自拟加味四逆散抗肝纤维化的实验研究
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摘要
目的:观察加味四逆散对实验性犬肝纤维化的预防效果和初步探索其机理,从而为该药临床应用提供较好的理论及实验依据。
方法:选用24只健康成年杂交犬,体重10-15Kg,雌雄不限,常规免疫驱虫一个星期后开始实验。随机分为三组:模型组,中药组,西药组。动物自由采食与饮水,试验期为8周。采用皮下多点注射45%的CCl4菜籽油乳剂制作肝纤维化模型。中药组在给予CCl_4的同时口服加味四逆散浓缩煎剂。西药组在给予CCl_4的同时口服秋水仙碱。试验前后,每周从犬颈静脉采血,测定各组犬的红细胞总数、白细胞总数、血红蛋白、红细胞压积、红细胞平均体积、平均红细胞血红蛋白含量、平均红细胞血红蛋白浓度;测定各组犬的肝功能(TP、ALB、ALT、AST、TBIL、DBIL)、血清丙二醛(MDA)、过氧化物歧化酶(SOD)、谷胱甘肽过氧化物酶(GSH-px)、血清羟脯氨酸(Hyp)等指标的变化。试验结束时,处死全部实验动物,部分肝作肝匀浆处理,用于测肝组织匀浆羟脯氨酸(HyP)含量。
结果:中药组犬的白细胞总数从试验开始到第三周一直呈升高的趋势,第四周下降,第五周反弹升高,从第六周开始逐渐降低。第三、四、五周时与造模前相比有显著差异(P＜0.05),第六、七周时与造模前相比无显著差异(P＞0.05);在第7周时,中药组与模型组的白蛋白含量相比较,存在极显著差异(P＜0.01);在第7周时,中药组的直接胆红素与试验前不存在显著差异(P＞0.05),而模型组的直接胆红素与试验前差异显著(P＜0.05);从第2周起中药组血清ALT与模型组存在显著差异(P＜0.05);从第4周起中药组血清AST显著低于模型组(P＜0.05);从第2周起中药组SOD的含量较模型组均显著升高(P＜0.01或P＜0.05),中药组GSH含量较模型组均显著升高(P＜0.01或P＜0.05),中药组的MDA含量均显著低于模型组(P＜0.01或P＜0.05);中药组犬血清中羟脯氨酸的含量也呈上升趋势,并从第2周开始一直显著高于试验前水平(P＜0.01);实验结束时,模型组肝脏胶原含量也极显著高于中药组和西药组(P＜0.01),中药组与西药组之间无显著差异(P＞0.05)。
结论:加味四逆散抗犬肝纤维化机理与改善肝功能、提高机体抗氧化能力,抑制脂质过氧化以及抑制胶原合成,促进胶原蛋白降解,减少胶原沉积有关。抗炎效果强于秋水仙碱。在肝纤维化尚未完全形成之前,早期使用加味四逆散治疗,可以防止肝纤维化的形成,阻断肝纤维化的发展,达到逆转肝纤维化的目的。
Objective: To study the effect of jiaweisinisan(JWSNS) on the prevention and its mechanism. Accordingly, it can offer preferably theoretics and experimentation thereunder for small animal clinic.
Methods: 24 adult healthy hybrid dogs weighed about 10 -15kg were used as experimental animals, and were randomly divided into 3 groups,the model group,the Chinese herb group and the colchicines group. Hepatic fibrosis in dogs was induced by mixture of carbon tetrachloride and colza oil. the dogs of Chinese herb group and colchicines group were given JWSNS and colchicines respectively to observe the effects of JWSNS and colchicines on the formation of hepatic fibrosis. Before and after the test,the blood cell were counted and the serum levels of Total protein(TP),Albumin(ALB),Alanine aminotransferase(ALT), Aspartate aminotransferase(AST),Total bilirubin(TBIL),Direct bilirubin(DBIL),Ma!ondia-ldehyde(MDA),Superoxide dismutase(SOD), glutathione peroxidase(GSH-px), Hydroxyp-roline(HyP) were determined each week.Hydroxyproline(HyP) level in the liver was detected after the experiment.
Reslut: The WBC of Chinese herb group had shown a rising trend from the start to the third week, declined in the fourth week ,a rebound increased in the fifth week,then came down in the sixth week. The WBC of Chinese herb group showed significant changes compare with the experiment start during the three,four,five weeks (P<0.05) .but it showed no significant difference compared with the experiment start during the six,seven weeks (P>0.05) . The serai levels of ALB of Chinese herb group showed significant changes compare with that of model group during the seven weeks (P<0.01) .The serm levels of DBIL of Chinese herb group showed no significant changes compared with the experiment start during the seven weeks (P>0.05 ),but that of model group showed significant changes compared with the experiment start during the seven weeks (P<0.05) . the serm levels of ALT of Chinese herb group showed significant difference compared with that of model group from the second week (P<0.05) . the serm levels of AST of Chinese herb group is significantly lower than that of model group from the fourth week (P<0.05) . the serum superoxid dismutase(SOD) and glutathione peroxidase(GSH-px) activity of Chinese herb group were significantly highter than that of model group,and the malondialdehyde(MDA) concentration was significantly lower than that of model group,the serum hydroxyproline concentration in Chinese herb group is significantly higher than that of model group(P<0.05) from the second week. At the end of the trial, the collagen content in liver tissues in Chinese herb group is significantly lower than that of model group (P<0.01) .
Conclusion: It's mechanism possibly has something with improve the canine liver function, enhance antioxidation, Inhibit peroxidation of lipid, Inhibit collagen synthesis, Promote collagen degradation and Slow progression of hepatic fibrosis. It has more powerful anti-inflammatory effect than that of colchicines. it is a availability prescription of prevent hepatic fibrosis.
方法:选用24只健康成年杂交犬,体重10-15Kg,雌雄不限,常规免疫驱虫一个星期后开始实验。随机分为三组:模型组,中药组,西药组。动物自由采食与饮水,试验期为8周。采用皮下多点注射45%的CCl4菜籽油乳剂制作肝纤维化模型。中药组在给予CCl_4的同时口服加味四逆散浓缩煎剂。西药组在给予CCl_4的同时口服秋水仙碱。试验前后,每周从犬颈静脉采血,测定各组犬的红细胞总数、白细胞总数、血红蛋白、红细胞压积、红细胞平均体积、平均红细胞血红蛋白含量、平均红细胞血红蛋白浓度;测定各组犬的肝功能(TP、ALB、ALT、AST、TBIL、DBIL)、血清丙二醛(MDA)、过氧化物歧化酶(SOD)、谷胱甘肽过氧化物酶(GSH-px)、血清羟脯氨酸(Hyp)等指标的变化。试验结束时,处死全部实验动物,部分肝作肝匀浆处理,用于测肝组织匀浆羟脯氨酸(HyP)含量。
结果:中药组犬的白细胞总数从试验开始到第三周一直呈升高的趋势,第四周下降,第五周反弹升高,从第六周开始逐渐降低。第三、四、五周时与造模前相比有显著差异(P＜0.05),第六、七周时与造模前相比无显著差异(P＞0.05);在第7周时,中药组与模型组的白蛋白含量相比较,存在极显著差异(P＜0.01);在第7周时,中药组的直接胆红素与试验前不存在显著差异(P＞0.05),而模型组的直接胆红素与试验前差异显著(P＜0.05);从第2周起中药组血清ALT与模型组存在显著差异(P＜0.05);从第4周起中药组血清AST显著低于模型组(P＜0.05);从第2周起中药组SOD的含量较模型组均显著升高(P＜0.01或P＜0.05),中药组GSH含量较模型组均显著升高(P＜0.01或P＜0.05),中药组的MDA含量均显著低于模型组(P＜0.01或P＜0.05);中药组犬血清中羟脯氨酸的含量也呈上升趋势,并从第2周开始一直显著高于试验前水平(P＜0.01);实验结束时,模型组肝脏胶原含量也极显著高于中药组和西药组(P＜0.01),中药组与西药组之间无显著差异(P＞0.05)。
结论:加味四逆散抗犬肝纤维化机理与改善肝功能、提高机体抗氧化能力,抑制脂质过氧化以及抑制胶原合成,促进胶原蛋白降解,减少胶原沉积有关。抗炎效果强于秋水仙碱。在肝纤维化尚未完全形成之前,早期使用加味四逆散治疗,可以防止肝纤维化的形成,阻断肝纤维化的发展,达到逆转肝纤维化的目的。
Objective: To study the effect of jiaweisinisan(JWSNS) on the prevention and its mechanism. Accordingly, it can offer preferably theoretics and experimentation thereunder for small animal clinic.
Methods: 24 adult healthy hybrid dogs weighed about 10 -15kg were used as experimental animals, and were randomly divided into 3 groups,the model group,the Chinese herb group and the colchicines group. Hepatic fibrosis in dogs was induced by mixture of carbon tetrachloride and colza oil. the dogs of Chinese herb group and colchicines group were given JWSNS and colchicines respectively to observe the effects of JWSNS and colchicines on the formation of hepatic fibrosis. Before and after the test,the blood cell were counted and the serum levels of Total protein(TP),Albumin(ALB),Alanine aminotransferase(ALT), Aspartate aminotransferase(AST),Total bilirubin(TBIL),Direct bilirubin(DBIL),Ma!ondia-ldehyde(MDA),Superoxide dismutase(SOD), glutathione peroxidase(GSH-px), Hydroxyp-roline(HyP) were determined each week.Hydroxyproline(HyP) level in the liver was detected after the experiment.
Reslut: The WBC of Chinese herb group had shown a rising trend from the start to the third week, declined in the fourth week ,a rebound increased in the fifth week,then came down in the sixth week. The WBC of Chinese herb group showed significant changes compare with the experiment start during the three,four,five weeks (P<0.05) .but it showed no significant difference compared with the experiment start during the six,seven weeks (P>0.05) . The serai levels of ALB of Chinese herb group showed significant changes compare with that of model group during the seven weeks (P<0.01) .The serm levels of DBIL of Chinese herb group showed no significant changes compared with the experiment start during the seven weeks (P>0.05 ),but that of model group showed significant changes compared with the experiment start during the seven weeks (P<0.05) . the serm levels of ALT of Chinese herb group showed significant difference compared with that of model group from the second week (P<0.05) . the serm levels of AST of Chinese herb group is significantly lower than that of model group from the fourth week (P<0.05) . the serum superoxid dismutase(SOD) and glutathione peroxidase(GSH-px) activity of Chinese herb group were significantly highter than that of model group,and the malondialdehyde(MDA) concentration was significantly lower than that of model group,the serum hydroxyproline concentration in Chinese herb group is significantly higher than that of model group(P<0.05) from the second week. At the end of the trial, the collagen content in liver tissues in Chinese herb group is significantly lower than that of model group (P<0.01) .
Conclusion: It's mechanism possibly has something with improve the canine liver function, enhance antioxidation, Inhibit peroxidation of lipid, Inhibit collagen synthesis, Promote collagen degradation and Slow progression of hepatic fibrosis. It has more powerful anti-inflammatory effect than that of colchicines. it is a availability prescription of prevent hepatic fibrosis.
引文
[1]Benyon RC,Arther MJ.Mechanisms of hepatic fibrosis[J].J Pediatr Gastroenterol Nutr,1998,27(1):75-85
[2]Itagaki T,Shimizu I,Cheng X,et.al.Opposing effects of oestradiol and progesterone on intracellular pathways and activation processes in the oxidative stress induced activation of cultured rat hepatic stellate cells.GUt,2005,54:1782-1789
[3]Novitskiy G,Potter J,Wang L,et.al.Influences of reactive oxygen species and nitric oxide on hepatic fibrogenesis.Liver Int,2006,26:1248-1257
[4]Bataller R,Brenner DA.Hepatic stellate cells as a target for the treatment of liver fibrosis.Semin Liver Dis,2001,21:437-451
[5]A.M.Gressner.R.Weiskirchen.Modern pathogenetic concepts of liver fibrosis suggest stellate cells and TGF-βas major players and therapeutic targets.J Cell Mol Med.2006,10:76-99
[6]Benyon RC.Michael JP.Extracellular matrix degradation and the role of hepatic stellate cells.Semin Liver Dis.2001,21:373-383
[7]Loizou S,Singh S,Wypkema E,et.al.Anticardiolipin,anti-β 2-glycoprotein Ⅰ and antiprothrombin antibodies in black South African patients with infectious disease.Ann Rheum Dis,2003,62:1106-1111
[8]高普均,朴云峰,王小丛,等.抗B2糖蛋白Ⅰ抗体与乙型肝炎后肝硬化细胞外基质的相关性研究[J].中国实用内科杂志,2002,22:732-734
[9]Martinuc Porobic J,Avcin T,Bozic B,et al.Anti-phospholipids antibodies following vaccination with recombinant hepatitis B vaccine.Clin Exp Immunol,2005,142:377-380
[10]Jose'R Yuste,Jesu's Prieto.Anticardiolipin antibodies in chronic viral hepatitis.Do they have clinical consequences? Eur J Gastroenterol Hepatol,2003,15:717-719
[11]Elefsiniotis I.Diamantis I.Dourakis S,et.al.Anticardiolipin antibodies in chronic hepatitis B and chronic hepatitis D infection,and hepatitis B-related hepatocellular carcinoma.Relationship with portal vein thrombosis.Eur J Gastroenterol Hepatol,2003,15:721-726
[12]Song KS,Kim HK.Prevalence of beta2-glycoprotein Ⅰ antibody in patients with liver cirrhosis:relationship with beta2-glycoprotein Ⅰ plasma levels and thrombosis.Clin Appl Thromb He-most,2004,10:183-186
[13]Chedid A Chadalawada KR,Morgan TR,et.al.Phospholipid antibodies in alcoholic liver disease.Hepatol,1994,20:1465-1471
[14]Rolla R,Vay D,Mottaran E,et.al.Antiphospholipid antibodies associated with alcoholic liver disease specifically recognize oxidised phospholipids.Gut,2001,49:852-859
[15]Perney P,Biron-Andreani C.Joomaye Z.et.al.Antiphospholipid antibodies in alcoholic liver disease are influenced by histological damage but not by alcohol consumption.Lupus,2000,9:451-455
[16]赵军,等.加减柴胡汤对大鼠肝纤维化防治作用[J].中西医结合肝病杂志,1997,7(3):160
[17]于世赢,等.清热利湿方药抗肝纤维化的形态学和免疫组织化学定量研究[J].北京中医药大学学报,1997,20(1):28
[18]李敏,等.中药五灵丸对硫代乙酰胺(TAA)所致大鼠肝损伤模型的修复作用[J].第四军医大学学报,1992,13(1):46
[19]Sakae Amagaya,等.小柴胡汤和大柴胡汤对大鼠实验性肝纤维化的影响[J].国外医学中医中药分册,1989,11(4):28
[20]马学惠,赵连三.抗纤维化的中药研究近况[J].四川医学,2000,21(11):994-995
[21]Zifroni A,Schaffner F.Long term follow up of patients with primary biliaryc irrhosis on colchicinestherapy,Hepatology,1991,14:990-993
[22]吉中和,等.柴等汤治疗试验性肝纤维化的研究[J].中西医结合肝病杂志,1995,5(3):31
[23]张玲霞,等.第一届中国消化系疾病学术周纪要[J].中国消化杂志,1998,18(1):37
[24]刘平,等.扶正化瘀319方抗大鼠肝纤维化的研究[J].中国实验方剂学杂志,1997,3(4):20
[25]申德林,等.软肝缩脾冲剂对大鼠中毒性肝纤维化的预防作用[J].中西医结合肝病杂志,1999,9(1):29
[26]郭来,等.肝心宁抗肝纤维化的研究[J].中西医结合肝病杂志,1999,9(4):25
[27]宋家武,等.血府逐瘀汤抗大鼠肝纤维化作用的研究[J].中西医结合肝病杂志,1997,7(1):38
[28]熊益群,等.乙肝定康对大鼠肝细胞DNA及胶原合成的影响[J],中西医结合肝病杂志,1997;17(2):98
[29]袁翠云,张瑞,程玲,等,核糖核酸联合冬虫夏草制剂对慢性肝炎血清肝纤维化指标的影响[J].中原医刊,1999,26(8):32-33
[30]陈建明,赵冬,强世平,等,水蛙桃仁汤对实验性肝纤维化鼠血清Ⅰ、Ⅲ型前胶原水平的影响[J].中国全科医学杂志,1998,1(3):165-166
[31]宋喜秀,等.中药软肝片的药效学研究[J].中西医结合肝病杂志,1993,3(1):20
[32]PROCTOR E Highield micronodular cirrhosis in the rat[J].Gastroenterology,1982,83,1183-1194
[33]韩德伍,马学惠,赵元昌,等,肝硬化模型的研究[J].山西医药杂志,1979,(4):166-168
[34]张万国,胡晋红,蔡溱,等.四氯化碳致大鼠肝纤维化模型血液流变学性质的研究[J].药学实践杂志,2001,
[35]钟鸣,余胜民,黄琳,等.金钱草总生物碱对实验性肝纤维化动物的相关指标的作用[J].肝脏,2001,6(3):168-169
[36]许建明,徐叔云,张运芳,等.四氯化碳诱导小鼠肝纤维化模型的建立[J].中国药理学通报,2000,16(3):339-341
[37]李培建,梁保忠,王爱民,等.四氯化碳、人血白蛋白所致大鼠肝纤维化模型的实验研究[J].实验动物科学管理,2000,17(2):32-34
[38]程明亮,刘三都.肝纤维化的基础研究与临床[M].北京:人民卫生出版社,2001,203-205.
[39]许光福,陆雄,陈文慧,等.DMN诱发肝纤维化过程中肝门静脉压力变化[J].肝脏,2001,6(3):200-201
[40]汪国运,蔡卫民,王金泉,等.肝纤维化组织学量化诊断的实验研究[J].中西医结合肝病杂志,1999,9(1):26-28
[41]张万国,胡晋红,蔡溱,等.四氯化碳致大鼠肝纤维化模型血液流变学性质的研究[J].药学实践杂志,2001,19(2):78-79
[42]傅沛藩,刘昌玉,余萍,等.小儿乙肝颗粒对大鼠肝纤维化的防治作用[J].中西医结合肝病杂志,1999,9(3):24-25
[43]吴晓玲,曾维政,蒋明得,等.人血白蛋白及四氯化碳诱导的大鼠肝纤维化模型对比分析[J].肝脏,2000,21(4):1108-1109
[44]于世瀛,贲长恩,杨美娟,等.免疫性与化学性损伤肝纤维化动物模型的比较[J].实验动物科学与管理,1995,12(4):5-12
[45]黄志刚,翟志刚,张月娥,等.异种动物血清诱导的大鼠肝纤维化模型及其机制[J].上海医科大学学报,1997,24(5):356-359
[46]薄爱划,田翠时,薛贵平,等.大鼠免疫性和酒精性肝病的形态学变化[J].世界华人消化杂志,2001,9(2):157-160
[47]成扬,李华,邬祥惠,等.T细胞介导的小鼠免疫性肝纤维化模型的建立及形态学观察[J].肝脏,2001,6(3):159-161
[48]朱清静,聂广,李翰,等.鸭乙型肝炎肝纤维化模型的研究[J].临床与实验病理学杂志,2000,16(6):501-503
[49]冯振卿,朱荣,李玉华,等.抗独特型抗体NP30对血吸虫病虫卵肉芽肿及肝纤维化的调节作用[J].中国寄生虫学与寄生虫病杂志,2001,19(1):33-36
[50]陈峰,蔡卫民,陈智,等.日本血吸虫病兔肝纤维化胶原合成与降解转录水平的研究[J].中国寄生虫学与寄生虫病杂志,2001,19(2):76-79
[51]贺永文,刘凤超,罗瑞德,等.前列腺素E1对日本血吸虫病大鼠肝纤维化形成的形响[J].中国寄生虫病防治杂志,2001,14(2):142-144
[52]王雪莉.血吸虫虫卵肉芽肿和肝纤维化的形成及调节机制研究进展[J].国外医学:寄生虫病分册,2001,28(5):207-210
[53]李德旭,杨镇,王保新,等.基质金属蛋白酶-2在猪胆汁性肝纤维化活性及表达的改变[J].中华实验外科杂志,2001,18(1):43-44
[54]张培林.PCⅢ检测丹参抗肝纤维化效力临床观察[J].中国中医急症,2002,11(2):103
[55]余世锋,黄贤樟,童光东.不同剂量丹参注射液抗肝纤维化临床研究[J].中国中西医结合杂志,2004,24(1):17-20
(56]袁翠云,付敏,王新国.复方丹参联合黄芪对慢性肝炎血清肝纤维化指标的影响[J].中原医刊,2001,26(12):24
[57]Hotamisligil GS,Shargill NS,Spiegelman BM.Adipose expression of tumor necrosis factor a direct role in obesitylinked insulin resistance.Science,1993,259(1):87
[58]Van Der Poll T,Romijin JA,Ender E,et.al.Tomur necrosis factor mimics the metabolic response to acute infection in healthy humans.Am J Physiol,1991,261(4):E457
[59]Roden M,et.al.Mechanism of FFA-induced insulin resistance in human.Clin Invest,1996,97:2859
[60]Roden M,et.al.Mechanism of FFA-induced insulin resistance in human.Clin Invest,1996,97:2859
[61]Miles PD G,et.al.TNFa induced insulin resistance in vivo and its prevention by troglitazone. Diabetes,1997,46:1678
[62]Vysal KT,et.al.procetion from obesity-induced insulin resistance in mice lacking TNFa function.Nature,1997,389:610
[63]Segal KR,et.al.Relationship between insulin sensitivity and plasma leptin concentration in lean and obeas men.Disbetes,1996,45:988
[64]Kirchgessner TG,et.al.TNFa contributes to obesityrelated hyperleptinemia by regulating leptin release from adipocytes.J Clin Invest,1997,100:2772
[65]陆家海,卢开柏,杜立志,等.犬肝硬化模型的建立[J].中国兽医学报,1994,14(3):291-293
[66]邓子德,等.改良小柴胡汤对慢性肝病患者肝纤维化标志物的作用[J].中国中西医结合脾胃杂志,1996,(4):205
[67]龙慎仪,等.加味防已黄芪汤治疗慢性活动肝炎肝纤维化的临床观察[J].中西医结合肝病杂志,1995,5(4):38
[68]王惠吉,等.中药复方丹参治疗肝纤维化远期疗效观察[J].中西医结合肝病杂志,1995,5(2):4
[69]刘成,等.桃仁提取物合虫菌丝治疗肝炎后肝硬化观察[J].中医杂志,1991,32(7):20
[70]刘成,等.扶正化瘀方治疗肝炎后肝硬化的临床观察[J].中西医结合肝病杂志,1993,3(4):1
[71]于世赢,等.清热利湿方药抗肝纤维化的形态学和免疫组织化学定量研究[J].北京中医药大学学报,1997,20(1):28
[72]吴嘉庚,等.乙型肝炎肝纤维化的辩证施治及与生化指标改变的关系.中医杂志,1994,35(7):416
[73]吴嘉庚,等.肝硬化患者透明质酸与辩证施治关系的探讨[J].中国中西医结合脾胃杂志,1995,3(2):73
[74]邓银泉,等.四逆散加味冶疗肝硬化32例实验指标的观察[J].辽宁中医杂志,1996,23(4):169
[75]赵国荣,等.四逆散及其加丹参桃仁对免疫性肝损伤大鼠CIC、ALT、TXB2/6-Keto-PGF1a 等指标的影响[J],湖南中医杂志,2000,16(2):55
[76]龚传美,等.四逆散对人、小白鼠微循环的影响[J].中药药理与临床,1991,7(2):6
[77]孙守才,等.中医药抗肝纤维化研究中若干问题的思考[J].中西医结合肝病杂志,2001,11(2):120
[78]叶维法主编,临床肝胆病学[M].第二版.天津科学技术出版社,1998,
[79]范建高,曾民德主编.脂肪肝[M].第1版.上海:上海医科大学出版社,2000,65
[80]许惠珍.三黄肝之宝对复合因素致大鼠肝纤维化的影响[J].湖北中医学院学报,2002,4(1):25-26
[81]Chitturi S,Farrell GC,Etiopathogenesis of nonalcoholic steatohepatitis.Semin Liver Dis.2001,21:27-41
[82]Farrel Gc.Non-alcoholic steatohepatitis:What is it and Why is it important in the Asia-Pacific region ? J Gastroenterol Hepatol,2003,18:124-138
[83]Angulo P Nonalcoholic fatty liver disease.N Engl J Med,2002,346:1221-1321
[84Chitturi S,Farrell GC,Etiopathogenesis of nonalcoholic steatohepatitis.Semin Liver Dis.2001,21:27-41
[85]Mehta K,Van Thiel DH,Shah N,Mobarhan S,Nonalcoholic fatty liver disease.Rthogenesis and the role of antioxidants.Nutr Rev 2002,60:289-303.
[86]Diehl AM.Nonalcoholic steatohepatitis.Semin Liver Dis,1999,19:221-230
[87]McCu llough AJ.Update on nonalcoholic fatty liver disease.J Clin Gastroenterol.2001,34:255-262
[88]Farrel Gc.Non-alcoholic steatohepatitis:What is it and Why is it important in the Asia-Pacific region ? J Gastroenterol Hepatol,2003,18:124-138
[89]Angulo P.Nonalcoholic fatty liver disease.N Engl J Med,2002,346:1221-1321
[90]Mata J M,Kershenobich D,Villarreal E,Rojkind M.Serum free praline and hydroxyproline in patients with chronic liver disease.Gastroenterology,1975,68(5part1):1265-1269
[91]姜术霞,等.活血疏肝健脾汤对犬实验性肝损伤血清学和组织学影响[J].动物医学进展,2004,25(2):78-81
[2]Itagaki T,Shimizu I,Cheng X,et.al.Opposing effects of oestradiol and progesterone on intracellular pathways and activation processes in the oxidative stress induced activation of cultured rat hepatic stellate cells.GUt,2005,54:1782-1789
[3]Novitskiy G,Potter J,Wang L,et.al.Influences of reactive oxygen species and nitric oxide on hepatic fibrogenesis.Liver Int,2006,26:1248-1257
[4]Bataller R,Brenner DA.Hepatic stellate cells as a target for the treatment of liver fibrosis.Semin Liver Dis,2001,21:437-451
[5]A.M.Gressner.R.Weiskirchen.Modern pathogenetic concepts of liver fibrosis suggest stellate cells and TGF-βas major players and therapeutic targets.J Cell Mol Med.2006,10:76-99
[6]Benyon RC.Michael JP.Extracellular matrix degradation and the role of hepatic stellate cells.Semin Liver Dis.2001,21:373-383
[7]Loizou S,Singh S,Wypkema E,et.al.Anticardiolipin,anti-β 2-glycoprotein Ⅰ and antiprothrombin antibodies in black South African patients with infectious disease.Ann Rheum Dis,2003,62:1106-1111
[8]高普均,朴云峰,王小丛,等.抗B2糖蛋白Ⅰ抗体与乙型肝炎后肝硬化细胞外基质的相关性研究[J].中国实用内科杂志,2002,22:732-734
[9]Martinuc Porobic J,Avcin T,Bozic B,et al.Anti-phospholipids antibodies following vaccination with recombinant hepatitis B vaccine.Clin Exp Immunol,2005,142:377-380
[10]Jose'R Yuste,Jesu's Prieto.Anticardiolipin antibodies in chronic viral hepatitis.Do they have clinical consequences? Eur J Gastroenterol Hepatol,2003,15:717-719
[11]Elefsiniotis I.Diamantis I.Dourakis S,et.al.Anticardiolipin antibodies in chronic hepatitis B and chronic hepatitis D infection,and hepatitis B-related hepatocellular carcinoma.Relationship with portal vein thrombosis.Eur J Gastroenterol Hepatol,2003,15:721-726
[12]Song KS,Kim HK.Prevalence of beta2-glycoprotein Ⅰ antibody in patients with liver cirrhosis:relationship with beta2-glycoprotein Ⅰ plasma levels and thrombosis.Clin Appl Thromb He-most,2004,10:183-186
[13]Chedid A Chadalawada KR,Morgan TR,et.al.Phospholipid antibodies in alcoholic liver disease.Hepatol,1994,20:1465-1471
[14]Rolla R,Vay D,Mottaran E,et.al.Antiphospholipid antibodies associated with alcoholic liver disease specifically recognize oxidised phospholipids.Gut,2001,49:852-859
[15]Perney P,Biron-Andreani C.Joomaye Z.et.al.Antiphospholipid antibodies in alcoholic liver disease are influenced by histological damage but not by alcohol consumption.Lupus,2000,9:451-455
[16]赵军,等.加减柴胡汤对大鼠肝纤维化防治作用[J].中西医结合肝病杂志,1997,7(3):160
[17]于世赢,等.清热利湿方药抗肝纤维化的形态学和免疫组织化学定量研究[J].北京中医药大学学报,1997,20(1):28
[18]李敏,等.中药五灵丸对硫代乙酰胺(TAA)所致大鼠肝损伤模型的修复作用[J].第四军医大学学报,1992,13(1):46
[19]Sakae Amagaya,等.小柴胡汤和大柴胡汤对大鼠实验性肝纤维化的影响[J].国外医学中医中药分册,1989,11(4):28
[20]马学惠,赵连三.抗纤维化的中药研究近况[J].四川医学,2000,21(11):994-995
[21]Zifroni A,Schaffner F.Long term follow up of patients with primary biliaryc irrhosis on colchicinestherapy,Hepatology,1991,14:990-993
[22]吉中和,等.柴等汤治疗试验性肝纤维化的研究[J].中西医结合肝病杂志,1995,5(3):31
[23]张玲霞,等.第一届中国消化系疾病学术周纪要[J].中国消化杂志,1998,18(1):37
[24]刘平,等.扶正化瘀319方抗大鼠肝纤维化的研究[J].中国实验方剂学杂志,1997,3(4):20
[25]申德林,等.软肝缩脾冲剂对大鼠中毒性肝纤维化的预防作用[J].中西医结合肝病杂志,1999,9(1):29
[26]郭来,等.肝心宁抗肝纤维化的研究[J].中西医结合肝病杂志,1999,9(4):25
[27]宋家武,等.血府逐瘀汤抗大鼠肝纤维化作用的研究[J].中西医结合肝病杂志,1997,7(1):38
[28]熊益群,等.乙肝定康对大鼠肝细胞DNA及胶原合成的影响[J],中西医结合肝病杂志,1997;17(2):98
[29]袁翠云,张瑞,程玲,等,核糖核酸联合冬虫夏草制剂对慢性肝炎血清肝纤维化指标的影响[J].中原医刊,1999,26(8):32-33
[30]陈建明,赵冬,强世平,等,水蛙桃仁汤对实验性肝纤维化鼠血清Ⅰ、Ⅲ型前胶原水平的影响[J].中国全科医学杂志,1998,1(3):165-166
[31]宋喜秀,等.中药软肝片的药效学研究[J].中西医结合肝病杂志,1993,3(1):20
[32]PROCTOR E Highield micronodular cirrhosis in the rat[J].Gastroenterology,1982,83,1183-1194
[33]韩德伍,马学惠,赵元昌,等,肝硬化模型的研究[J].山西医药杂志,1979,(4):166-168
[34]张万国,胡晋红,蔡溱,等.四氯化碳致大鼠肝纤维化模型血液流变学性质的研究[J].药学实践杂志,2001,
[35]钟鸣,余胜民,黄琳,等.金钱草总生物碱对实验性肝纤维化动物的相关指标的作用[J].肝脏,2001,6(3):168-169
[36]许建明,徐叔云,张运芳,等.四氯化碳诱导小鼠肝纤维化模型的建立[J].中国药理学通报,2000,16(3):339-341
[37]李培建,梁保忠,王爱民,等.四氯化碳、人血白蛋白所致大鼠肝纤维化模型的实验研究[J].实验动物科学管理,2000,17(2):32-34
[38]程明亮,刘三都.肝纤维化的基础研究与临床[M].北京:人民卫生出版社,2001,203-205.
[39]许光福,陆雄,陈文慧,等.DMN诱发肝纤维化过程中肝门静脉压力变化[J].肝脏,2001,6(3):200-201
[40]汪国运,蔡卫民,王金泉,等.肝纤维化组织学量化诊断的实验研究[J].中西医结合肝病杂志,1999,9(1):26-28
[41]张万国,胡晋红,蔡溱,等.四氯化碳致大鼠肝纤维化模型血液流变学性质的研究[J].药学实践杂志,2001,19(2):78-79
[42]傅沛藩,刘昌玉,余萍,等.小儿乙肝颗粒对大鼠肝纤维化的防治作用[J].中西医结合肝病杂志,1999,9(3):24-25
[43]吴晓玲,曾维政,蒋明得,等.人血白蛋白及四氯化碳诱导的大鼠肝纤维化模型对比分析[J].肝脏,2000,21(4):1108-1109
[44]于世瀛,贲长恩,杨美娟,等.免疫性与化学性损伤肝纤维化动物模型的比较[J].实验动物科学与管理,1995,12(4):5-12
[45]黄志刚,翟志刚,张月娥,等.异种动物血清诱导的大鼠肝纤维化模型及其机制[J].上海医科大学学报,1997,24(5):356-359
[46]薄爱划,田翠时,薛贵平,等.大鼠免疫性和酒精性肝病的形态学变化[J].世界华人消化杂志,2001,9(2):157-160
[47]成扬,李华,邬祥惠,等.T细胞介导的小鼠免疫性肝纤维化模型的建立及形态学观察[J].肝脏,2001,6(3):159-161
[48]朱清静,聂广,李翰,等.鸭乙型肝炎肝纤维化模型的研究[J].临床与实验病理学杂志,2000,16(6):501-503
[49]冯振卿,朱荣,李玉华,等.抗独特型抗体NP30对血吸虫病虫卵肉芽肿及肝纤维化的调节作用[J].中国寄生虫学与寄生虫病杂志,2001,19(1):33-36
[50]陈峰,蔡卫民,陈智,等.日本血吸虫病兔肝纤维化胶原合成与降解转录水平的研究[J].中国寄生虫学与寄生虫病杂志,2001,19(2):76-79
[51]贺永文,刘凤超,罗瑞德,等.前列腺素E1对日本血吸虫病大鼠肝纤维化形成的形响[J].中国寄生虫病防治杂志,2001,14(2):142-144
[52]王雪莉.血吸虫虫卵肉芽肿和肝纤维化的形成及调节机制研究进展[J].国外医学:寄生虫病分册,2001,28(5):207-210
[53]李德旭,杨镇,王保新,等.基质金属蛋白酶-2在猪胆汁性肝纤维化活性及表达的改变[J].中华实验外科杂志,2001,18(1):43-44
[54]张培林.PCⅢ检测丹参抗肝纤维化效力临床观察[J].中国中医急症,2002,11(2):103
[55]余世锋,黄贤樟,童光东.不同剂量丹参注射液抗肝纤维化临床研究[J].中国中西医结合杂志,2004,24(1):17-20
(56]袁翠云,付敏,王新国.复方丹参联合黄芪对慢性肝炎血清肝纤维化指标的影响[J].中原医刊,2001,26(12):24
[57]Hotamisligil GS,Shargill NS,Spiegelman BM.Adipose expression of tumor necrosis factor a direct role in obesitylinked insulin resistance.Science,1993,259(1):87
[58]Van Der Poll T,Romijin JA,Ender E,et.al.Tomur necrosis factor mimics the metabolic response to acute infection in healthy humans.Am J Physiol,1991,261(4):E457
[59]Roden M,et.al.Mechanism of FFA-induced insulin resistance in human.Clin Invest,1996,97:2859
[60]Roden M,et.al.Mechanism of FFA-induced insulin resistance in human.Clin Invest,1996,97:2859
[61]Miles PD G,et.al.TNFa induced insulin resistance in vivo and its prevention by troglitazone. Diabetes,1997,46:1678
[62]Vysal KT,et.al.procetion from obesity-induced insulin resistance in mice lacking TNFa function.Nature,1997,389:610
[63]Segal KR,et.al.Relationship between insulin sensitivity and plasma leptin concentration in lean and obeas men.Disbetes,1996,45:988
[64]Kirchgessner TG,et.al.TNFa contributes to obesityrelated hyperleptinemia by regulating leptin release from adipocytes.J Clin Invest,1997,100:2772
[65]陆家海,卢开柏,杜立志,等.犬肝硬化模型的建立[J].中国兽医学报,1994,14(3):291-293
[66]邓子德,等.改良小柴胡汤对慢性肝病患者肝纤维化标志物的作用[J].中国中西医结合脾胃杂志,1996,(4):205
[67]龙慎仪,等.加味防已黄芪汤治疗慢性活动肝炎肝纤维化的临床观察[J].中西医结合肝病杂志,1995,5(4):38
[68]王惠吉,等.中药复方丹参治疗肝纤维化远期疗效观察[J].中西医结合肝病杂志,1995,5(2):4
[69]刘成,等.桃仁提取物合虫菌丝治疗肝炎后肝硬化观察[J].中医杂志,1991,32(7):20
[70]刘成,等.扶正化瘀方治疗肝炎后肝硬化的临床观察[J].中西医结合肝病杂志,1993,3(4):1
[71]于世赢,等.清热利湿方药抗肝纤维化的形态学和免疫组织化学定量研究[J].北京中医药大学学报,1997,20(1):28
[72]吴嘉庚,等.乙型肝炎肝纤维化的辩证施治及与生化指标改变的关系.中医杂志,1994,35(7):416
[73]吴嘉庚,等.肝硬化患者透明质酸与辩证施治关系的探讨[J].中国中西医结合脾胃杂志,1995,3(2):73
[74]邓银泉,等.四逆散加味冶疗肝硬化32例实验指标的观察[J].辽宁中医杂志,1996,23(4):169
[75]赵国荣,等.四逆散及其加丹参桃仁对免疫性肝损伤大鼠CIC、ALT、TXB2/6-Keto-PGF1a 等指标的影响[J],湖南中医杂志,2000,16(2):55
[76]龚传美,等.四逆散对人、小白鼠微循环的影响[J].中药药理与临床,1991,7(2):6
[77]孙守才,等.中医药抗肝纤维化研究中若干问题的思考[J].中西医结合肝病杂志,2001,11(2):120
[78]叶维法主编,临床肝胆病学[M].第二版.天津科学技术出版社,1998,
[79]范建高,曾民德主编.脂肪肝[M].第1版.上海:上海医科大学出版社,2000,65
[80]许惠珍.三黄肝之宝对复合因素致大鼠肝纤维化的影响[J].湖北中医学院学报,2002,4(1):25-26
[81]Chitturi S,Farrell GC,Etiopathogenesis of nonalcoholic steatohepatitis.Semin Liver Dis.2001,21:27-41
[82]Farrel Gc.Non-alcoholic steatohepatitis:What is it and Why is it important in the Asia-Pacific region ? J Gastroenterol Hepatol,2003,18:124-138
[83]Angulo P Nonalcoholic fatty liver disease.N Engl J Med,2002,346:1221-1321
[84Chitturi S,Farrell GC,Etiopathogenesis of nonalcoholic steatohepatitis.Semin Liver Dis.2001,21:27-41
[85]Mehta K,Van Thiel DH,Shah N,Mobarhan S,Nonalcoholic fatty liver disease.Rthogenesis and the role of antioxidants.Nutr Rev 2002,60:289-303.
[86]Diehl AM.Nonalcoholic steatohepatitis.Semin Liver Dis,1999,19:221-230
[87]McCu llough AJ.Update on nonalcoholic fatty liver disease.J Clin Gastroenterol.2001,34:255-262
[88]Farrel Gc.Non-alcoholic steatohepatitis:What is it and Why is it important in the Asia-Pacific region ? J Gastroenterol Hepatol,2003,18:124-138
[89]Angulo P.Nonalcoholic fatty liver disease.N Engl J Med,2002,346:1221-1321
[90]Mata J M,Kershenobich D,Villarreal E,Rojkind M.Serum free praline and hydroxyproline in patients with chronic liver disease.Gastroenterology,1975,68(5part1):1265-1269
[91]姜术霞,等.活血疏肝健脾汤对犬实验性肝损伤血清学和组织学影响[J].动物医学进展,2004,25(2):78-81