基于温散法的肝积散抗肝纤维化的机理研究
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摘要
目的：研究中医古典理论“五积”中“肝积”、“脾积”与肝纤维化的相关性,提出“温散”的中医康复法则,在古方基础上创制方药“肝积散”。通过实验研究,观察肝积散对肝纤维化大鼠肝细胞酶、血清肝纤维化标志物、抗脂质过氧化、肝星状细胞及细胞因子的影响,探讨基于温散法的肝积散抗肝纤维化的作用机理。
方法：用Wister雄性大鼠102只,适应性饲养1周后随机分为2组,分别为正常对照组12只、造模组90只。
造模组腹腔注射40%的四氯化碳石蜡油造模剂,首次0.5ml/100g体重,之后每次为0.3m1/100g体重,每周2次,正常对照组注射等量0.9%氯化钠注射液。进行4周造模之后改为每周1次,再进行8周,共进行12周。造模并以10%的酒精作为以上造模组的唯一饮料,正常对照组给以生理盐水。造模4周之后随机抽取造模组中10只处死,证实肝纤维化模型已经建立成功之后的60只大鼠分为正常对照组、模型组、秋水仙碱片组、肝积散低剂量组、肝积散中剂量组、肝积散高剂量组,并开始进行灌胃给药治疗。具体方法：模型组和正常对照组给予蒸馏水1.5ml/100g体重,秋水仙碱片组按每只0.01mg/100g,肝积散低剂量治疗组给予中药复方0.05g/200g,中剂量治疗组给予中药复方0.1g/200g,高剂量治疗组给予中药复方0.2g/200g,共治疗8周。
治疗8周后,眼球后取血后处死大鼠。统一留取大鼠肝右叶标本置于10%甲醛溶液固定,常规石蜡包埋切片,HE染色。
结果：根据病理组织切片所示,本研究所有造模大鼠肝脏均可见不同程度的肝细胞水样变性和脂肪变性、纤维结缔组织增生、炎细胞浸润,表明本研究造模成功。模型组大鼠肝组织炎症和纤维化程度较正常组明显增高(P<0.01)；血清丙氨酸氨基转移酶(ALT)、天冬氨酸氨基转移酶(AST)、透明质酸(HA)、层粘连蛋白(LN)、Ⅲ型前胶原(PCⅢ)、丙二醛(MDA)、转化生长因子β1(TGF-β1)、肝组织结缔组织生长因子(CTGF)、金属蛋白酶组织抑制因子-1(TIMP-1)、CTGFmRNA、TIMP-1mRNA、肝星状细胞大麻素受体CB1和CB2、活化的肝星状细胞的表达均较正常组明显增高(P<0.05,P<0.01)；血清中超氧化物歧化酶(SOD)较正常组明显降低(P<0.01)。
用肝积散高、中、低剂量治疗后,大鼠肝组织炎症和纤维化程度较模型组明显减轻(P<0.05,P<0.01)；血清丙氨酸氨基转移酶(ALT)、天冬氨酸氨基转移酶(AST)、透明质酸(HA)、层粘连蛋白(LN)、Ⅲ型前胶原(PCIII).丙二醛(MDA)、转化生长因子β1(TGF-β1)、肝组织结缔组织生长因子(CTGF).金属蛋白酶组织抑制因子-1(TIMP-1)、 CTGFmRNA、TIMP-1mRNA、肝星状细胞大麻素受体CB1、活化的肝星状细胞的表达均较模型组明显降低(P 结论：基于温散法的肝积散能够下调肝纤维化大鼠血清ALT、AST、HA、LN、PCⅢ、 MDA、TGF-β1、肝组织CTGF、TIMP-1、CTGFmRNA、TIMP-1mRNA.肝星状细胞大麻素受体CB1、活化的肝星状细胞的表达；升高血清SOD和肝星状细胞大麻素受体CB2的表达,这些可能是其抗肝纤维化的部分作用机制。
Objective:To study the ancient literature of Chinese medicine with hepatic fibrosis related "Tive ji""hepatic ji"," spleen ji" theory, the principle and prescription are summarized, put forward " warm yang and expell cole" traditional Chinese medicine rehabilitation law, the Cuban side on the basis of creation of prescription" hepatic ji powder". Through the experimental study, observation of hepatic ji powder on hepatic fibrosis of rat liver cell enzymes, serum markers of hepatic fibrosis, lipid peroxidation, hepatic stellate cell and cell factors, based on warm yang and expell cole's hepatic ji powder on hepatic fibrosis mechanism.
Methods:102male Wister rats were raised for1weeks, adaptability and randomly divided into6groups, each group of17. For normal control group, model group, colchicine tablets group, hepatic ji powder low dose group, hepatic ji powder dose group, high dose group of hepatic ji powder.
In addition to the normal control group, other groups of intraperitoneal injection of40%carbon tetrachloride paraffin molding agent, the first0.5ml/100g body weight, after each0.3ml/100g body weight,2times a week, normal control group received the same amount of0.9%sodium chloride injection. Zhou Zao dies after4tol times a week. By8weeks, a total of12weeks, molding and by10%alcohol as the above model the only drink. Normal control group with normal saline. Model for4weeks after a random sample of each model in any ldeath, confirmed hepatic fibrosis models have been established successfully started after gavage administration in the treatment of. Specific methods are as follows:the model group and normal control group were given distilled waterl.5ml/100g body weight, colchicine tablets group according to each0.01mg/100g, hepatic ji powder low dose treatment group were treated with compound herb0.05g/200g, hepatic ji powder doses treatment group were treated with compound herb0.1g/200g, hepatic ji powder high dose therapy group was given Chinese medicine compound0.2g/200g, for8weeks.
8weeks after treatment, retrobulbar blood rats were sacrificed after. Unified take rat liver right leaf specimens in10%formaldehyde fixed, embedded in paraffin sections stained with HE.
Results:According to the pathological tissue section below, all of this research model of rat liver were observed in varying degrees of liver cell hydropic degeneration and fatty degeneration, fibrous connective tissue hyperplasia, infiltration of inflammatory cells, this study demonstrated successfully mould. in the model group rats liver inflammation and fibrosis degree lower than normal group were significantly higher (P<0.01); serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), hyaluronic acid (HA), laminin (LN), type III procollagen (PC III), MDA (MDA), transforming growth factor beta1(TGF beta1), liver tissue connective tissue growth factor (CTGF), tissue inhibitor of metalloproteinase-1(TIMP-1), CTGFmRNA, TIMP-1mRNA, hepatic stellate cell receptors CB1and CB2, activation of hepatic stellate cells expression were higher than normal group increased (P<0.05, P<0.01); serum superoxide dismutase (SOD) compared with the normal group were significantly reduced (P<0.01).
Using hepatic ji powder high, medium, low dose treatment, rat liver inflammation and fibrosis degree than those in the model group reduced significantly (P<0.05, P<0.01); serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), hyaluronic acid (HA), laminin (LN), type III procollagen (PC III), malondialdehyde (MDA), transforming growth factor beta1(TGF beta1), liver tissue connective tissue growth factor (CTGF), tissue inhibitor of metalloproteinase-1(TIMP-1), CTGFmRNA, TIMP-1mRNA, hepatic stellate cells, activation of the cannabinoid receptor CB1hepatic stellate cell expression than those in model group were significantly reduced (P<0.05, P<0.01); serum superoxide dismutase (SOD) and hepatic stellate cell receptor CB2than those in the model group increased significantly (P<0.01).
Conclusion:Based on warm yang and expell cole's hepatic ji powder downregulation of hepatic fibrosis rats serum ALT, AST, HA, LN, PC III, MDA, TGF beta1, liver tissue CTGF, TIMP-1, CTGFmRNA, TIMP-1mRNA, hepatic stellate cell receptor CB1, activation of hepatic stellate cells express; elevated serum SOD and liver stellate cell receptor CB2expression may be the part of the mechanism of anti hepatic fibrosis.
方法：用Wister雄性大鼠102只,适应性饲养1周后随机分为2组,分别为正常对照组12只、造模组90只。
造模组腹腔注射40%的四氯化碳石蜡油造模剂,首次0.5ml/100g体重,之后每次为0.3m1/100g体重,每周2次,正常对照组注射等量0.9%氯化钠注射液。进行4周造模之后改为每周1次,再进行8周,共进行12周。造模并以10%的酒精作为以上造模组的唯一饮料,正常对照组给以生理盐水。造模4周之后随机抽取造模组中10只处死,证实肝纤维化模型已经建立成功之后的60只大鼠分为正常对照组、模型组、秋水仙碱片组、肝积散低剂量组、肝积散中剂量组、肝积散高剂量组,并开始进行灌胃给药治疗。具体方法：模型组和正常对照组给予蒸馏水1.5ml/100g体重,秋水仙碱片组按每只0.01mg/100g,肝积散低剂量治疗组给予中药复方0.05g/200g,中剂量治疗组给予中药复方0.1g/200g,高剂量治疗组给予中药复方0.2g/200g,共治疗8周。
治疗8周后,眼球后取血后处死大鼠。统一留取大鼠肝右叶标本置于10%甲醛溶液固定,常规石蜡包埋切片,HE染色。
结果：根据病理组织切片所示,本研究所有造模大鼠肝脏均可见不同程度的肝细胞水样变性和脂肪变性、纤维结缔组织增生、炎细胞浸润,表明本研究造模成功。模型组大鼠肝组织炎症和纤维化程度较正常组明显增高(P<0.01)；血清丙氨酸氨基转移酶(ALT)、天冬氨酸氨基转移酶(AST)、透明质酸(HA)、层粘连蛋白(LN)、Ⅲ型前胶原(PCⅢ)、丙二醛(MDA)、转化生长因子β1(TGF-β1)、肝组织结缔组织生长因子(CTGF)、金属蛋白酶组织抑制因子-1(TIMP-1)、CTGFmRNA、TIMP-1mRNA、肝星状细胞大麻素受体CB1和CB2、活化的肝星状细胞的表达均较正常组明显增高(P<0.05,P<0.01)；血清中超氧化物歧化酶(SOD)较正常组明显降低(P<0.01)。
用肝积散高、中、低剂量治疗后,大鼠肝组织炎症和纤维化程度较模型组明显减轻(P<0.05,P<0.01)；血清丙氨酸氨基转移酶(ALT)、天冬氨酸氨基转移酶(AST)、透明质酸(HA)、层粘连蛋白(LN)、Ⅲ型前胶原(PCIII).丙二醛(MDA)、转化生长因子β1(TGF-β1)、肝组织结缔组织生长因子(CTGF).金属蛋白酶组织抑制因子-1(TIMP-1)、 CTGFmRNA、TIMP-1mRNA、肝星状细胞大麻素受体CB1、活化的肝星状细胞的表达均较模型组明显降低(P
Objective:To study the ancient literature of Chinese medicine with hepatic fibrosis related "Tive ji""hepatic ji"," spleen ji" theory, the principle and prescription are summarized, put forward " warm yang and expell cole" traditional Chinese medicine rehabilitation law, the Cuban side on the basis of creation of prescription" hepatic ji powder". Through the experimental study, observation of hepatic ji powder on hepatic fibrosis of rat liver cell enzymes, serum markers of hepatic fibrosis, lipid peroxidation, hepatic stellate cell and cell factors, based on warm yang and expell cole's hepatic ji powder on hepatic fibrosis mechanism.
Methods:102male Wister rats were raised for1weeks, adaptability and randomly divided into6groups, each group of17. For normal control group, model group, colchicine tablets group, hepatic ji powder low dose group, hepatic ji powder dose group, high dose group of hepatic ji powder.
In addition to the normal control group, other groups of intraperitoneal injection of40%carbon tetrachloride paraffin molding agent, the first0.5ml/100g body weight, after each0.3ml/100g body weight,2times a week, normal control group received the same amount of0.9%sodium chloride injection. Zhou Zao dies after4tol times a week. By8weeks, a total of12weeks, molding and by10%alcohol as the above model the only drink. Normal control group with normal saline. Model for4weeks after a random sample of each model in any ldeath, confirmed hepatic fibrosis models have been established successfully started after gavage administration in the treatment of. Specific methods are as follows:the model group and normal control group were given distilled waterl.5ml/100g body weight, colchicine tablets group according to each0.01mg/100g, hepatic ji powder low dose treatment group were treated with compound herb0.05g/200g, hepatic ji powder doses treatment group were treated with compound herb0.1g/200g, hepatic ji powder high dose therapy group was given Chinese medicine compound0.2g/200g, for8weeks.
8weeks after treatment, retrobulbar blood rats were sacrificed after. Unified take rat liver right leaf specimens in10%formaldehyde fixed, embedded in paraffin sections stained with HE.
Results:According to the pathological tissue section below, all of this research model of rat liver were observed in varying degrees of liver cell hydropic degeneration and fatty degeneration, fibrous connective tissue hyperplasia, infiltration of inflammatory cells, this study demonstrated successfully mould. in the model group rats liver inflammation and fibrosis degree lower than normal group were significantly higher (P<0.01); serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), hyaluronic acid (HA), laminin (LN), type III procollagen (PC III), MDA (MDA), transforming growth factor beta1(TGF beta1), liver tissue connective tissue growth factor (CTGF), tissue inhibitor of metalloproteinase-1(TIMP-1), CTGFmRNA, TIMP-1mRNA, hepatic stellate cell receptors CB1and CB2, activation of hepatic stellate cells expression were higher than normal group increased (P<0.05, P<0.01); serum superoxide dismutase (SOD) compared with the normal group were significantly reduced (P<0.01).
Using hepatic ji powder high, medium, low dose treatment, rat liver inflammation and fibrosis degree than those in the model group reduced significantly (P<0.05, P<0.01); serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), hyaluronic acid (HA), laminin (LN), type III procollagen (PC III), malondialdehyde (MDA), transforming growth factor beta1(TGF beta1), liver tissue connective tissue growth factor (CTGF), tissue inhibitor of metalloproteinase-1(TIMP-1), CTGFmRNA, TIMP-1mRNA, hepatic stellate cells, activation of the cannabinoid receptor CB1hepatic stellate cell expression than those in model group were significantly reduced (P<0.05, P<0.01); serum superoxide dismutase (SOD) and hepatic stellate cell receptor CB2than those in the model group increased significantly (P<0.01).
Conclusion:Based on warm yang and expell cole's hepatic ji powder downregulation of hepatic fibrosis rats serum ALT, AST, HA, LN, PC III, MDA, TGF beta1, liver tissue CTGF, TIMP-1, CTGFmRNA, TIMP-1mRNA, hepatic stellate cell receptor CB1, activation of hepatic stellate cells express; elevated serum SOD and liver stellate cell receptor CB2expression may be the part of the mechanism of anti hepatic fibrosis.
引文
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[2]Jimenez W. Endocannabinoids and liver disease [J].Hepatology,2005,41(5):983-985
[3]Zamora-Valdes D, Ponciano-Rodriguez G, Chavez-Tapia N C, et al. The endocannabinoid system in chronic liver disease [J].AnnHepatol,2005,4(4):248-254
[4]Mechoulam R, Ben-Shabat S, Hanus L, et al. Identification of an endogenous 2-monoglyceride, present in canine gut,that binds to cannabinoid receptors [J].Biochem Pharmacol,1995,50(1):83-90
[5]Mahadevan A,Razdan R K. Further advances in the synthesis of endocannabinoid-related ligands[J].AAPS J,2005,7(2):E496-E502
[6]Porter A C, Sauer JM, KniermanMD, et al. Characterization of a novel endocannabinoid, virodhamine, with antagonist activity at the CB1 receptor [J].J Pharmacol Exp Ther,2002,301(3):1020-1024
[7]Friedman S L. Reefer madness? Assessing the effects of cannabinoids with a less jaundiced eye [J].J Hepatol,2007,46(1):180-182
[8]Demuth D G, Molleman A. Cannabinoid signalling [J].Life Sci,2006,78(6):549-563
[9]Teixeira-Clerc F, Julien B, Grenard P, et al. CB1 cannabinoid receptor antagonism:a newstrategy forthe treatment of liver fibrosis [J].Nat Med,2006,12(6):671-676
[10]Julien B,Grenard P,Teixeira-Clerc F,et al.Antifibrogenic role of the cannabinoid receptor CB2in the liver-Gastroenterology,2005,128:742-755
[11]Rippe RA. Life or death:the fate of the hepatic stellate cell following hepatic injury[J]. Hepatology, 1998,27(2):1447-1448
[1]王锡默,姜名瑛,沈映君,等.中药药理学[M].上海：上海科技出版社,1985：104.
[2]FriedmanSL, BansalMB. Reversal of heptic fibrosis-fact or fantasy [J].Hepatology.2006,43:S82-S88
[3]Lotersztajn S, Julien B, Teixeira-Clerc F, etal. Hepatic fibrosis: molecular mechanisms and drug targets Annual review of pharmacology and toxicology,2005,45:605-628
[4]徐列明.肝纤维化中医药治疗和评价[J].药品评价,2007,4：285-288.
[5]徐慧媛.论中医药治疗肝纤维化[J].中国临床医生,2011,39(8)：6-7
[6]王俊文,王天芳,刘建平.肝纤维化中医辨证分型和辨证依据的现代临床文献研究[J].北京中医药大学学报,2008,31：210-214
[7]胡锡琪.乙型肝炎病理[J].胃肠病学,2002,7：295-298
[8]崔焱,贾继东.肝纤维化的药物治疗研究现状[J].药品评价,2007,4(4)：267—269
[9]唐尹萍,胡春玲,陈进文,等.鳖甲抗肝纤维化有效部位的初步筛选研究[J].亚太传统医药,2010,6(11)：27—29
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[18]王珏,裴林,周英,等.藿香、白芍复方逆转慢性肝纤维化的从浊毒论治效果[J].中国临床康复,2006,10(43)：108—111
[19]程明亮,周明玉.中医药防治肝纤维化[J].中华中医药杂志,2011,26(12)：2761-2765
[20]闫晓风,刘平,孙明瑜,等.黄芪汤对二甲基亚硝胺诱导大鼠肝纤维化模型作用的机制.世界华人消化杂志,2010,18(23)：2410-2415
[21]王永林.肝纤维化的病因病机与中医药治疗初探[J].现代中西医结合杂志,2011,20(36)：4693-4694
[2]FriedmanSL,BansalMB.Reversal of heptic fibrosis-fact or fantasy [J]. Hepatology.2006,43:S82-S88
[3]Lotersztajn S,Julien B,Teixeira-Clerc F,etal.Hepatic fibrosis:molecular mechanisms and drug targets Annual review of pharmacology and toxicology,2005,45:605-628
[4]徐列明.肝纤维化中医药治疗和评价[J].药品评价,2007,4：285-288
[5]徐慧媛.论中医药治疗肝纤维化[J].中国临床医生,2011,39(8)：6-7
[6]王俊文,王天芳,刘建平.肝纤维化中医辨证分型和辨证依据的现代临床文献研究[J].北京中医药大学学报,2008,31：210-214
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[9]唐尹萍,胡春玲,陈进文,等.鳖甲抗肝纤维化有效部位的初步筛选研究[J].亚太传统医药,2010,6(11)：27-29
[10]李延昌,孙玉凤,冯志杰,等.赤芍抗肝纤维化的实验研究[J].中国中西医结合杂志,2003,23(10)：767-768
[11]陈在中,王红.川芎嗪抗肝纤维化作用的实验研究[J].中西医结合肝病杂志,2007,7(3)：156-158
[12]赵文丽,姜庆久,吴影.红花对实验性大鼠肝纤维化的抑制作用[J].黑龙江医药科学,2004,27(4)：4-5
[13]张桂灵,石小枫,冉长清,等.三七总皂甙对抗大鼠免疫性肝纤维化的实验研究[J].第三军医大学学报,2007,29(23)：2212-2214
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[15]肖柳英,曾文铤,马佩球,等.荔枝核治疗慢性乙型肝炎48例[J].中医研究,2005,18(7)：21-23
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[17]邹增平,尹常健.复方鳖甲软肝片治疗早期肝硬化临床疗效观察[J].山东中医药大学学报,2007,31(3)：214-215
[18]王珏,裴林,周英,等.藿香、白芍复方逆转慢性肝纤维化的从浊毒论治效果[J].中国临床康复,2006,10(43)：108-111
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[1]Nocerino E, Amato M, Izzo AA. Cannabis and cannabinoid receptors [J].Fitoterapia,2000,71 (Suppl 1):S6-S12
[2]Jimenez W. Endocannabinoids and liver disease [J].Hepatology,2005,41(5):983-985
[3]Zamora-Valdes D, Ponciano-Rodriguez G, Chavez-Tapia N C, et al. The endocannabinoid system in chronic liver disease [J].AnnHepatol,2005,4(4):248-254
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[5]Mahadevan A,Razdan R K. Further advances in the synthesis of endocannabinoid-related ligands[J].AAPS J,2005,7(2):E496-E502
[6]Porter A C, Sauer JM, KniermanMD, et al. Characterization of a novel endocannabinoid, virodhamine, with antagonist activity at the CB1 receptor [J].J Pharmacol Exp Ther,2002,301(3):1020-1024
[7]Friedman S L. Reefer madness? Assessing the effects of cannabinoids with a less jaundiced eye [J].J Hepatol,2007,46(1):180-182
[8]Demuth D G, Molleman A. Cannabinoid signalling [J].Life Sci,2006,78(6):549-563
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[1]王锡默,姜名瑛,沈映君,等.中药药理学[M].上海：上海科技出版社,1985：104.
[2]FriedmanSL, BansalMB. Reversal of heptic fibrosis-fact or fantasy [J].Hepatology.2006,43:S82-S88
[3]Lotersztajn S, Julien B, Teixeira-Clerc F, etal. Hepatic fibrosis: molecular mechanisms and drug targets Annual review of pharmacology and toxicology,2005,45:605-628
[4]徐列明.肝纤维化中医药治疗和评价[J].药品评价,2007,4：285-288.
[5]徐慧媛.论中医药治疗肝纤维化[J].中国临床医生,2011,39(8)：6-7
[6]王俊文,王天芳,刘建平.肝纤维化中医辨证分型和辨证依据的现代临床文献研究[J].北京中医药大学学报,2008,31：210-214
[7]胡锡琪.乙型肝炎病理[J].胃肠病学,2002,7：295-298
[8]崔焱,贾继东.肝纤维化的药物治疗研究现状[J].药品评价,2007,4(4)：267—269
[9]唐尹萍,胡春玲,陈进文,等.鳖甲抗肝纤维化有效部位的初步筛选研究[J].亚太传统医药,2010,6(11)：27—29
[10]李延昌,孙玉凤,冯志杰,等.赤芍抗肝纤维化的实验研究[J].中国中西医结合杂志,2003,23(10)：767—768
[11]陈在中，王红.川芎嗪抗肝纤维化作用的实验研究[J].中西医结合肝病杂志,2007,7(3)：156—158
[12]赵文丽,姜庆久,吴影.红花对实验性大鼠肝纤维化的抑制作用[J].黑龙江医药科学,2004,27(4)：4—5
[13]张桂灵,石小枫,冉长清,等.三七总皂甙对抗大鼠免疫性肝纤维化的实验研究[J].第三军医大学学报,2007,29(23)：2212—2214
[14]孙学强,张晨光,毛致方.水蛭抗纤维化临床疗效观察[J].淮海医药,2008,26(4)：312-313
[15]肖柳英,曾文铤,马佩球,等.荔枝核治疗慢性乙型肝炎48例[J].中医研究,2005,18(7)：21-23
[16]凌霄华,于欣,汪丽燕,等.自拟化纤汤对肝纤维化患者肝功能及血清肝纤维化的影响[J].中医药学报,2006,34(4)：7—8
[17]邹增平,尹常健.复方鳖甲软肝片治疗早期肝硬化临床疗效观察[J].山东中医药大学学报,2007,31(3)：214—215
[18]王珏,裴林,周英,等.藿香、白芍复方逆转慢性肝纤维化的从浊毒论治效果[J].中国临床康复,2006,10(43)：108—111
[19]程明亮,周明玉.中医药防治肝纤维化[J].中华中医药杂志,2011,26(12)：2761-2765
[20]闫晓风,刘平,孙明瑜,等.黄芪汤对二甲基亚硝胺诱导大鼠肝纤维化模型作用的机制.世界华人消化杂志,2010,18(23)：2410-2415
[21]王永林.肝纤维化的病因病机与中医药治疗初探[J].现代中西医结合杂志,2011,20(36)：4693-4694