八味抗纤方抗肝纤维化的临床和实验研究
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摘要
目的:
1.观察八味抗纤方对四氯化碳CCl_4诱导的肝纤维化大鼠的治疗作用,并初步探讨其可能机制。
2.观察八味抗纤方治疗慢性乙型肝炎肝纤维化的临床疗效。
方法:
1.采用四氯化碳橄榄油溶液腹腔注射,每周2次,共8周,制作大鼠肝纤维化模型,自造模之日起,分别给予中药高剂量、低剂量灌胃,观察高、低剂量的八味抗纤方对慢性肝损伤大鼠血清中ALT、AST含量的影响,采用Ishak肝病组织病变计分修正方案,结合H.E.染色、Masson染色和免疫组化染色研究八味抗纤方对肝纤维化大鼠肝组织病理改变的影响,以活化HSC特异性标记α-SMA标记显示活化HSC,以探讨八位抗纤方抗肝纤维化的可能的作用机制。
2.将66例中医辨证为气虚血瘀,湿热未尽的慢性乙型肝炎患者按2:1比例随机分为中药治疗组和对照组,中药治疗组44例,对照组22例,两组患者均给予基本保肝治疗:维生素C片2粒,每日3次+复合维生素B片2粒,每日3次,其中中药治疗组加用八味抗纤方(黄芪、丹参、党参、白术、郁金、黄芩、陈皮、石菖蒲),每日300ml,早晚分服,疗程6个月。观察两组患者中医症状变化、肝功能、血清肝纤维化指标(透明质酸、Ⅲ型前胶原肽、Ⅳ型胶原、层粘连蛋白)等,结合部分病例治疗前后肝组织活检对比,观察八味抗纤方对慢性乙型肝炎肝纤维化的治疗作用。
结果:
1.肝纤维化模型大鼠的血清ALT、AST和TBIL均显著高于正常组,中药低剂量组和高剂量组的AST均显著低于模型组;模型组大鼠肝细胞气球样变性,脂肪变性明显,见到较多的嗜酸性变性及,Masson染色显示肝小叶结构紊乱,汇管区扩大明显,胶原沉积明显增多,纤维间隔较宽,胶原致密,甚至见到假小叶形成;肝组织α-SMA阳性染色区域较宽,着色强烈,汇管区、纤维间隔区、肝窦均有大量表达,纤维间隔区阳性染色呈条带状分布,粗细不均,随肝纤维化程度加重而增多。中药低剂量组、中药高剂量组肝细胞气球样变性,脂肪变性、嗜酸性变性均少于模型组,也有纤维组织增生,程度较轻,纤维间隔较少、较细;α-SMA阳性细胞数少于模型组,部分阳性染色呈细束状分布。根据Ishak肝病组织病变计分修正方案计分,中药低剂量组、中药高剂量组炎症和纤维化程度明显轻于模型组,三组间炎症和纤维化评分均有显著性差异。
2.两组慢性乙型肝炎患者治疗前在年龄、肝功能、血清肝纤维化指标、肝组织病变等方面具有良好可比性。中药治疗组乏力症状显著改善,对血清肝纤维化指标的联合评价显示中药治疗组显著优于对照组(P=0.020),中药尤其可以明显改善患者血清HA的异常升高。18例患者完成治疗前后的二次肝活检,治疗组纤维化分期较治疗前下降的2例,8例无变化,较治疗前升高的1例;对照组4例患者纤维化分期与治疗前相比无变化,3例较治疗前升高。
结论:
八味抗纤方能够抑制CCl_4诱导的大鼠肝纤维化,抑制纤维结缔组织的增生和假小叶的形成。其作用机制可能是:保护肝细胞,抑制肝星状细胞的活化及促进细胞外基质降解。
慢性乙型肝炎肝纤维化的基本病机是气虚血瘀,湿热疫毒残留难尽。中药八味抗纤方具有益气活血,清化湿热,化痰散结的功效,祛邪不伤正,化瘀而生新,能有效改善血清肝纤维化指标,治疗前后肝活检病理组织学变化显示能阻止肝纤维化的进展。
Objective:To observe therapeutic effect of Eight-Ingredient Decoction of Anti-Fibrosis against experimental liver fibrosis induced by carbon tetrachloride(CCl_4),and to discuss its therapeutic mechanism initially.
To observe the clinical effect of the Eight-Ingredient Decoction of Anti-Fibrosis treated liver fibrosis in chronic hepatitis B.
Method:1.The carbon tetrachloride mixed with olive oil was injected intraperitoneal for 16 times to establish the model of the rat with liver fibrosis.Since the beginning of the model establishment,the rats were administrated with high dose of TCM.and low dose of TCM separately.Observe the influence of ALT and AST of the rats with 'hepatic injuries. Referring to of Ishak liver disease pathological changes correction scoring scheme,make use of HE stain,Masson stain and immunohistochemistry stain to study the influence of the Eight-Ingredient Decoction of Anti-Fibrosis against rats' liver fibrosis.Make use of a-SMA immunohistochemistry stain marked the activating HSC to discuss the probably mechanism of Eight-Ingredient Decoction of Anti-Fibrosis against liver fibrosis.
2.Sixty-six patients with chronic hepatitis B who are differentiated with Qi deficiency and blood stasis along with Dampness and Heat are randomly separated into TCM group and control group by ratio of 2:1,with 44 patients in TCM group and 22 patients in control group.The patients in both group were treated with basic liver protection treatment which is made of 2 vitamin C pills t.i.d and vitamin B complex pills t.i.d.The TCM group was also treated with Eight-Ingredient Decoction of Anti-Fibrosis which consists of huangqi, danshen,dangshen,baizhu,yujin,huangqin,chenpi,shichangpu,300ml a day,patients drink the liquor in the morning and at night for six months.To observe the TCM symptoms, liver function,mark of liver fibrosis which is made up with hyaluronic acid,precollagenⅢ,Ⅳtype collagen,laminin.Compared to the liver issue biopsy of some cases before the treatment,we observe the therapeutic action of Eight-Ingredient Decoction of Anti-Fibrosis against liver fibrosis of chronic hepatitis B.
Results:1.The level of ALT,AST,TBIL of model of the rats with liver fibrosis are significantly higher than the normal group.The AST level of both group with high TCM dose and low TCM dose are all significant lower than the model control group.Ballooning degeneration and fatty degeneration of liver cells can be seen very clear in the model group, which has more acidophilic degeneration and apoptotic body.Masson stain shows loss of normal structure of hepatic lobules,portal areas is enlarged,collagen deposition is increased,the fibrous septa is broadened,collagen is compact and even pseudolobule proliferation in the model group.Theα-SMA positive stain region of liver issue is broad and significantly stained along with portal areas,the fibrous septa and hepatic sinusoid,the positive stain of the portal areas shows zonal distribution and the width odds,and increased by the level of liver fibrosis.While in the TCM group,Ballooning degeneration and fatty degeneration of liver cells,acidophilic degeneration and apoptotic body are all fewer than the model group.There are few fibrous tissue and hyperplasia with lower degrees,the fibrous septa are fewer and finer.The number ofα-SMA positive cells is smaller,which shows fine bundles distribution.According to pathological changes of liver disease correction scoring scheme,both level of inflammation and fibrosis of the group with high TCM dose and low TCM dose are significantly lower than that of the model control group. The score of level of inflammation and fibrosis is significantly different.
2.The two group patients of chronic hepatitis B is comparable in age,liver function, multiply serum marks and fibrosis lever of liver biopsy.The patients' symptom of hypodynamia is remarkable improved in TCM treatment group.The TCM treatment group shows marked effect on the basis of multiply serum marks of fibrosis compared to the control group(P=0.020).TCM can improve the abnormally increased of HA.Eighteen patients completed both the liver biopsy before and after the treatment.Two of the patients' lever of fibrosis in the treatment group declined,seven cases remained the same,while only one case ascends.At the same time,five patients' lever of fibrosis in the control group remained the same,and three cases ascend.
Conclusion:
Eight-Ingredient Decoction of Anti-Fibrosis can inhibit rat liver fibrosis induced by CCl_4,fiber connective tissue hyperplasia and formation of pseudo-lobe.The mechanism of it is likely to be inhibition of hepatic stellate cell activation and collagen synthesis to protect hepatic cells.
The basic pathogenesis of chronic hepatitis with liver fibrosis is qi deficiency and blood stasis,and phlegm-damp obstruction in collaterals.This decoction has the function of replenishing qi and activating blood,clearing heat and resolving dampness,resolving phlegm and dissipating mass,which can make vital qi sufficient,circulation of qi and blood fluent,treat both root and manifestation and interrupt live fibrosis.
1.观察八味抗纤方对四氯化碳CCl_4诱导的肝纤维化大鼠的治疗作用,并初步探讨其可能机制。
2.观察八味抗纤方治疗慢性乙型肝炎肝纤维化的临床疗效。
方法:
1.采用四氯化碳橄榄油溶液腹腔注射,每周2次,共8周,制作大鼠肝纤维化模型,自造模之日起,分别给予中药高剂量、低剂量灌胃,观察高、低剂量的八味抗纤方对慢性肝损伤大鼠血清中ALT、AST含量的影响,采用Ishak肝病组织病变计分修正方案,结合H.E.染色、Masson染色和免疫组化染色研究八味抗纤方对肝纤维化大鼠肝组织病理改变的影响,以活化HSC特异性标记α-SMA标记显示活化HSC,以探讨八位抗纤方抗肝纤维化的可能的作用机制。
2.将66例中医辨证为气虚血瘀,湿热未尽的慢性乙型肝炎患者按2:1比例随机分为中药治疗组和对照组,中药治疗组44例,对照组22例,两组患者均给予基本保肝治疗:维生素C片2粒,每日3次+复合维生素B片2粒,每日3次,其中中药治疗组加用八味抗纤方(黄芪、丹参、党参、白术、郁金、黄芩、陈皮、石菖蒲),每日300ml,早晚分服,疗程6个月。观察两组患者中医症状变化、肝功能、血清肝纤维化指标(透明质酸、Ⅲ型前胶原肽、Ⅳ型胶原、层粘连蛋白)等,结合部分病例治疗前后肝组织活检对比,观察八味抗纤方对慢性乙型肝炎肝纤维化的治疗作用。
结果:
1.肝纤维化模型大鼠的血清ALT、AST和TBIL均显著高于正常组,中药低剂量组和高剂量组的AST均显著低于模型组;模型组大鼠肝细胞气球样变性,脂肪变性明显,见到较多的嗜酸性变性及,Masson染色显示肝小叶结构紊乱,汇管区扩大明显,胶原沉积明显增多,纤维间隔较宽,胶原致密,甚至见到假小叶形成;肝组织α-SMA阳性染色区域较宽,着色强烈,汇管区、纤维间隔区、肝窦均有大量表达,纤维间隔区阳性染色呈条带状分布,粗细不均,随肝纤维化程度加重而增多。中药低剂量组、中药高剂量组肝细胞气球样变性,脂肪变性、嗜酸性变性均少于模型组,也有纤维组织增生,程度较轻,纤维间隔较少、较细;α-SMA阳性细胞数少于模型组,部分阳性染色呈细束状分布。根据Ishak肝病组织病变计分修正方案计分,中药低剂量组、中药高剂量组炎症和纤维化程度明显轻于模型组,三组间炎症和纤维化评分均有显著性差异。
2.两组慢性乙型肝炎患者治疗前在年龄、肝功能、血清肝纤维化指标、肝组织病变等方面具有良好可比性。中药治疗组乏力症状显著改善,对血清肝纤维化指标的联合评价显示中药治疗组显著优于对照组(P=0.020),中药尤其可以明显改善患者血清HA的异常升高。18例患者完成治疗前后的二次肝活检,治疗组纤维化分期较治疗前下降的2例,8例无变化,较治疗前升高的1例;对照组4例患者纤维化分期与治疗前相比无变化,3例较治疗前升高。
结论:
八味抗纤方能够抑制CCl_4诱导的大鼠肝纤维化,抑制纤维结缔组织的增生和假小叶的形成。其作用机制可能是:保护肝细胞,抑制肝星状细胞的活化及促进细胞外基质降解。
慢性乙型肝炎肝纤维化的基本病机是气虚血瘀,湿热疫毒残留难尽。中药八味抗纤方具有益气活血,清化湿热,化痰散结的功效,祛邪不伤正,化瘀而生新,能有效改善血清肝纤维化指标,治疗前后肝活检病理组织学变化显示能阻止肝纤维化的进展。
Objective:To observe therapeutic effect of Eight-Ingredient Decoction of Anti-Fibrosis against experimental liver fibrosis induced by carbon tetrachloride(CCl_4),and to discuss its therapeutic mechanism initially.
To observe the clinical effect of the Eight-Ingredient Decoction of Anti-Fibrosis treated liver fibrosis in chronic hepatitis B.
Method:1.The carbon tetrachloride mixed with olive oil was injected intraperitoneal for 16 times to establish the model of the rat with liver fibrosis.Since the beginning of the model establishment,the rats were administrated with high dose of TCM.and low dose of TCM separately.Observe the influence of ALT and AST of the rats with 'hepatic injuries. Referring to of Ishak liver disease pathological changes correction scoring scheme,make use of HE stain,Masson stain and immunohistochemistry stain to study the influence of the Eight-Ingredient Decoction of Anti-Fibrosis against rats' liver fibrosis.Make use of a-SMA immunohistochemistry stain marked the activating HSC to discuss the probably mechanism of Eight-Ingredient Decoction of Anti-Fibrosis against liver fibrosis.
2.Sixty-six patients with chronic hepatitis B who are differentiated with Qi deficiency and blood stasis along with Dampness and Heat are randomly separated into TCM group and control group by ratio of 2:1,with 44 patients in TCM group and 22 patients in control group.The patients in both group were treated with basic liver protection treatment which is made of 2 vitamin C pills t.i.d and vitamin B complex pills t.i.d.The TCM group was also treated with Eight-Ingredient Decoction of Anti-Fibrosis which consists of huangqi, danshen,dangshen,baizhu,yujin,huangqin,chenpi,shichangpu,300ml a day,patients drink the liquor in the morning and at night for six months.To observe the TCM symptoms, liver function,mark of liver fibrosis which is made up with hyaluronic acid,precollagenⅢ,Ⅳtype collagen,laminin.Compared to the liver issue biopsy of some cases before the treatment,we observe the therapeutic action of Eight-Ingredient Decoction of Anti-Fibrosis against liver fibrosis of chronic hepatitis B.
Results:1.The level of ALT,AST,TBIL of model of the rats with liver fibrosis are significantly higher than the normal group.The AST level of both group with high TCM dose and low TCM dose are all significant lower than the model control group.Ballooning degeneration and fatty degeneration of liver cells can be seen very clear in the model group, which has more acidophilic degeneration and apoptotic body.Masson stain shows loss of normal structure of hepatic lobules,portal areas is enlarged,collagen deposition is increased,the fibrous septa is broadened,collagen is compact and even pseudolobule proliferation in the model group.Theα-SMA positive stain region of liver issue is broad and significantly stained along with portal areas,the fibrous septa and hepatic sinusoid,the positive stain of the portal areas shows zonal distribution and the width odds,and increased by the level of liver fibrosis.While in the TCM group,Ballooning degeneration and fatty degeneration of liver cells,acidophilic degeneration and apoptotic body are all fewer than the model group.There are few fibrous tissue and hyperplasia with lower degrees,the fibrous septa are fewer and finer.The number ofα-SMA positive cells is smaller,which shows fine bundles distribution.According to pathological changes of liver disease correction scoring scheme,both level of inflammation and fibrosis of the group with high TCM dose and low TCM dose are significantly lower than that of the model control group. The score of level of inflammation and fibrosis is significantly different.
2.The two group patients of chronic hepatitis B is comparable in age,liver function, multiply serum marks and fibrosis lever of liver biopsy.The patients' symptom of hypodynamia is remarkable improved in TCM treatment group.The TCM treatment group shows marked effect on the basis of multiply serum marks of fibrosis compared to the control group(P=0.020).TCM can improve the abnormally increased of HA.Eighteen patients completed both the liver biopsy before and after the treatment.Two of the patients' lever of fibrosis in the treatment group declined,seven cases remained the same,while only one case ascends.At the same time,five patients' lever of fibrosis in the control group remained the same,and three cases ascend.
Conclusion:
Eight-Ingredient Decoction of Anti-Fibrosis can inhibit rat liver fibrosis induced by CCl_4,fiber connective tissue hyperplasia and formation of pseudo-lobe.The mechanism of it is likely to be inhibition of hepatic stellate cell activation and collagen synthesis to protect hepatic cells.
The basic pathogenesis of chronic hepatitis with liver fibrosis is qi deficiency and blood stasis,and phlegm-damp obstruction in collaterals.This decoction has the function of replenishing qi and activating blood,clearing heat and resolving dampness,resolving phlegm and dissipating mass,which can make vital qi sufficient,circulation of qi and blood fluent,treat both root and manifestation and interrupt live fibrosis.
引文
1 晏军,王熙.王锦之教授治疗肝纤维化经验撷菁.中国医药学刊,2001,19(5):410-411
2 钱英.“体用共调”治疗肝纤维化的经验.江苏中医药,2007,39(5):7
3 刘绍能,刘为民.从络脉理论探讨肝纤维化证治规律.中国中医药信息杂志,2003,10(7):3-4
4 杨玲,朱清静,张赤志.软坚消痰活血化瘀法抗肝纤维化的作用机制概述.中医药学刊,2005,23(11):1969-1971
5 杨倩,冯玉彦,蒋树林.姚希贤瘀血论治慢性肝纤维化经验.中华中医药杂志,2007,22(3):168-171
6 尹珊珊,王宝恩,王泰龄,等.复方861治疗慢性乙型肝炎肝纤维化与早期肝硬化的临床研究.中华肝脏病杂志,2004,12(8):467-470
7 冯继红,贾玉杰.肝复康抗肝纤维化临床疗效的初步观察.中华临床医学实践杂志,2004,3(6):495-496
8 王志华.扶正化瘀法为主治疗慢性重型肝炎后肝纤维化的临床观察.中国中话医结合杂志,2004,24(7):647-648
9 黄古叶.健肝散治疗慢性乙型肝炎肝纤维化35例.中国中西医结合消化杂志,2005,13(1):53-54
10 刘平,胡义扬,刘成,等.扶正化瘀胶囊干预慢性乙型肝炎肝纤维化作用的多中心临床观察.世界科学技术:中医药现代化,2005,7(1):24-32
11 胡义扬,刘平,刘成,等.扶正化瘀胶囊抗肝纤维化的适应症和疗效判断的非创伤性指征探讨——50例慢性乙型肝炎患者治疗前后肝活检资料分析.中国中西医结合杂志,2006,26(1):18-22
12 顾杰,洪嘉禾,徐列明,等.扶正化瘀胶囊对肝硬化患者门脉血流动力学的影响.上海中医药杂志,2005,39(11):31-32
13 黄运坤,赵长青,胡义扬,等.扶正化瘀胶囊对慢性肝病患者血清氨基酸谱异常的调整作用.中华肝脏病杂志,2005,13(3):230-231
14 周光德,李文淑,赵景民,等.复方鳖甲软肝片抗肝纤维化机制的临床病理研究.解放军医学杂志,2004,29(7):563-564
15 王先开,赵春,娄国强.γ-干扰素合复方鳖甲软肝片抗肝纤维化疗效观察.浙江中西医结合杂志,2005,15(8):491-492
16 黄莉,王伟东,王琳.柔肝汤治疗慢性病毒性肝炎肝肾虚兼血瘀证肝纤维化临床观察.中华实用中西医杂志,2006,19(9):1007-1010
17 赵景民,周光德,李文淑,等.复方鳖甲软肝片抗肝纤维化机制的实验研究.解放军医学杂志,2004,29(7):560-562
18 郭顺根,张玮,戴敏,等.复方鳖甲软肝方对肝星形细胞胶原表达及降解的影响.中国临床康复,2004,8(27):5890-5893
19 崔红燕,姜哲浩,刘成,等.扶正化瘀方对肝纤维化大鼠间质性基质金属蛋白酶活性的影响.上海中医药大学学报,2003,17(3):35-38
20 胡泰洪,葛娅,张赤志,等.抗纤软肝颗粒对肝纤维化大鼠肝脏MMP-1 mRNA及TIMP-1mRNA表达的影响.中国中医药信息杂志,2004,11(4):303-304
21 马雪梅,赵新颜,阴赪宏,等.复方861抑制四氯化碳大鼠肝纤维化模Ⅰ、Ⅲ型胶原表mRNA 达的研究.中医药通报,2004,3(6):39-41
22 王芳,齐京,梁代英,等.益气活血解毒化痰方对DMN诱导的大鼠肝纤维化的预防和治疗.北京中医药大学学报,2005,28(3):50-54
23 姜春萌,刘成海,刘成.扶正化瘀胶囊对肝星状细胞激活的干预.中国中西医结合消化杂志,2003,11(5):280-283
24 丁惠国,唐淑珍,王宝恩,等.复方861对肝星状细胞分泌表达内皮素-1蛋白及mRNA的影响.中华肝脏病杂志,2003,11(5):308-308
25 王海燕,朱跃科,申凤俊,等.复方861对DMN损伤性大鼠肝纤维化肝脏中MMP-2表达的影响.中国现代医药杂志,2007,9(4):31-34
26 Yang L,Zhang CZ,Zhu QJ.Kangxian ruangan keli inhibits hepatic stellate cell proliferation mediated by PDGF.World Journal of Gastroenterology,2003,9(9):2050
27 谭春雨,谭善忠,蒋健,等.扶正化瘀方对肝纤维化大鼠肝脏明胶酶、TIMP-2和星状细胞凋亡的影响.上海中医药大学学报,2003,17(4):40-44
28 刘林,杨玲,严红梅,等.抗纤软肝颗粒药物血清对肝星状细胞整合素信号及凋亡的影响.中医药学刊,2006,24(12):2269-2271
29 耿晓霞,吴亚云,程明亮.丹芍化纤胶囊对体外活化HSCs增殖、凋亡及Fas/FasL途径的影响.中华中医药杂志,2005,20(7):404-408
30 孙劲晖,丁霞,田德禄.调肝理脾方药血清对大鼠离体肝星状细胞相关凋亡基因产物的影响.中医药学报,2005,33(6):6-7
31 刘莺,刘平,王磊.扶正化瘀方对肝纤维化大鼠不同病理阶段肝组织蛋白质组变化的影响.中华肝脏病杂志,2006,14(6):422-425
32 刘莺,刘平,胡义扬,等.纤维化大鼠肝组织与物质代谢相关蛋白质动态变化及扶正化瘀方的调节作用.中国中西医结合杂志,2006,26(3):224-227
33 刘莺,刘平,徐列明.CC14大鼠肝纤维化形成与消减过程中肝组织蛋白质组的动态变化及扶正化瘀方的干预作用.中西医结合肝病杂志,2005,15(3):146-148
34 刘杰,王吉耀,魏黎明,等.扶正化瘀方干预肝硬化大鼠血浆蛋白质组的初步研究.中华医学杂志,2007,87(18):1272-1275
1 Hernandez-Munoz R,Diaz-Munoz M,Suarez J,et al.Adenosine partially prevents cirrhosis induced by carbon tetrachloride in rats.Hepatology,1990,12(2):242-8
2 Ishak K,Baptista A,Bianchi L,et al.Histological grading and staging of chronic hepatitis.J Hepatol,1995,22(6):696-9
3 A:Schmitt-Graff,S.Kruger,F.Bochard,et al.Modulation of Alpha Smooth Muscle Actin and Desmin Expression in Perisinusoidal Cells of Normal and Diseased Human Livers.American Journal of Pathology,1991,138(5):1233-1242
4 Friedman SL.Liver fibrosis--from bench to bedside.J Hepatol,2003,38 Suppl 1:S38-53
5 Arthur MJ,Mann DA,Iredale JP.Tissue inhibitors of metalloproteinases,hepatic stellate cells and liver fibrosis.J Gastroenterol Hepatol.1998 Sep;13 Suppl:S33-8
6 Friedman SL.Molecular regulation of hepatic fibrosis,an integrated cellular response to tissue injury.Biol Chem.2000 Jan 28;275(4):2247-50
7 Sato M,Suzuki S,Senoo H.Hepatic stellate cells:unique characteristics in cell biology and phenotype.Cell Struct Funct.2003 Apr;28(2):105-12
8 Murphy FR,Issa R,Zhou X.et al.Inhibition of apoptosis of activated hepatic stellate cells by tissue inhibitor of metalloproteinase-1 is mediated via effects on matrix metalloproteinase inhibition:implications for reversibility of liver fibrosis.J Biol Chem,2002,277(13):11069-76
9 Kmiec Z.Cooperation of liver cells in health and disease[J].Adv Anat Embryol Cell Biol,2001,161:Ⅲ-ⅩⅢ,1-151
10 Sokol RJ.Liver cell injury and fibrosis.J Pediatr Gastroenterol Nutr,2002,35(Suppl 1l):S7-10
11 蒋树林,姚希贤,郭林选.CCl_4和PS两种SD大鼠模型肝纤维化进程时效关系对比研究.中国实验动物学报,2003,11(2):81-84
12 北京中医医院编,关幼波临床经验选。人民卫生出版社,1979:12
13 刘树农编著,刘树农医论选,上海科学技术出版社,1987:292
14 马红,王宝恩,陈翌阳,等.黄芪对肝纤维化治疗作用的实验研究.中华肝脏病杂志,1997,5(1):32-33
15 王要军,权启镇,孙自勤,等.黄芪对实验性肝纤维化组织ICAM-1表达影响的免疫组化研究.中国临床药理学与治疗学杂志,2000,5(1):49-51
16 周贤,戴立里,贾丽萍,等.黄芪注射液对肝纤维化抑制作用的实验研究.中华肝脏病杂志,2005,13(8):575-578
17 刘成海,刘平,胡义扬,等.丹酚酸B盐对转化生长因子-β1刺激肝星状细胞活化与胞内信号转导的作用.中华医学杂志,2002,82(18):1267-1272,2002,82(18):1267-1272
18 郑元义,戴立里,王文兵,等.丹参素治疗肝纤维化及其作用机制研究.中华肝脏病杂志,2003,11(5):288-290
19 王占魁,姜慧卿,刘丽,等.丹参单体IH764-3抗肝纤维化作用研究.中国中西医结合消化杂志,2004,12(3):140-142
20 Wasser S,Ho JM,Ang HK,et al.Salvia miltiorrhiza reduces experimentally-induced hepatic fibrosis in rats.J Hepatol,1998,29(5):760-71
21 蔡方刚,林永堃,翁山耕,等.丹参对大鼠肝星状细胞转化生长因子β1与Ⅰ型胶原mRNA表达的影响.中国现代医学杂志,2002,12(13):17-21
22 Rukkumani R,Aruna K,Varma PS,et al.Curcumin influences hepatic expression patterns of matrix metalloproteinases in liver toxicity.Ital J Biochem,2004,53(2):61-6
23 Xu J,Fu Y,Chen A.Activation of peroxisome proliferator-activated receptor-gamma contributes to the inhibitory effects of curcumin on rat hepatic stellate cell growth.Am J Physiol Gastrointest Liver Physiol,2003,285(1):G20-30
24 KangHC,Nan JX,Park PH,et al.Curcumin inhibits collagen synthesis and hepatic stellate cell activation in-vivo and in-vitro.JPharm Pharmacol,2002,54(1):119-26
25 Zheng S,Chen A.Activation of PPARgamma is required for curcumin to induce apoptosis and to inhibit the expression of extracellular matrix genes in hepatic stellate cells in vitro.Biochem J,2004,384(Pt 1):149-57
26 Shimizu I.Sho-saiko-to:Japanese herbal medicine for protection against hepatic fibrosis and carcinoma.Gastroenterol Hepatology,15(Suppl):84-90
27 刘平主编,现代中医肝脏病学,人民卫生出版社,2002,540-546
28 江宇泳,王宪波.复方中药抗肝纤维化的研究进展.时珍国医国药,2008,19(11):2725-2727
29 展玉涛.魏红山.李定国.肝星状细胞活化的细胞学基础.临床肝胆病杂志,2003,16(3):140-141
30 Gressner AM.Transdi5erentation of hepatic stellate cells(Ito cells) to myofibroblast:a key event in hepatic fibrosis[J]Kidney international.1996,49(s):39
31 Gressner AM,Lotfi S,Gressner G et al.Synergism between hepatocytesand kuffer cells in the activation of fat-storing cells(J).J Hepatol,1993,19(1):117
32 Rokey DC,Housset CN,Friedman SL.Activation dependent contractility of rat hepatic lipocytes in culture and in uiuo.J Clin Invest,1993;92:1795
1 中华医学会传染病和寄生虫病学分会、肝病学分会.病毒性肝炎防治方案.中华肝脏病杂志,2000,8:324-329
2 Dienstag J.The role of liver biopsy in chronic hepatitis C.Hepatology 2002;36:S152-160
3 Patel K,Lajoie A,Heaton S,Clinical use of hyaluronic acid as a predictor of fibrosis change in hepatitis C.Gastroenterol Hepatol 2003;18:253-257
4 牛春红,田新强,米亚英.慢性肝病患者肝纤维化血清学指标与肝组织纤维化分期的量化关系.山西医药杂志,2008,37(6):494-496
5 马瑞琼,张书永,张卫光等.实验性肝纤维化大鼠胶原网络构筑的扫描电镜观察.解剖学报,2004,35(3):302-305
6 王宪波,刘平,唐志鹏等.肝窦毛细血管化的形成机制研究.中华消化杂志,2004,24(5):289-292
7 Murawaki Y,Koda M,Okamoto K,et al.Diagnostic value of serum type Ⅳ collagen test in comparison with platelet count for predicting the fibrotic stage in patients with chronic hepatitis C.,Gastroenterol Hepatol 2001;16:777-781
8 Walsh KM,Fletcher A,MacSween RN,et al.Basement membrane peptides as markers of liver disease in chronic hepatitis C.,Hepatol 2000;32:325-330
9 王宝恩,贾继东,张文胜.肝纤维化无创诊断模型的研究进展.中国中西医结合杂志,2006,26(1):5-7
10 陆伦根,曾民德.肝纤维化的诊断和评估.中华肝脏病杂志,2005,13(8):603-604.
11 蒋忠胜,温小凤.慢性肝病肝纤维化非创伤性诊断模型的研究进展.肝脏,2008,13(5):430-433
12 王丽春,赵连三,唐红,等。血清透明质酸、Ⅲ型前胶原、Ⅳ型胶原及层粘蛋白水平与实 验性肝纤维化的关系。华西医学,2006,20(1):91-92
13 TakamatsuS,Nakabayashi H.Okamoto Y,et al.Noninvasive determination of liver collagen content in chronic hepatitis.Multivariate regression modeling with blood chemical parameters as variables.J Gastroenterol,1997,32:355-360
2 钱英.“体用共调”治疗肝纤维化的经验.江苏中医药,2007,39(5):7
3 刘绍能,刘为民.从络脉理论探讨肝纤维化证治规律.中国中医药信息杂志,2003,10(7):3-4
4 杨玲,朱清静,张赤志.软坚消痰活血化瘀法抗肝纤维化的作用机制概述.中医药学刊,2005,23(11):1969-1971
5 杨倩,冯玉彦,蒋树林.姚希贤瘀血论治慢性肝纤维化经验.中华中医药杂志,2007,22(3):168-171
6 尹珊珊,王宝恩,王泰龄,等.复方861治疗慢性乙型肝炎肝纤维化与早期肝硬化的临床研究.中华肝脏病杂志,2004,12(8):467-470
7 冯继红,贾玉杰.肝复康抗肝纤维化临床疗效的初步观察.中华临床医学实践杂志,2004,3(6):495-496
8 王志华.扶正化瘀法为主治疗慢性重型肝炎后肝纤维化的临床观察.中国中话医结合杂志,2004,24(7):647-648
9 黄古叶.健肝散治疗慢性乙型肝炎肝纤维化35例.中国中西医结合消化杂志,2005,13(1):53-54
10 刘平,胡义扬,刘成,等.扶正化瘀胶囊干预慢性乙型肝炎肝纤维化作用的多中心临床观察.世界科学技术:中医药现代化,2005,7(1):24-32
11 胡义扬,刘平,刘成,等.扶正化瘀胶囊抗肝纤维化的适应症和疗效判断的非创伤性指征探讨——50例慢性乙型肝炎患者治疗前后肝活检资料分析.中国中西医结合杂志,2006,26(1):18-22
12 顾杰,洪嘉禾,徐列明,等.扶正化瘀胶囊对肝硬化患者门脉血流动力学的影响.上海中医药杂志,2005,39(11):31-32
13 黄运坤,赵长青,胡义扬,等.扶正化瘀胶囊对慢性肝病患者血清氨基酸谱异常的调整作用.中华肝脏病杂志,2005,13(3):230-231
14 周光德,李文淑,赵景民,等.复方鳖甲软肝片抗肝纤维化机制的临床病理研究.解放军医学杂志,2004,29(7):563-564
15 王先开,赵春,娄国强.γ-干扰素合复方鳖甲软肝片抗肝纤维化疗效观察.浙江中西医结合杂志,2005,15(8):491-492
16 黄莉,王伟东,王琳.柔肝汤治疗慢性病毒性肝炎肝肾虚兼血瘀证肝纤维化临床观察.中华实用中西医杂志,2006,19(9):1007-1010
17 赵景民,周光德,李文淑,等.复方鳖甲软肝片抗肝纤维化机制的实验研究.解放军医学杂志,2004,29(7):560-562
18 郭顺根,张玮,戴敏,等.复方鳖甲软肝方对肝星形细胞胶原表达及降解的影响.中国临床康复,2004,8(27):5890-5893
19 崔红燕,姜哲浩,刘成,等.扶正化瘀方对肝纤维化大鼠间质性基质金属蛋白酶活性的影响.上海中医药大学学报,2003,17(3):35-38
20 胡泰洪,葛娅,张赤志,等.抗纤软肝颗粒对肝纤维化大鼠肝脏MMP-1 mRNA及TIMP-1mRNA表达的影响.中国中医药信息杂志,2004,11(4):303-304
21 马雪梅,赵新颜,阴赪宏,等.复方861抑制四氯化碳大鼠肝纤维化模Ⅰ、Ⅲ型胶原表mRNA 达的研究.中医药通报,2004,3(6):39-41
22 王芳,齐京,梁代英,等.益气活血解毒化痰方对DMN诱导的大鼠肝纤维化的预防和治疗.北京中医药大学学报,2005,28(3):50-54
23 姜春萌,刘成海,刘成.扶正化瘀胶囊对肝星状细胞激活的干预.中国中西医结合消化杂志,2003,11(5):280-283
24 丁惠国,唐淑珍,王宝恩,等.复方861对肝星状细胞分泌表达内皮素-1蛋白及mRNA的影响.中华肝脏病杂志,2003,11(5):308-308
25 王海燕,朱跃科,申凤俊,等.复方861对DMN损伤性大鼠肝纤维化肝脏中MMP-2表达的影响.中国现代医药杂志,2007,9(4):31-34
26 Yang L,Zhang CZ,Zhu QJ.Kangxian ruangan keli inhibits hepatic stellate cell proliferation mediated by PDGF.World Journal of Gastroenterology,2003,9(9):2050
27 谭春雨,谭善忠,蒋健,等.扶正化瘀方对肝纤维化大鼠肝脏明胶酶、TIMP-2和星状细胞凋亡的影响.上海中医药大学学报,2003,17(4):40-44
28 刘林,杨玲,严红梅,等.抗纤软肝颗粒药物血清对肝星状细胞整合素信号及凋亡的影响.中医药学刊,2006,24(12):2269-2271
29 耿晓霞,吴亚云,程明亮.丹芍化纤胶囊对体外活化HSCs增殖、凋亡及Fas/FasL途径的影响.中华中医药杂志,2005,20(7):404-408
30 孙劲晖,丁霞,田德禄.调肝理脾方药血清对大鼠离体肝星状细胞相关凋亡基因产物的影响.中医药学报,2005,33(6):6-7
31 刘莺,刘平,王磊.扶正化瘀方对肝纤维化大鼠不同病理阶段肝组织蛋白质组变化的影响.中华肝脏病杂志,2006,14(6):422-425
32 刘莺,刘平,胡义扬,等.纤维化大鼠肝组织与物质代谢相关蛋白质动态变化及扶正化瘀方的调节作用.中国中西医结合杂志,2006,26(3):224-227
33 刘莺,刘平,徐列明.CC14大鼠肝纤维化形成与消减过程中肝组织蛋白质组的动态变化及扶正化瘀方的干预作用.中西医结合肝病杂志,2005,15(3):146-148
34 刘杰,王吉耀,魏黎明,等.扶正化瘀方干预肝硬化大鼠血浆蛋白质组的初步研究.中华医学杂志,2007,87(18):1272-1275
1 Hernandez-Munoz R,Diaz-Munoz M,Suarez J,et al.Adenosine partially prevents cirrhosis induced by carbon tetrachloride in rats.Hepatology,1990,12(2):242-8
2 Ishak K,Baptista A,Bianchi L,et al.Histological grading and staging of chronic hepatitis.J Hepatol,1995,22(6):696-9
3 A:Schmitt-Graff,S.Kruger,F.Bochard,et al.Modulation of Alpha Smooth Muscle Actin and Desmin Expression in Perisinusoidal Cells of Normal and Diseased Human Livers.American Journal of Pathology,1991,138(5):1233-1242
4 Friedman SL.Liver fibrosis--from bench to bedside.J Hepatol,2003,38 Suppl 1:S38-53
5 Arthur MJ,Mann DA,Iredale JP.Tissue inhibitors of metalloproteinases,hepatic stellate cells and liver fibrosis.J Gastroenterol Hepatol.1998 Sep;13 Suppl:S33-8
6 Friedman SL.Molecular regulation of hepatic fibrosis,an integrated cellular response to tissue injury.Biol Chem.2000 Jan 28;275(4):2247-50
7 Sato M,Suzuki S,Senoo H.Hepatic stellate cells:unique characteristics in cell biology and phenotype.Cell Struct Funct.2003 Apr;28(2):105-12
8 Murphy FR,Issa R,Zhou X.et al.Inhibition of apoptosis of activated hepatic stellate cells by tissue inhibitor of metalloproteinase-1 is mediated via effects on matrix metalloproteinase inhibition:implications for reversibility of liver fibrosis.J Biol Chem,2002,277(13):11069-76
9 Kmiec Z.Cooperation of liver cells in health and disease[J].Adv Anat Embryol Cell Biol,2001,161:Ⅲ-ⅩⅢ,1-151
10 Sokol RJ.Liver cell injury and fibrosis.J Pediatr Gastroenterol Nutr,2002,35(Suppl 1l):S7-10
11 蒋树林,姚希贤,郭林选.CCl_4和PS两种SD大鼠模型肝纤维化进程时效关系对比研究.中国实验动物学报,2003,11(2):81-84
12 北京中医医院编,关幼波临床经验选。人民卫生出版社,1979:12
13 刘树农编著,刘树农医论选,上海科学技术出版社,1987:292
14 马红,王宝恩,陈翌阳,等.黄芪对肝纤维化治疗作用的实验研究.中华肝脏病杂志,1997,5(1):32-33
15 王要军,权启镇,孙自勤,等.黄芪对实验性肝纤维化组织ICAM-1表达影响的免疫组化研究.中国临床药理学与治疗学杂志,2000,5(1):49-51
16 周贤,戴立里,贾丽萍,等.黄芪注射液对肝纤维化抑制作用的实验研究.中华肝脏病杂志,2005,13(8):575-578
17 刘成海,刘平,胡义扬,等.丹酚酸B盐对转化生长因子-β1刺激肝星状细胞活化与胞内信号转导的作用.中华医学杂志,2002,82(18):1267-1272,2002,82(18):1267-1272
18 郑元义,戴立里,王文兵,等.丹参素治疗肝纤维化及其作用机制研究.中华肝脏病杂志,2003,11(5):288-290
19 王占魁,姜慧卿,刘丽,等.丹参单体IH764-3抗肝纤维化作用研究.中国中西医结合消化杂志,2004,12(3):140-142
20 Wasser S,Ho JM,Ang HK,et al.Salvia miltiorrhiza reduces experimentally-induced hepatic fibrosis in rats.J Hepatol,1998,29(5):760-71
21 蔡方刚,林永堃,翁山耕,等.丹参对大鼠肝星状细胞转化生长因子β1与Ⅰ型胶原mRNA表达的影响.中国现代医学杂志,2002,12(13):17-21
22 Rukkumani R,Aruna K,Varma PS,et al.Curcumin influences hepatic expression patterns of matrix metalloproteinases in liver toxicity.Ital J Biochem,2004,53(2):61-6
23 Xu J,Fu Y,Chen A.Activation of peroxisome proliferator-activated receptor-gamma contributes to the inhibitory effects of curcumin on rat hepatic stellate cell growth.Am J Physiol Gastrointest Liver Physiol,2003,285(1):G20-30
24 KangHC,Nan JX,Park PH,et al.Curcumin inhibits collagen synthesis and hepatic stellate cell activation in-vivo and in-vitro.JPharm Pharmacol,2002,54(1):119-26
25 Zheng S,Chen A.Activation of PPARgamma is required for curcumin to induce apoptosis and to inhibit the expression of extracellular matrix genes in hepatic stellate cells in vitro.Biochem J,2004,384(Pt 1):149-57
26 Shimizu I.Sho-saiko-to:Japanese herbal medicine for protection against hepatic fibrosis and carcinoma.Gastroenterol Hepatology,15(Suppl):84-90
27 刘平主编,现代中医肝脏病学,人民卫生出版社,2002,540-546
28 江宇泳,王宪波.复方中药抗肝纤维化的研究进展.时珍国医国药,2008,19(11):2725-2727
29 展玉涛.魏红山.李定国.肝星状细胞活化的细胞学基础.临床肝胆病杂志,2003,16(3):140-141
30 Gressner AM.Transdi5erentation of hepatic stellate cells(Ito cells) to myofibroblast:a key event in hepatic fibrosis[J]Kidney international.1996,49(s):39
31 Gressner AM,Lotfi S,Gressner G et al.Synergism between hepatocytesand kuffer cells in the activation of fat-storing cells(J).J Hepatol,1993,19(1):117
32 Rokey DC,Housset CN,Friedman SL.Activation dependent contractility of rat hepatic lipocytes in culture and in uiuo.J Clin Invest,1993;92:1795
1 中华医学会传染病和寄生虫病学分会、肝病学分会.病毒性肝炎防治方案.中华肝脏病杂志,2000,8:324-329
2 Dienstag J.The role of liver biopsy in chronic hepatitis C.Hepatology 2002;36:S152-160
3 Patel K,Lajoie A,Heaton S,Clinical use of hyaluronic acid as a predictor of fibrosis change in hepatitis C.Gastroenterol Hepatol 2003;18:253-257
4 牛春红,田新强,米亚英.慢性肝病患者肝纤维化血清学指标与肝组织纤维化分期的量化关系.山西医药杂志,2008,37(6):494-496
5 马瑞琼,张书永,张卫光等.实验性肝纤维化大鼠胶原网络构筑的扫描电镜观察.解剖学报,2004,35(3):302-305
6 王宪波,刘平,唐志鹏等.肝窦毛细血管化的形成机制研究.中华消化杂志,2004,24(5):289-292
7 Murawaki Y,Koda M,Okamoto K,et al.Diagnostic value of serum type Ⅳ collagen test in comparison with platelet count for predicting the fibrotic stage in patients with chronic hepatitis C.,Gastroenterol Hepatol 2001;16:777-781
8 Walsh KM,Fletcher A,MacSween RN,et al.Basement membrane peptides as markers of liver disease in chronic hepatitis C.,Hepatol 2000;32:325-330
9 王宝恩,贾继东,张文胜.肝纤维化无创诊断模型的研究进展.中国中西医结合杂志,2006,26(1):5-7
10 陆伦根,曾民德.肝纤维化的诊断和评估.中华肝脏病杂志,2005,13(8):603-604.
11 蒋忠胜,温小凤.慢性肝病肝纤维化非创伤性诊断模型的研究进展.肝脏,2008,13(5):430-433
12 王丽春,赵连三,唐红,等。血清透明质酸、Ⅲ型前胶原、Ⅳ型胶原及层粘蛋白水平与实 验性肝纤维化的关系。华西医学,2006,20(1):91-92
13 TakamatsuS,Nakabayashi H.Okamoto Y,et al.Noninvasive determination of liver collagen content in chronic hepatitis.Multivariate regression modeling with blood chemical parameters as variables.J Gastroenterol,1997,32:355-360
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