柔肝颗粒对肝纤维化大鼠TGF-β_1/Smads信号转导通路的影响
摘要
目的:观察柔肝颗粒对肝纤维化大鼠TGF-β1/Smads信号转导通路中Smad3、Smad7及TGF-β1表达的影响,并对其作用机制进行探讨。
方法:Wistar大鼠105只(雄性),体重200g±20g,共分为7组,正常对照组、模型组、秋水仙碱组、大黄虫丸组、柔肝颗粒高、中、低剂量组,每组15只。采用CCL4复合法进行造模,用柔肝颗粒作为治疗组分高、中、低三种剂量,以秋水仙碱作为西药对照组,以大黄虫丸为中药对照组,同时设正常对照组和模型组,造模同时给予药物治疗。除正常空白组外,其余6组首次用50% CCL4与橄榄油的混合液0.5ml/100g背部皮下注射,以后每隔3天用50 % CCL4与橄榄油的混合液0.3ml/100g背部皮下注射,每周称体重一次,并以此调整药物的剂量。柔肝颗粒低、中、高剂量按成人临床等效量(20g·d)进行换算,分别为3.6g/ kg·d, 7.2g/ kg·d,14.4 g/kg·d,稀释不同浓度,1ml/100g。同样大黄虫丸按(6g·d)进行换算为0.18g/kg·d。秋水仙碱每片1mg,参照成人量1mg·d,按体表面积折合为人的2倍量则为0.108mg/ kg·d,动物灌胃,正常空白组和模型组以同体积蒸馏水灌胃。前两周用高脂低蛋白饲料(80%玉米面+0.5%胆固醇+20%猪油)喂养,5%酒精为唯一饮料,两周以后改为普通饲料。正常空白组皮下注射等量生理盐水给予正常饲料及饮用水。8周后取材、取血。检测肝功AST、ALT、PH、TP,肝纤维化指标HA、LN、C-Ⅳ、PCⅢ,观察肝组织学变化:HE染色和Masson三色胶原染色,同时运用免疫组化法检测TGF-β1以及其信号转导分子Smad3、Smad7的蛋白表达,运用RT-PCR技术检测肝组织TGF-β1、Smad3、Smad7mRNA的表达差异。
结果:
1.柔肝颗粒能够降低肝纤维化大鼠血中AST、ALT、PH的水平,升高TP的水平,柔肝颗粒高剂量组最为明显,作用明显优于秋水仙碱组、大黄虫丸组、柔肝颗粒中、低剂量组(P<0.05);柔肝颗粒中、低剂量组与秋水仙碱组、大黄虫丸组药效相当,四者间无显著性差异(P>0.05)。
2.柔肝颗粒能够降低肝纤维化大鼠血中HA、LN、C-Ⅳ、PCⅢ的水平,柔肝颗粒高剂量组最为明显,作用明显优于秋水仙碱组、大黄虫丸组、柔肝颗粒中、低剂量组(P<0.05);柔肝颗粒中、低剂量组与秋水仙碱组、大黄虫丸组药效相当,四者间无显著性差异(P>0.05)。
3.经HE染色后光镜观察显示:柔肝颗粒高剂量组能够减轻肝纤维化大鼠肝组织中炎症活动度及纤维化程度,作用明显优于秋水仙碱组、柔肝颗粒中、低剂量组、大黄虫丸组(P<0.05),柔肝颗粒中、低剂量组与秋水仙碱组、大黄虫丸组药效相当,四者间无显著性差异(P>0.05)。
4.经Masson三色胶原染色后,用MIAS图像分析系统计算肝组织胶原面积与胶原面积占总视野面积比的结果显示:柔肝颗粒高剂量组能够减少肝纤维化大鼠肝组织中胶原总面积及胶原面积占总视野面积的比例,作用明显优于秋水仙碱组、大黄虫丸组、柔肝颗粒中、低剂量组(P<0.05),柔肝颗粒中、低剂量组与秋水仙碱组、大黄虫丸组药效相当,四者间无显著性差异(P>0.05)。
5.柔肝颗粒能够抑制TGF-β1、Smad3,增强Smad7在肝纤维化大鼠肝组织中的蛋白表达,柔肝颗粒高剂量组最为明显,作用明显优于秋水仙碱组、大黄虫丸组、柔肝颗粒中、低剂量组(P<0.05),柔肝颗粒中、低剂量组与秋水仙碱组、大黄虫丸组药效相当,四者间无显著性差异(P>0.05)。
6.柔肝颗粒能够降低TGF-β1、Smad3mRNA在肝纤维化大鼠肝组织中的表达水平,增加Smad7mRNA在肝纤维化大鼠肝组织中的表达水平,柔肝颗粒高剂量组最为明显,作用明显优于秋水仙碱组、大黄虫丸组、柔肝颗粒中、低剂量组(P<0.05),柔肝颗粒中、低剂量组与秋水仙碱组、大黄虫丸组药效相当,四者间无显著性差异(P>0.05)。
7.柔肝颗粒的药效具有一定的剂量依赖关系:高剂量组疗效优于中、低剂量组,中剂量组与低剂量组药效相当,与疗程无明显关系。
结论:
1.柔肝颗粒能明显降低肝纤维化大鼠血中AST、ALT、PH的水平,升高TP的水平,能显著降低肝纤维化大鼠血中HA、LN、C-Ⅳ、PCⅢ的水平。
2.柔肝颗粒能够有效地减少肝纤维化大鼠肝组织中胶原总面积及胶原面积占总视野面积的比例,提示本方有抑制胶原增生以及在肝脏细胞外间质沉积的作用。
3.柔肝颗粒能够抑制肝纤维化大鼠肝组织中TGF-β1以及其信号转导分子Smad3的蛋白表达,增强Smad7的蛋白表达,从而抑制TGF-β1通过信号转导分子Smad3、Smad7促肝纤维化的作用。
4.柔肝颗粒能够降低肝纤维化大鼠肝组织中TGF-β1以及其信号转导分子Smad3mRNA的表达水平,增加Smad7mRNA的表达水平,这可能是柔肝颗粒抗肝纤维化的主要机制之一。
Objective: To investigate the effects and mechanisms of Rougan Decoction resisting hepatic fibrosis induced by CCL4 in rats, provide theoretical basis for clinical medicine.
Methods: One hundred and five male Wistar rats with 200g士20g in weight were randomly divided into blank control group, model control group, colchicines group, Dahuangzhechongwan group, and high、middle and low-dose group of Chinese Medicine, N=15。After one week’s adaptive breeding, fasting 12 hours and weighting. Using the CCL4 composite approach to make the rat modle. Excepting normal blank control group, other six groups firstly use 0.5ml/100g mixture of 50% CCL4 and oliver oil to do hypodermic injection in the back, afterthen inject in the back every other 3 days. Weighing the rats every week to adjust the medicine dosage. Rougan Decoction low, medium and high dosage of adults, the amount of clinical equivalence(20g/d)for conversion, respectively, 3.6g/kg, 7.2g/kg, 14.4g/kg, diluted with different concentrations,1ml/100g.Likewise,by(6g/d)conversion, Dahuangzhechongwan is coincidently 0.108g /kg,1ml/100g. Each colchicine 1mg, referring to adult dosage of 1mg/d, calculation for 0.18mg/kg/d, double of human’s dose according to the body surface. Animal sausage: normal blank group and model control group infuse in stomach with the same volume distilled water, oberseving the ordinary conditions(behavior、hair、stools and so on). First two weeks feeding the rats with high fat and low protein food(80% corn meal, 0.5% cholesterin and 20% lard), only beverage of 5% alcohol, transform commom feed after two weeks. The normal blank group accept hypodermic injection with equivalent normal saline, normal food and drinks.Take materials and blood to detect AST、ALT、PH、TP、HA、LN、C-IV、PCⅢafter eight weeks. Investigating the variation of liver histology: Hestain and Masson trichrome stain. Meanwhile detecting TGF-β1 and protein expression of Smad3、Smad7 by immunohistochemical method.
Results:
1. Rougan Decoction effectively reduce the level of AST、ALT、PH、TP of heptic fibrosis in rats, the influnce of high-dose group is the optimal, better than colchicine group, Dahuangzhechong group, low and medium-dose of Rougan Decoction group(P<0.05).Efficacy of low and medium-dose group of Rougan Decoction, colchicine group and Dahuangzhechong group is similar to each other, there is no obvious difference among the four groups(P>0.05).
2. Rougan Decction can effectively reduce the plasma level of HA、LN、C-Ⅳ、PCⅢof the heptic fibrosis in rats, the therapeutic efficacy of high-dose group is the best, better than colchicine group, Dahuangzhechong group, low and medium-dose group of Rougan Decoction(P<0.05). Efficacy of low and medium-dose group of Rouganjian, colchicine group and Dahuangzhechong group have equivalent effects, no obvious difference exist among the four groups(P>0.05).
3. Observations with light microscope after HE staining: the high-dose group of Rougan Decoction significantly reduce the activity extent of inflammation in hepatic tissue and the degree of hepatic fibrosis, the efficacy of high dose group is better than colchicine group, Dahuangzhechong group, low and medium-dose group of Rougan Decoction(P<0.05). Efficacy of low and medium-dose group of Rougan Decoction, colchicine group and Dahuangzhechong group is almost similar, no obvious difference exist among the four groups(P>0.05).
4. After Masson trichrome stain, the result of counting the collagenous area in hepatic tissue and the proportion of the total collagenous area to the visual field shows that: the high-dose group of Rougan Decoction significently reduce the total collagenous area of hepatic tissue and also decrease the proportion of the total field of vision.The effect is markedly better than colchicine group, Dahuangzhechong group, low and medium-dose group of Rougan Decoction(P<0.05). Efficacy of low and medium-dose group of Rougan Decoction, colchicine group and Dahuangzhechong group is almost resembled, no obvious difference exist among the four groups(P>0.05).
5.Rougan Decoction can effectively inhibit the expression of TGF-β1,Smad3 and markedly increase the expression of Smad7 in the liver tissue, the efficacy of high-dose group is the optimal.The influnce is better than colchicine group, Dahuangzhechong group, low and medium-dose group of Rougan Decocotion(P<0.05). Efficacy of low and medium-dose group of Rougan Decoction, colchicine group and Dahuangzhechong group has a equivalent effect, there is no markble variance among the four groups(P>0.05).
6. Rougan Decoction can effectively reduce the TGF-β1,Smad3mRNA in the liver tissue,and increase the Smad7mRNA in liver tissue levels of high-dose group of Rougan Decoction most obviously was superior to colchicine group, Dahuangzhechong group, low and medium-dose group of Rougan Decoction(P<0.05). Efficacy of low and medium-dose group of Rougan Decoction , colchicine group and Dahuangzhechong group is equivalent ,there is no significant difference among the four groups(P>0.05).
7.The therapic efficacy of Rougan Decoction is related to the definite dosage: the high-dose group is superior to the low and medium one, the medical influnce of the medium-dose group is similar to the low one, no significant relationship with treatment course.
Conclutions:
1. Rougan Decoction effectively reduce the level of AST、ALT、PH and increase TP of heptic fibrosis in rats.It also can effectively reduce the plasma level of HA、LN、C-Ⅳ、PCⅢ.
2. Rougan Decoction apparently reduce the total collagenous area in hepatic tissue and the proportion of the total field to vision which points out Rougan Decoction has efficacy of inhibiting collagenous hyperplasis and collagen sendiment in the extracellular matrix of liver.
3. Rougan Decoction obviously inhibit the expression of TGF-β1,Smad3 and enhance the expression of Smad7 in the hepatic tissue,accordingly inhibit TGF-β1 by means of Smad3、Smad7 to promote hepatic fibrosis.
4. Rougan Decoction can reduce the mRNA expression of TGF-β1 and Smad3 and increase the mRNA expression of Smad7.This may be one mechanism of resist hepatic fibrosis by Rougan Decoction.
方法:Wistar大鼠105只(雄性),体重200g±20g,共分为7组,正常对照组、模型组、秋水仙碱组、大黄虫丸组、柔肝颗粒高、中、低剂量组,每组15只。采用CCL4复合法进行造模,用柔肝颗粒作为治疗组分高、中、低三种剂量,以秋水仙碱作为西药对照组,以大黄虫丸为中药对照组,同时设正常对照组和模型组,造模同时给予药物治疗。除正常空白组外,其余6组首次用50% CCL4与橄榄油的混合液0.5ml/100g背部皮下注射,以后每隔3天用50 % CCL4与橄榄油的混合液0.3ml/100g背部皮下注射,每周称体重一次,并以此调整药物的剂量。柔肝颗粒低、中、高剂量按成人临床等效量(20g·d)进行换算,分别为3.6g/ kg·d, 7.2g/ kg·d,14.4 g/kg·d,稀释不同浓度,1ml/100g。同样大黄虫丸按(6g·d)进行换算为0.18g/kg·d。秋水仙碱每片1mg,参照成人量1mg·d,按体表面积折合为人的2倍量则为0.108mg/ kg·d,动物灌胃,正常空白组和模型组以同体积蒸馏水灌胃。前两周用高脂低蛋白饲料(80%玉米面+0.5%胆固醇+20%猪油)喂养,5%酒精为唯一饮料,两周以后改为普通饲料。正常空白组皮下注射等量生理盐水给予正常饲料及饮用水。8周后取材、取血。检测肝功AST、ALT、PH、TP,肝纤维化指标HA、LN、C-Ⅳ、PCⅢ,观察肝组织学变化:HE染色和Masson三色胶原染色,同时运用免疫组化法检测TGF-β1以及其信号转导分子Smad3、Smad7的蛋白表达,运用RT-PCR技术检测肝组织TGF-β1、Smad3、Smad7mRNA的表达差异。
结果:
1.柔肝颗粒能够降低肝纤维化大鼠血中AST、ALT、PH的水平,升高TP的水平,柔肝颗粒高剂量组最为明显,作用明显优于秋水仙碱组、大黄虫丸组、柔肝颗粒中、低剂量组(P<0.05);柔肝颗粒中、低剂量组与秋水仙碱组、大黄虫丸组药效相当,四者间无显著性差异(P>0.05)。
2.柔肝颗粒能够降低肝纤维化大鼠血中HA、LN、C-Ⅳ、PCⅢ的水平,柔肝颗粒高剂量组最为明显,作用明显优于秋水仙碱组、大黄虫丸组、柔肝颗粒中、低剂量组(P<0.05);柔肝颗粒中、低剂量组与秋水仙碱组、大黄虫丸组药效相当,四者间无显著性差异(P>0.05)。
3.经HE染色后光镜观察显示:柔肝颗粒高剂量组能够减轻肝纤维化大鼠肝组织中炎症活动度及纤维化程度,作用明显优于秋水仙碱组、柔肝颗粒中、低剂量组、大黄虫丸组(P<0.05),柔肝颗粒中、低剂量组与秋水仙碱组、大黄虫丸组药效相当,四者间无显著性差异(P>0.05)。
4.经Masson三色胶原染色后,用MIAS图像分析系统计算肝组织胶原面积与胶原面积占总视野面积比的结果显示:柔肝颗粒高剂量组能够减少肝纤维化大鼠肝组织中胶原总面积及胶原面积占总视野面积的比例,作用明显优于秋水仙碱组、大黄虫丸组、柔肝颗粒中、低剂量组(P<0.05),柔肝颗粒中、低剂量组与秋水仙碱组、大黄虫丸组药效相当,四者间无显著性差异(P>0.05)。
5.柔肝颗粒能够抑制TGF-β1、Smad3,增强Smad7在肝纤维化大鼠肝组织中的蛋白表达,柔肝颗粒高剂量组最为明显,作用明显优于秋水仙碱组、大黄虫丸组、柔肝颗粒中、低剂量组(P<0.05),柔肝颗粒中、低剂量组与秋水仙碱组、大黄虫丸组药效相当,四者间无显著性差异(P>0.05)。
6.柔肝颗粒能够降低TGF-β1、Smad3mRNA在肝纤维化大鼠肝组织中的表达水平,增加Smad7mRNA在肝纤维化大鼠肝组织中的表达水平,柔肝颗粒高剂量组最为明显,作用明显优于秋水仙碱组、大黄虫丸组、柔肝颗粒中、低剂量组(P<0.05),柔肝颗粒中、低剂量组与秋水仙碱组、大黄虫丸组药效相当,四者间无显著性差异(P>0.05)。
7.柔肝颗粒的药效具有一定的剂量依赖关系:高剂量组疗效优于中、低剂量组,中剂量组与低剂量组药效相当,与疗程无明显关系。
结论:
1.柔肝颗粒能明显降低肝纤维化大鼠血中AST、ALT、PH的水平,升高TP的水平,能显著降低肝纤维化大鼠血中HA、LN、C-Ⅳ、PCⅢ的水平。
2.柔肝颗粒能够有效地减少肝纤维化大鼠肝组织中胶原总面积及胶原面积占总视野面积的比例,提示本方有抑制胶原增生以及在肝脏细胞外间质沉积的作用。
3.柔肝颗粒能够抑制肝纤维化大鼠肝组织中TGF-β1以及其信号转导分子Smad3的蛋白表达,增强Smad7的蛋白表达,从而抑制TGF-β1通过信号转导分子Smad3、Smad7促肝纤维化的作用。
4.柔肝颗粒能够降低肝纤维化大鼠肝组织中TGF-β1以及其信号转导分子Smad3mRNA的表达水平,增加Smad7mRNA的表达水平,这可能是柔肝颗粒抗肝纤维化的主要机制之一。
Objective: To investigate the effects and mechanisms of Rougan Decoction resisting hepatic fibrosis induced by CCL4 in rats, provide theoretical basis for clinical medicine.
Methods: One hundred and five male Wistar rats with 200g士20g in weight were randomly divided into blank control group, model control group, colchicines group, Dahuangzhechongwan group, and high、middle and low-dose group of Chinese Medicine, N=15。After one week’s adaptive breeding, fasting 12 hours and weighting. Using the CCL4 composite approach to make the rat modle. Excepting normal blank control group, other six groups firstly use 0.5ml/100g mixture of 50% CCL4 and oliver oil to do hypodermic injection in the back, afterthen inject in the back every other 3 days. Weighing the rats every week to adjust the medicine dosage. Rougan Decoction low, medium and high dosage of adults, the amount of clinical equivalence(20g/d)for conversion, respectively, 3.6g/kg, 7.2g/kg, 14.4g/kg, diluted with different concentrations,1ml/100g.Likewise,by(6g/d)conversion, Dahuangzhechongwan is coincidently 0.108g /kg,1ml/100g. Each colchicine 1mg, referring to adult dosage of 1mg/d, calculation for 0.18mg/kg/d, double of human’s dose according to the body surface. Animal sausage: normal blank group and model control group infuse in stomach with the same volume distilled water, oberseving the ordinary conditions(behavior、hair、stools and so on). First two weeks feeding the rats with high fat and low protein food(80% corn meal, 0.5% cholesterin and 20% lard), only beverage of 5% alcohol, transform commom feed after two weeks. The normal blank group accept hypodermic injection with equivalent normal saline, normal food and drinks.Take materials and blood to detect AST、ALT、PH、TP、HA、LN、C-IV、PCⅢafter eight weeks. Investigating the variation of liver histology: Hestain and Masson trichrome stain. Meanwhile detecting TGF-β1 and protein expression of Smad3、Smad7 by immunohistochemical method.
Results:
1. Rougan Decoction effectively reduce the level of AST、ALT、PH、TP of heptic fibrosis in rats, the influnce of high-dose group is the optimal, better than colchicine group, Dahuangzhechong group, low and medium-dose of Rougan Decoction group(P<0.05).Efficacy of low and medium-dose group of Rougan Decoction, colchicine group and Dahuangzhechong group is similar to each other, there is no obvious difference among the four groups(P>0.05).
2. Rougan Decction can effectively reduce the plasma level of HA、LN、C-Ⅳ、PCⅢof the heptic fibrosis in rats, the therapeutic efficacy of high-dose group is the best, better than colchicine group, Dahuangzhechong group, low and medium-dose group of Rougan Decoction(P<0.05). Efficacy of low and medium-dose group of Rouganjian, colchicine group and Dahuangzhechong group have equivalent effects, no obvious difference exist among the four groups(P>0.05).
3. Observations with light microscope after HE staining: the high-dose group of Rougan Decoction significantly reduce the activity extent of inflammation in hepatic tissue and the degree of hepatic fibrosis, the efficacy of high dose group is better than colchicine group, Dahuangzhechong group, low and medium-dose group of Rougan Decoction(P<0.05). Efficacy of low and medium-dose group of Rougan Decoction, colchicine group and Dahuangzhechong group is almost similar, no obvious difference exist among the four groups(P>0.05).
4. After Masson trichrome stain, the result of counting the collagenous area in hepatic tissue and the proportion of the total collagenous area to the visual field shows that: the high-dose group of Rougan Decoction significently reduce the total collagenous area of hepatic tissue and also decrease the proportion of the total field of vision.The effect is markedly better than colchicine group, Dahuangzhechong group, low and medium-dose group of Rougan Decoction(P<0.05). Efficacy of low and medium-dose group of Rougan Decoction, colchicine group and Dahuangzhechong group is almost resembled, no obvious difference exist among the four groups(P>0.05).
5.Rougan Decoction can effectively inhibit the expression of TGF-β1,Smad3 and markedly increase the expression of Smad7 in the liver tissue, the efficacy of high-dose group is the optimal.The influnce is better than colchicine group, Dahuangzhechong group, low and medium-dose group of Rougan Decocotion(P<0.05). Efficacy of low and medium-dose group of Rougan Decoction, colchicine group and Dahuangzhechong group has a equivalent effect, there is no markble variance among the four groups(P>0.05).
6. Rougan Decoction can effectively reduce the TGF-β1,Smad3mRNA in the liver tissue,and increase the Smad7mRNA in liver tissue levels of high-dose group of Rougan Decoction most obviously was superior to colchicine group, Dahuangzhechong group, low and medium-dose group of Rougan Decoction(P<0.05). Efficacy of low and medium-dose group of Rougan Decoction , colchicine group and Dahuangzhechong group is equivalent ,there is no significant difference among the four groups(P>0.05).
7.The therapic efficacy of Rougan Decoction is related to the definite dosage: the high-dose group is superior to the low and medium one, the medical influnce of the medium-dose group is similar to the low one, no significant relationship with treatment course.
Conclutions:
1. Rougan Decoction effectively reduce the level of AST、ALT、PH and increase TP of heptic fibrosis in rats.It also can effectively reduce the plasma level of HA、LN、C-Ⅳ、PCⅢ.
2. Rougan Decoction apparently reduce the total collagenous area in hepatic tissue and the proportion of the total field to vision which points out Rougan Decoction has efficacy of inhibiting collagenous hyperplasis and collagen sendiment in the extracellular matrix of liver.
3. Rougan Decoction obviously inhibit the expression of TGF-β1,Smad3 and enhance the expression of Smad7 in the hepatic tissue,accordingly inhibit TGF-β1 by means of Smad3、Smad7 to promote hepatic fibrosis.
4. Rougan Decoction can reduce the mRNA expression of TGF-β1 and Smad3 and increase the mRNA expression of Smad7.This may be one mechanism of resist hepatic fibrosis by Rougan Decoction.
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