化浊解毒调肝方对免疫性肝纤维化大鼠MMP-1、TIMP-1表达的影响
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摘要
目的:以“浊毒”理论为依据观察化浊解毒调肝方对免疫性肝纤维化大鼠病理形态学及基质金属蛋白酶-1(MMP-1)、基质金属蛋白酶抑制剂-1(TIMP-1)表达的影响,探讨其抗肝纤维化的疗效及作用机理。
方法:选用清洁级Wistar大鼠60只,雄性,体重200士20g。适应性喂养一周后随机分为正常对照组、模型对照组、化浊解毒调肝方大剂量组(简称大剂组)、化浊解毒调肝方中剂量组(简称中剂组)、化浊解毒调肝方小剂量组(简称小剂组)、秋水仙碱治疗组(简称西药组)6组,每组10只。除正常对照组外,其余各组均采用未灭活的猪血清腹腔注射,每次0.5ml/只,每周2次,连续8周。秋水仙碱治疗组和中药治疗组于造模的第8周末给药,每天上午灌胃一次,每次2ml,连续4周。正常对照组和模型对照组给予等量生理盐水。各组分别于治疗的第4周末处死,留取大鼠肝组织,采用苏木精-伊红染色观察肝组织病理形态学的变化。采用免疫组化技术测定肝组织MMP-1、TIMP-1表达情况。所得数据经过整理,采用SPSS13.0统计软件进行检验和方差分析。
结果:
1化浊解毒调肝方对免疫性肝纤维化大鼠体重、肝重、脾重的影响
与正常对照组大鼠比较,模型组、西药治疗组大鼠体重明显降低(P<0.05),肝重、脾重明显增加(均P<0.05);各剂量中药治疗组大鼠体重、肝重、脾重较正常对照组均无明显改变(均P>0.05)。与模型组大鼠比较,各剂量中药治疗组大鼠体重明显增加(P<0.05),肝重和脾重明显减轻(P<0.05)。中药大剂量组大鼠体重高于西药治疗组(P<0.05)。各剂量中药治疗组之间比较无显著性差异(P>0.05)。
2化浊解毒调肝方对免疫性肝纤维化大鼠病理形态学的影响
正常组肝小叶结构完整,肝细胞围绕中央静脉呈放射状排列,无变性坏死,无纤维组织增生。模型组肝组织病变区域多,面积大,正常肝小叶结构破坏,汇管区扩大有大量炎性细胞浸润,肝细胞肿胀,排列拥挤,见大小不等的空泡,脂肪变性广泛,有部分坏死,汇管区及中央静脉周围纤维组织增生。西药组可见肝小叶结构基本正常,以中央静脉周围肝细胞肿胀变性明显,周边区域较轻,炎细胞浸润、纤维组织增生较模型组明显减轻。大剂组可见肝小叶结构基本正常,肝组织病变区域较少,损伤程度轻,肝细胞排列正常,仅见中央静脉周围肝细胞空泡样变性。中剂组病变区域面积较小剂组小。小剂组肝细胞炎症不显著,可见少量脂肪变性空泡,肝小叶结构基本正常,肝细胞排列尚整齐,中央静脉周围可见部分肝细胞变性,病变区域面积较模型组、西药组小,且肝细胞变性程度轻。
3化浊解毒调肝方对免疫性肝纤维化大鼠肝组织MMP-1表达的影响
MMP-1主要表达在纤维间隔和汇管区的间质细胞,颜色呈棕黄色。其表达强度依次为大剂组、中剂组、小剂组、西药组、模型组,在正常组表达最弱。各药物治疗组与模型组相比差异有统计学意义(P<0.05),说明治疗组对MMP-1阳性表达有显著的激活作用;西药组与正常组比较差异有统计学意义(P<0.05);大剂组与西药组比较差异有统计学意义(P<0.05);大剂组与中、小剂组比较差异不明显(P>0.05);因此中药治疗组对MMP-1阳性表达的激活作用优于西药对照组。
4化浊解毒调肝方对免疫性肝纤维化大鼠肝组织TIMP-1表达的影响
TIMP-1表达强度依次为模型组、西药组、大剂组、中剂组、小剂组,在正常组表达最弱。正常组大鼠肝组织见少许TIMP-1阳性表达细胞,模型组大鼠肝组织中表达的阳性细胞比例显著高于正常组,表现为不均匀的黄褐色颗粒状物。与模型组相比,各药物治疗组大鼠肝组织TIMP-1蛋白表达下降,差异有统计学意义(P<0.05);西药组与正常组比较差异有统计学意义(P<0.05);大剂组与西药组比较差异有统计学意义(P<0.05);大剂组与中、小剂组比较差异无统计学意义(P>0.05)。因此中药治疗组作用优于西药对照组。
结论:
1化浊解毒调肝方可以改善免疫性肝纤维化大鼠模型的一般状况。
2 HE染色结果显示:化浊解毒调肝方能使HF模型大鼠肝小叶大部分恢复,中央静脉和汇管区纤维组织减少,该方能增强机体的纤维溶解能力,对肝纤维化大鼠有较强的恢复作用。
3化浊解毒调肝方能促进HF模型大鼠MMP-1的表达,同时抑制TIMP-1的表达,通过调节MMPS和TIMPS的失衡,促进异常合成的细胞外基质的降解,减少细胞外基质的过度沉积,而逆转肝纤维化。
4实验结果表明,化浊解毒调肝方对HF的治疗具有较高的临床应用价值,从而为本病的治疗开辟一条新的途径。
Objectives:The research based on the theory of ZhuoDu. By observing the effect of HuaZhuo JieDu TiaoGan decoction on pathological liver tissue ,MMP-1 and TIMP-1 in rats model of immunity hepatic fibrosis,to discuss the mechanism of antifibrotic action further.
Methods:60 SPF level weighed 200-220 grams Wistar rats randomly divided into six groups:the normal group, the model group, HuaZhuo JieDu TiaoGan decoction high dose group(HJT high dose group for short), HuaZhuo JieDu TiaoGan decoction middle dose group(HJT middle dose group) , HuaZhuo JieDu TiaoGan decoction low dose group(HJT low dose group) , colchicine treatment group(western medicine treatment group) ,with 10 rats for each group .Except the normal group, established pig’s serum( 0.5ml per mouse, twice a week) in rats by intraperitoneal injection for eight weeks. The treatment groups were given drug at the end of the eighth week. The equal saline(2ml each time) was given to the normal control group and the model group. Each group executes separately in the treatment 4th weekend. The livers were taken and the degree of hepatic fibrosis was judged by routine haematoxylin-eosin staining. MMP-1,TIMP-1 expression were determined using immunohistochemical technique .Data was collected and analyzed through test or analysis of variance. The statistic software was SPSS13.0.
Results:
1 Effect of HuaZhuo JieDu TiaoGan decoction on the levels of body weight, liver weight, spleen weight in rats model of immunity hepatic fibrosis. Compared with the normal control group and the model group, the body weight of treatment groups decreased significantly (P<0.05).The liver weight, spleen weight increased significantly (all P<0.05); Compared with the normal control group,the body weight, liver weight and spleen weight of the TCM treatmengt groups, there is no significant difference (all P> 0.05). Compared with the model group, the body weight of TCM treatmengt groups increased significantly (P <0.05), liver weight and spleen weight reduced significantly (P <0.05).The body weight of TCM high dose group is higher than western medicine treatment group (P <0.05). The dose of TCM treatmengt groups showed no significant difference (P> 0.05).
2 Effect of HuaZhuo JieDu TiaoGan decoction on the levels of pathomorphology in rats model of immunity hepatic fibrosis.
The structures of hepatic lobule are integrated, hepatic cord neatly ranged in the center of navel vein.There is not degeneration and necrosis in the liver tissue. The model group liver organization pathological change region are many, the area is big, the normal hepatic lobe disarrangement of the structure, collects the district expansion to have the massive inflammatory cell infiltration, the liver cell swelling, the arrangement is crowded, sees the size different vacuole, the fatty degeneration to be widespread, has a part of necrosis, collects around the district and the central vein the Fiber structure proliferation. Western medicine group obvious hepatic lobe structure basic normal, the liver cell swelling denaturation is obvious by the central vein around, the peripheral region is light, the phlogocyte infiltration, the Fiber structure proliferation compare the model group to reduce obviously. Big medicinal preparation group obvious hepatic lobe structure basic normal, the liver organization pathological change region are few, the extent of damage is light, the liver cell arrangement is normal, only sees around the central vein the liver cell vacuole type denaturation. The medicinal preparation group pathological change region area small medicinal preparation group is small. The small medicinal preparation group liver cell inflammation is not remarkable, obviously few fatty degeneration vacuole, hepatic lobe structure basic normal, the liver cell arrangement was still neat, around the central vein the visible part liver cell denaturates, the pathological change region area compares the model group, the western medicine group to be small, and the liver cell denatured degree is light.
3 Experimental study on the effect of HuaZhuo JieDu TiaoGan decoction on MMP- 1 in rats model of immunity hepatic fibrosis.
MMP-1 expressed mainly in the cells between the fiber spacing and periportal mesenchymal, stained brown. Intensity of its expression followed as: HJT high dose group , HJT middle dose group, HJT low dose group, western medicine group, model group. The expression in the normal control group is weakest.There are significant difference between the model group and the traetment groups(P<0.05).Indicate that the treatment group can activate the MMP-1 expression; There is significant difference between western medication group and normal group(P<0.05); There is significant difference between HJT high dose group and western medicine group (P<0.05); There is no significant difference between HJT high dose group, HJT middle dose group and HJT low dose group(P> 0.05) .That is to say,the TCM treatment groups show a better effect on the expression of the MMP-1.
4 Experimental study on the effect of HuaZhuo JieDu TiaoGan decoction on TIMP- 1 in rats model of immunity hepatic fibrosis.
Intensity of TIMP- 1 expression followed as: model group , western medicine group ,HJT high dose group , HJT middle dose group, HJT low dose group. The expression in the normal control group is weakest. A little TIMP-1 positive cells are visible in the normal rat liver tissue. In the model group the The proportion of positive cells in rat liver tissues were significantly higher than the the normal group . uneven brown granular material are visible. Compared with the model group, TIMP-1 protein expression in the TCM treatment groups decreased significantly (P<0.05); There is significant difference between western medication group and normal group(P<0.05); There is significant difference between HJT high dose group and western medicine group (P<0.05); There is no significant difference between HJT high dose group, HJT middle dose group and HJT low dose group(P> 0.05). Therefore, the TCM treatment groups show a better effect on the expression of the TIMP-1.
Conclusions:
1 HuaZhuo JieDu TiaoGan decoction can improve the general state of rats model of immunity hepatic fibrosis.
2 HE pigmentation result show: HuaZhuo JieDu TiaoGan decoction can recover the texture fibrous of hepatic fibrosis,and can raise the ability of fibrous solution.
3 HuaZhuo JieDu TiaoGan decoction can improve the content of MMP-l,and drepress obviously of TIMP-1, which might play a role in regulating the disequilibrium between MMPS and TIMPS, promoting the degrading of ECM, decreaing the deposition of ECM,so it can resolve fibrous of liver.
4 The result shows that the clinicao value of HuaZhuo JieDu TiaoGan decoction is very high and it make a new gateway to the therapy of Hepatic fibrosis.
方法:选用清洁级Wistar大鼠60只,雄性,体重200士20g。适应性喂养一周后随机分为正常对照组、模型对照组、化浊解毒调肝方大剂量组(简称大剂组)、化浊解毒调肝方中剂量组(简称中剂组)、化浊解毒调肝方小剂量组(简称小剂组)、秋水仙碱治疗组(简称西药组)6组,每组10只。除正常对照组外,其余各组均采用未灭活的猪血清腹腔注射,每次0.5ml/只,每周2次,连续8周。秋水仙碱治疗组和中药治疗组于造模的第8周末给药,每天上午灌胃一次,每次2ml,连续4周。正常对照组和模型对照组给予等量生理盐水。各组分别于治疗的第4周末处死,留取大鼠肝组织,采用苏木精-伊红染色观察肝组织病理形态学的变化。采用免疫组化技术测定肝组织MMP-1、TIMP-1表达情况。所得数据经过整理,采用SPSS13.0统计软件进行检验和方差分析。
结果:
1化浊解毒调肝方对免疫性肝纤维化大鼠体重、肝重、脾重的影响
与正常对照组大鼠比较,模型组、西药治疗组大鼠体重明显降低(P<0.05),肝重、脾重明显增加(均P<0.05);各剂量中药治疗组大鼠体重、肝重、脾重较正常对照组均无明显改变(均P>0.05)。与模型组大鼠比较,各剂量中药治疗组大鼠体重明显增加(P<0.05),肝重和脾重明显减轻(P<0.05)。中药大剂量组大鼠体重高于西药治疗组(P<0.05)。各剂量中药治疗组之间比较无显著性差异(P>0.05)。
2化浊解毒调肝方对免疫性肝纤维化大鼠病理形态学的影响
正常组肝小叶结构完整,肝细胞围绕中央静脉呈放射状排列,无变性坏死,无纤维组织增生。模型组肝组织病变区域多,面积大,正常肝小叶结构破坏,汇管区扩大有大量炎性细胞浸润,肝细胞肿胀,排列拥挤,见大小不等的空泡,脂肪变性广泛,有部分坏死,汇管区及中央静脉周围纤维组织增生。西药组可见肝小叶结构基本正常,以中央静脉周围肝细胞肿胀变性明显,周边区域较轻,炎细胞浸润、纤维组织增生较模型组明显减轻。大剂组可见肝小叶结构基本正常,肝组织病变区域较少,损伤程度轻,肝细胞排列正常,仅见中央静脉周围肝细胞空泡样变性。中剂组病变区域面积较小剂组小。小剂组肝细胞炎症不显著,可见少量脂肪变性空泡,肝小叶结构基本正常,肝细胞排列尚整齐,中央静脉周围可见部分肝细胞变性,病变区域面积较模型组、西药组小,且肝细胞变性程度轻。
3化浊解毒调肝方对免疫性肝纤维化大鼠肝组织MMP-1表达的影响
MMP-1主要表达在纤维间隔和汇管区的间质细胞,颜色呈棕黄色。其表达强度依次为大剂组、中剂组、小剂组、西药组、模型组,在正常组表达最弱。各药物治疗组与模型组相比差异有统计学意义(P<0.05),说明治疗组对MMP-1阳性表达有显著的激活作用;西药组与正常组比较差异有统计学意义(P<0.05);大剂组与西药组比较差异有统计学意义(P<0.05);大剂组与中、小剂组比较差异不明显(P>0.05);因此中药治疗组对MMP-1阳性表达的激活作用优于西药对照组。
4化浊解毒调肝方对免疫性肝纤维化大鼠肝组织TIMP-1表达的影响
TIMP-1表达强度依次为模型组、西药组、大剂组、中剂组、小剂组,在正常组表达最弱。正常组大鼠肝组织见少许TIMP-1阳性表达细胞,模型组大鼠肝组织中表达的阳性细胞比例显著高于正常组,表现为不均匀的黄褐色颗粒状物。与模型组相比,各药物治疗组大鼠肝组织TIMP-1蛋白表达下降,差异有统计学意义(P<0.05);西药组与正常组比较差异有统计学意义(P<0.05);大剂组与西药组比较差异有统计学意义(P<0.05);大剂组与中、小剂组比较差异无统计学意义(P>0.05)。因此中药治疗组作用优于西药对照组。
结论:
1化浊解毒调肝方可以改善免疫性肝纤维化大鼠模型的一般状况。
2 HE染色结果显示:化浊解毒调肝方能使HF模型大鼠肝小叶大部分恢复,中央静脉和汇管区纤维组织减少,该方能增强机体的纤维溶解能力,对肝纤维化大鼠有较强的恢复作用。
3化浊解毒调肝方能促进HF模型大鼠MMP-1的表达,同时抑制TIMP-1的表达,通过调节MMPS和TIMPS的失衡,促进异常合成的细胞外基质的降解,减少细胞外基质的过度沉积,而逆转肝纤维化。
4实验结果表明,化浊解毒调肝方对HF的治疗具有较高的临床应用价值,从而为本病的治疗开辟一条新的途径。
Objectives:The research based on the theory of ZhuoDu. By observing the effect of HuaZhuo JieDu TiaoGan decoction on pathological liver tissue ,MMP-1 and TIMP-1 in rats model of immunity hepatic fibrosis,to discuss the mechanism of antifibrotic action further.
Methods:60 SPF level weighed 200-220 grams Wistar rats randomly divided into six groups:the normal group, the model group, HuaZhuo JieDu TiaoGan decoction high dose group(HJT high dose group for short), HuaZhuo JieDu TiaoGan decoction middle dose group(HJT middle dose group) , HuaZhuo JieDu TiaoGan decoction low dose group(HJT low dose group) , colchicine treatment group(western medicine treatment group) ,with 10 rats for each group .Except the normal group, established pig’s serum( 0.5ml per mouse, twice a week) in rats by intraperitoneal injection for eight weeks. The treatment groups were given drug at the end of the eighth week. The equal saline(2ml each time) was given to the normal control group and the model group. Each group executes separately in the treatment 4th weekend. The livers were taken and the degree of hepatic fibrosis was judged by routine haematoxylin-eosin staining. MMP-1,TIMP-1 expression were determined using immunohistochemical technique .Data was collected and analyzed through test or analysis of variance. The statistic software was SPSS13.0.
Results:
1 Effect of HuaZhuo JieDu TiaoGan decoction on the levels of body weight, liver weight, spleen weight in rats model of immunity hepatic fibrosis. Compared with the normal control group and the model group, the body weight of treatment groups decreased significantly (P<0.05).The liver weight, spleen weight increased significantly (all P<0.05); Compared with the normal control group,the body weight, liver weight and spleen weight of the TCM treatmengt groups, there is no significant difference (all P> 0.05). Compared with the model group, the body weight of TCM treatmengt groups increased significantly (P <0.05), liver weight and spleen weight reduced significantly (P <0.05).The body weight of TCM high dose group is higher than western medicine treatment group (P <0.05). The dose of TCM treatmengt groups showed no significant difference (P> 0.05).
2 Effect of HuaZhuo JieDu TiaoGan decoction on the levels of pathomorphology in rats model of immunity hepatic fibrosis.
The structures of hepatic lobule are integrated, hepatic cord neatly ranged in the center of navel vein.There is not degeneration and necrosis in the liver tissue. The model group liver organization pathological change region are many, the area is big, the normal hepatic lobe disarrangement of the structure, collects the district expansion to have the massive inflammatory cell infiltration, the liver cell swelling, the arrangement is crowded, sees the size different vacuole, the fatty degeneration to be widespread, has a part of necrosis, collects around the district and the central vein the Fiber structure proliferation. Western medicine group obvious hepatic lobe structure basic normal, the liver cell swelling denaturation is obvious by the central vein around, the peripheral region is light, the phlogocyte infiltration, the Fiber structure proliferation compare the model group to reduce obviously. Big medicinal preparation group obvious hepatic lobe structure basic normal, the liver organization pathological change region are few, the extent of damage is light, the liver cell arrangement is normal, only sees around the central vein the liver cell vacuole type denaturation. The medicinal preparation group pathological change region area small medicinal preparation group is small. The small medicinal preparation group liver cell inflammation is not remarkable, obviously few fatty degeneration vacuole, hepatic lobe structure basic normal, the liver cell arrangement was still neat, around the central vein the visible part liver cell denaturates, the pathological change region area compares the model group, the western medicine group to be small, and the liver cell denatured degree is light.
3 Experimental study on the effect of HuaZhuo JieDu TiaoGan decoction on MMP- 1 in rats model of immunity hepatic fibrosis.
MMP-1 expressed mainly in the cells between the fiber spacing and periportal mesenchymal, stained brown. Intensity of its expression followed as: HJT high dose group , HJT middle dose group, HJT low dose group, western medicine group, model group. The expression in the normal control group is weakest.There are significant difference between the model group and the traetment groups(P<0.05).Indicate that the treatment group can activate the MMP-1 expression; There is significant difference between western medication group and normal group(P<0.05); There is significant difference between HJT high dose group and western medicine group (P<0.05); There is no significant difference between HJT high dose group, HJT middle dose group and HJT low dose group(P> 0.05) .That is to say,the TCM treatment groups show a better effect on the expression of the MMP-1.
4 Experimental study on the effect of HuaZhuo JieDu TiaoGan decoction on TIMP- 1 in rats model of immunity hepatic fibrosis.
Intensity of TIMP- 1 expression followed as: model group , western medicine group ,HJT high dose group , HJT middle dose group, HJT low dose group. The expression in the normal control group is weakest. A little TIMP-1 positive cells are visible in the normal rat liver tissue. In the model group the The proportion of positive cells in rat liver tissues were significantly higher than the the normal group . uneven brown granular material are visible. Compared with the model group, TIMP-1 protein expression in the TCM treatment groups decreased significantly (P<0.05); There is significant difference between western medication group and normal group(P<0.05); There is significant difference between HJT high dose group and western medicine group (P<0.05); There is no significant difference between HJT high dose group, HJT middle dose group and HJT low dose group(P> 0.05). Therefore, the TCM treatment groups show a better effect on the expression of the TIMP-1.
Conclusions:
1 HuaZhuo JieDu TiaoGan decoction can improve the general state of rats model of immunity hepatic fibrosis.
2 HE pigmentation result show: HuaZhuo JieDu TiaoGan decoction can recover the texture fibrous of hepatic fibrosis,and can raise the ability of fibrous solution.
3 HuaZhuo JieDu TiaoGan decoction can improve the content of MMP-l,and drepress obviously of TIMP-1, which might play a role in regulating the disequilibrium between MMPS and TIMPS, promoting the degrading of ECM, decreaing the deposition of ECM,so it can resolve fibrous of liver.
4 The result shows that the clinicao value of HuaZhuo JieDu TiaoGan decoction is very high and it make a new gateway to the therapy of Hepatic fibrosis.
引文
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3李沛波,王永刚.田基黄中三个黄酮类化合物保肝退黄作用的实验研究[J].中山大学学报(医学科学版),2007,28(1):40-42
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5蒋明德,甘新宇,解方为,等.红景天苷对乙醛刺激的大鼠肝星状细胞增殖及胶原基因表达的影响[J].药学学报, 2002, 37(11):841-844
6 Busarawan Sriwanthana,Weena Treesangsri, Bongkod Boriboontrakul,et al. In vitro effects of Thaimedicinal plants on human lymphocyte activity[J].Songklanakarin J Sci Technol,2007,29 (Supp1.1): 17-28
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51文彬,彭齐荣,贺松其.清香散对肝纤维化大鼠转化生长因子β1及Smad4免疫组化的影响[J].江苏中医药,2006,27(3):55-57
2陈天宇,余世春.田基黄化学成分及药理作用研究进展[J].现代中药研究与实践,2009,23(2):78-80
3李沛波,王永刚.田基黄中三个黄酮类化合物保肝退黄作用的实验研究[J].中山大学学报(医学科学版),2007,28(1):40-42
4王晓东,刘永忠,刘永刚,等.红景天苷体外抗肝纤维化的实验研究[J].时珍国医国药,2004,15(3):138-139
5蒋明德,甘新宇,解方为,等.红景天苷对乙醛刺激的大鼠肝星状细胞增殖及胶原基因表达的影响[J].药学学报, 2002, 37(11):841-844
6 Busarawan Sriwanthana,Weena Treesangsri, Bongkod Boriboontrakul,et al. In vitro effects of Thaimedicinal plants on human lymphocyte activity[J].Songklanakarin J Sci Technol,2007,29 (Supp1.1): 17-28
7陈几香,张建国,张莉,等.绞股蓝总皂苷保肝作用实验研究[J].中国业,2007,16(13):7
8崔学军.黄连及其有效成分的药理研究进展[J].中国药师,2006,9(5):469-470
9宋旦哥,孟庆刚.黄芩药理作用研究述评[J].中华中医药学刊,2009,27(8):1619-1622
10董学,姚庆强.中药三棱的化学成分及药理研究进展[J].齐鲁药事,2005,24(10):612-614
11李彬,郭力城.鳖甲的化学成分和药理作用研究概况[J].中医药信息,2009,26(1):25-27
12裴莲花,吴学,金光洙.虎杖化学成分及药理作用研究现状[J].延边大学医学学报,2006,29(2):147-149
13孟繁钦,吴宜艳,雷涛,等.茵陈的药理作用及临床应用进展[J].牡丹江医学院学报,2009,30(1):46-48
14褚云香.MMP-1,TIMP-1及其在肝纤维化中的作用[J].国际消化杂志2006;23(10):111-112
15邝胜利,胡兵.肝纤维化大鼠模型研究进展[J].实验动物与比较医学,2008,28(1):62-66
1武哲丽,陈群,徐志伟,等.论中药复方抗肝纤维化的证治研究[J].中医药学刊,2006,24(1):489-490
2管仁方.苦参素对慢性乙肝患者血清肝纤维化指标影响的研究[J].临床和实验医学杂志,2007,6(12):33-34
3黄庆松,王朝,孙成山,等.苦参素对慢性乙型肝炎患者血清肝纤维化指标及细胞子的影响[J].山西医药杂志,2007,36(11):984-985
4陶艳艳,王晓玲,刘成海,等.丹酚酸B对TIH/3T3成纤维细胞TGF-β1 /ERK胞内信号转导的影响[J].首都医科大学学报,2007,28(2): 192-195
5李风华,刘平,熊卫国,等.虫草多糖逆转DMN诱导大鼠肝纤维化的作用及机制研究[J].中国中药杂志,2006,31(23):1968-1971
6孙保木,宣红萍,李风华,等.虫草菌丝提取物对大鼠脂肪性肝炎与肝纤维化的影响[J].中国新药与临床杂志,2008,27(1):6-11
7穆静,刘平,王宪波.虫草菌丝提取物抗DMN大鼠肝纤维化的作用及其机制的研究[J].宁夏医学杂志,2007,29(2):101-103
8吴建红,陕光,张端莲,等.川芎嗪抗实验性肝纤维化组织中TGF-β1阳性面积率表达的比较[J].数理医药学杂志,2006,19(3):237-238
9谈博,宋健平,张奉学,等.川芎嗪对HSC-T6细胞smad蛋白细胞内转位的影响[J].中药新药与临床药理,2006,17(5):320-322
10华海婴,李艳瑛,戈士文.川芎嗪抗大鼠免疫损伤性肝纤维化作用及机制研究[J].中药药理与临床,2007,23(5):60-62
11王宁,贾继东,马雪梅,等.水飞蓟素、己酮可可碱对大鼠胆管阻塞性肝纤维化的疗效及机制[J].胃肠病学和肝病学杂志,2007,16(1):51-56
12孙守才,宋健,李长秦,等.姜黄素对肝纤维化大鼠血清HA、LN、PCⅢ、Ⅳ-C含量及肝组织TGF-β1的影响[J].陕西中医,2007,28(9):1247-1249
13郑旭锐,孙守才,李长秦,等.姜黄素对肝纤维化模型肝组织Ⅰ、Ⅲ型胶原mRNA影响的研究[J].中药材,2007,30(9):1118-1120
14周朝晖,蔡瑜,沈锡中,等.甘草酸对CCL4肝纤维化大鼠肝组织smad7免疫组化表达的影响[J].中国临床医学,2006,13(1):67-69
15黄玲,孙剑勇,朱新宇,等.甘草酸对肝星状细胞增殖、活化和细胞外基质合成的影响[J].中国临床医学,2006,23(1):70-71
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