减轻肝纤维化程度，但各组间在在护肝效果上有差异. 另外，与模型组比较，中药对转氨酶ALT降低的影响不明显，但对AST有一定降低作用.
结论: 中药多种组方，均能达一定程度的减轻肝纤维化效果，阻止肝组织进一步损害.但应进一步研究各组中药对肝脏保护差异的原因.
王育强, 蒋书勤, 李茹. 四组复方中药对实验性肝损伤大鼠肝纤维化状态的影响比较. 世界华人消化杂志 2004;12(1):217-220
0 引言为观察按不同中医机制和不同药物组方的4组复方中药对CCl4所致肝损伤大鼠的肝保护作用，比较药物疗效，为临床合理选药提供借鉴，我们观察了按中医“活血化瘀，养血柔肝”组方的两组药物“人参四物汤”、“桃红四物汤”和一组按“清热解毒，行气散结”理论组方的药物“复方鳖甲四黄丸”、及市售治肝中药“益肝草”对CCl4所致肝损伤大鼠肝纤维化状态的影响，现报告如下:
1 材料和方法
1.1 材料 药物组成: 方1人参四物汤含 白人参、丹参 熟地 当归、赤芍 川芎; 方2 含桃仁 红花、熟地 当归、赤芍 川芎; 方3 含麝香、当归、鳖甲、黄芩、枝子、神曲、龙胆草、黄连、大黄、柴胡、砂仁、青黛、芦荟、丹皮、黄柏、由大枣、生姜、核仁、黑豆等调其性味; 方4市售中成药 益肝草 贵洲特色药业有限责任公司生产 批号: 960815. 动物分组: SD大鼠56只，随机分为4组，模型组8只; 正常对照组8只; 实验1组10只; 实验2组10只; 实验3组10只; 实验4组10只; 药物配制: 方1和方2药物每10付水煮，制成600 mL浓缩药液，冰箱贮藏. 方3中 麝香、鳖甲研成细粉，余药温火熬制，去渣，将药溶合制成3:1药液，即20 g溶质配成60 mL药液.方4按说明每袋5 g加水10 mL配成药液应用.
1.2 方法 大鼠分组后，除正常对照组外，其余动物给40% CC14油溶液皮下注射2次/wk，注射CC14时精确计算剂量. 同时实验各组均分别灌服各自药物，即1 mL原液/100 g体重.每3 d根据鼠体重变化调整1次给予CC14的量和灌服药物的剂量. 8 wk后处死动物，测定肝功能，剖取大鼠肝脏做病理检查.
2 结果2.1 40%CC14油溶液皮下注射8 wk后各组动物之间肝功能的比较(表1)
表1 实验各组动物8 wk时肝功能指标与正常对照的比较(mean±s)
| 分组 | n | ALT(mg/L) | AST(mg/L) |
| 正常对照组 | 8 | 18.7±7.3 | 73.3±17.2 |
| 模型组 | 8 | 178.4±45.4a | 262.0±162.4a |
| 人参四物汤 | 10 | 213.6±133.2a | 120.4±25b |
| 桃红四物汤 | 10 | 190.4±59.9a | 184.8±74.72b |
| 鳖甲四黄丸 | 10 | 161.6±31.5a | 145.5±50.6b |
| 益肝草 | 10 | 240.8±49.4a | 160±48.72b |
aP <0.01 vs 对照组; bP <0.05 vs 模型组.
2.2 40%CC14油溶液皮下注射8wk后各组动物与正常对照组的肝病理状态比较，见表2.
表2 各组动物肝脏外观及镜下病理状态比较
| 项目 | n | 肝脏外观 | 周围组织粘连 | 镜下病理改变 |
| 正常对照 | 8 | 红润光滑 | 无周围组织粘连 | 肝细胞未见变性坏死，肝小叶结构正常，见图1-2. |
| 模型组 | 10 | 质灰暗, 有结节 | 和周围组织粘连较重 | 肝细胞呈灶、片状坏死，广泛的纤维组织增生，部分或全部的肝小叶结构被破坏，假小叶形成，见图3-4. |
| 实验1～2组 | 20 | 润滑有光泽,无结节 | 有周围组织粘连且4只出现腹水 | 肝细胞中心性脂肪变性轻度肝坏死纤维组织增生较重但无假小叶形成，见图5-6. |
| 实验3～4组 | 20 | 质红滑有光泽无结节 | 无周围组织粘连无腹水 | 肝细胞中心性脂肪变性轻度肝坏死，一般纤维组织增生,无假小叶形成, 见图7-8 |
图1正常对照低倍镜肝切片.
图2正常对照中倍镜肝切片.
图3模型组低倍镜肝病理.
图4模型组中倍镜肝病理.
图5 服方1药物的大鼠中倍镜肝病理.
图6 服方2药物的大鼠中倍镜肝病理.
图7 服方3药物的大鼠中倍镜肝病理.
图8 服方3药物的大鼠高倍镜肝病理.
3 讨论近些年，中药治疗肝纤维化的研究较多[1-29]，CC14动物肝纤维化模型的建立较简便，病变典型，被广泛应用.本文所述的4组药物，前2组为古方药，第3组为中医经验方，第4组是随机选取的1个成药. 4组药物均曾在临床上用于病毒性肝损害患者，各家报道认为有减轻肝损害作用. 本次实验显示，各实验组动物在用中药予以保护后转氨酶仍很高，这可能是CC14对肝脏的破坏作用较强而呈急性损害，中药难以逆转CC14造成的肝细胞破坏，但AST较模型组降低，也在一定程度上说明中药对阻止肝细胞进一步损害有作用. 模型组大鼠肝脏有广泛的纤维组织增生甚至部分或全部的肝小叶结构被破坏，有假小叶形成或形成趋势，说明造模成功.用中药的各治疗组大鼠肝脏多数仅见肝细胞的中心性脂肪变性及轻度的肝坏死，纤维组织增生较模型组明显减轻，肝脏未见假小叶形成. 这提示，中药对阻断肝损伤动物的肝脏纤维化有一定作用. 但从病理切片看各组中药组方的合理与否对动物肝保护作用还是有较大差别.因此，选择有效的方剂，进行长期观察和改进，并就其机制进行分析是以后中药治疗肝病的一项任务.
4 参考文献1 程明亮, 刘三都. 肝纤维化基础研究与临床. 第1版. 北京: 人民卫生出版社, 1996:228-271
2 Liu P, Hu YY, Liu C, Zhu DY, Xue HM, Xu ZQ, Xu LM, Liu CH, Gu HT, Zhang ZQ. Clinical observation of salvianolic acid B
in treatment of liver fibrosis in chronic hepatitis B. World J Gastroenterol 2002;8:679-685
3 Liu P, Liu CH, Wang HN, HuYY, Liu C. Effect of salvianolic acid B on collagen production and mitogen-activated protein
kinase activity in rat hepatic stellate cells. Acta Pharmacol Sin 2002;23:733-738
4 Liu P, Hu Y, Liu C, Liu C, Zhu D. Effects of salviainolic acid A (SA-A) on liver injury: SA-A action on hepatic peroxidation.
Liver 2001;21:384-390
5 Yao L, Yao ZM, Yu T. Influence of BOL on hyaluronic acid, laminin and hyperplasia in hepatofibrotic rats. World J
Gastroenterol 2001;7:872-875
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