鬼针草总黄酮对免疫性肝纤维化大鼠治疗作用及部分机制研究
|
摘要
肝纤维化是以星状细胞(HSC)激活,细胞外基质(ECM)的合成大于降解导致肝内ECM过度沉积为特征的病理过程,是肝硬化的早期和必经阶段。导致肝纤维化的因素有很多,如病毒、药物、乙醇、缺氧、免疫因素等,都可损伤肝脏,造成炎症、细胞坏死、凋亡,进而发展成肝纤维化。现在研究认为,肝纤维病理过程是可逆的,因此寻找合适药物抑制和治疗肝纤维化具有重要意义。
鬼针草,菊科,鬼针草属,一年生草本植物。其药材资源非常丰富,广泛分布在我国大多数地区。鬼针草药用历史悠久,味苦、性平而无毒,具有清热解毒,散瘀消肿等功效,民间用于治疗痢疾、腹泻、肝炎、胃痛等疾病,文献显示鬼针草的醇提物有抗炎、清除自由基和免疫调节等作用。鬼针草活性成分很多,包括黄酮苷、皂苷、生物碱、挥发油等,经我院天然药物化学教研室研究确定,从鬼针草叶中提取的鬼针草总黄酮(total flavones of Bidens bipinnataL,TFB)为其有效部位。我们前期实验发现,TFB对CCl_4诱导的小鼠肝损伤和大鼠化学性肝纤维化均有显著的治疗作用,但对大鼠免疫性肝纤维化是否有作用尚不清楚。为进一步探讨TFB的药理作用,本文在查阅大量文献和前期研究基础上,采用猪血清诱导的大鼠免疫性肝纤维化模型方法,研究TFB对免疫性肝纤维化的治疗作用和部分机制。
1.TFB对免疫性肝纤维化大鼠的治疗作用
48只大鼠,随机分为正常组、模型组、TFB 160 mg/kg、TFB 80 mg/kg、TFB 40mg/kg等6组,每组8只。除正常组外,其余各组采用腹腔注射猪血清(0.5 ml/只,每周2次)诱导免疫性肝纤维化模型,共12周,病理组织学检查造模情况。检验造模成功后,给药组分别灌服相应的受试药物,正常组和模型组灌服等容量的生理盐水,疗程10周。处死大鼠,常规方法取血、肝脏、脾脏等组织备检。研究发现,与模型组相比,TFB能增加大鼠体重,抑制肝纤维化大鼠肝、脾指数上升;能降低血清中升高的ALT、AST、HA、LN、PCⅢ、CⅣ和肝组织中Hyp含量;病理组织学结果显示TFB组肝脏组织结构明显改善,肝纤维化增生程度减轻。提示TFB对猪血清所致大鼠免疫性肝纤维化有明显的治疗。
2.TFB对免疫性肝纤维化治疗作用的部分机制研究
与模型组比较,TFB能显著降低肝组织中MDA含量,升高肝组织中SOD和GSH-Px活性;免疫组织化学法显示,TFB组显著抑制肝组织中α-SMA、TGF-β1蛋白表达;RT-PCR显示TFB组抑制TGF-β1/Smads通路中TGF-β1,smads2 mRNA表达,升高smads7 mRNA表达;TUNEL和α-SMA双染检验细胞凋亡,显示TFB显著减少活化的HSC数目,可检测到其凋亡。提示TFB治疗实验性肝纤维化的作用可能与其抗脂质过氧化损伤和抑制TGF-β1/Smads通路减少体内HSC活化及诱导体内活化的HSC凋亡有关。
结论:以上实验结果表明,TFB对猪血清诱导的大鼠肝纤维化具有明显的治疗作用,其作用机制可能与抗氧化、抑制TGF-β1/Smads信号通路及诱导体内活化的HSC凋亡有关。
Liver fibrosis is result from the majority of chronic liver,which is characterized by acute liver injury,activating of HSC,increasing and deposition of extracellular matrix in the liver.It is mostly induced by viral hepatitis,alcoholism,iron overload,or drug toxicity. So it is very important clinical significant to control the development and process of liver injury in time.In summary,accumulating evidence suggests that liver fibrosis is reversible and that recovery from cirrhosis may be possible.However,it is still difficult to achieve satisfied therapeutic effect.
Bidens bipinnata L.,a species of the genus Bidens(Compositae),is widely distributed in majority province in China.Bidens bipinnata L.had been traditionally used for many years.It is bitter in taste,neutral in nature and innocuity,and has the effect of heat-clearing, detoxicating and eliminating stasis to subdue swelling.It was largely used to treat hepatitis, inflammation,malaria,hypertension,diabetes,pepticulcer,snake bite,smallpox.Previous report show it has anti-inflammatory,removal of oxygen free radicals and the regulation of the immune.It contains many chemical compositions,such as flavonoid glycoside,saponin,alkaloid, aetherolea.Our previous study show its mainly active composition is total flavones of Bipinnata L (TFB),which is extracted from the leaves of Bidens pilosa L.TFB has been preliminarily assessed to be of protection against acute liver injury and experimental liver fibrosis by CCl_4.To further explore the effect of total flavones of Bidens Bipinnata L(TFB) on immunological liver fibrosis,the immunological model was induced by pig serum in Sprague-Dawley rats.The mechanisms of action of TFB on liver fibrosis by using the methods in vivo and molecular levels were studied.
The main contents were divided into some sections as follows:
1.Therapeutic effects of TFB on pig serum-induced liver fibrosis
The pig serum was injected into abdominal cavity(0.5 ml,twice a week) for 12 weeks so as to induce hepatic fibrosis,and then the rats were treated with TFB daily for 10 weeks and killed at the 22~(nd) week.Compared with model group,TFB increased weight and inhibited the elevation of index of liver and spleen.Furthermore,TFB treatment significantly reduced ALT,AST,HA,LN,PCⅢ,CⅣcontent in serum and Hyp in liver tissue.Liver histopathological examination showed TFB could also ameliorate fibrogenesis and pseudolobule formation by hematoxylin-eosin(HE) staining and masson staining. These results suggest that TFB has positively preventive effects and treatment effects on immunological liver fibrosis by pig serum.
2.The mechanisms of Therapeutic effects of TFB on immunological liver fibrosis
Further study showed that TFB treatment markedly reduced MDA in liver tissue, increased SOD,GSH-Px activity.TFB treatment decreased the expression of protein TGF-β1,α-SMA mRNA in liver by Immunohistochemistry.And then TFB treatment could significantly down-regulated TGF-β1 and Smads2 mRNA expression and up-regulated Smads7 mRNA expression in liver by RT-PCR analysis.In addition TFB treatment decreased the number of activated HSC and increased the quantity of apoptosis HSC by TUNEL andα-SMA staining.
Conclusion:TFB significantly had therapeutical effect on immunological liver fibrosis in rats probably by its free-radical scavenging ability,inhibition of HSC TGF-β1/Smads pathway,suppressive effects on HSC proliferation and collagen production,stimulation of activated HSC apoptosis.
鬼针草,菊科,鬼针草属,一年生草本植物。其药材资源非常丰富,广泛分布在我国大多数地区。鬼针草药用历史悠久,味苦、性平而无毒,具有清热解毒,散瘀消肿等功效,民间用于治疗痢疾、腹泻、肝炎、胃痛等疾病,文献显示鬼针草的醇提物有抗炎、清除自由基和免疫调节等作用。鬼针草活性成分很多,包括黄酮苷、皂苷、生物碱、挥发油等,经我院天然药物化学教研室研究确定,从鬼针草叶中提取的鬼针草总黄酮(total flavones of Bidens bipinnataL,TFB)为其有效部位。我们前期实验发现,TFB对CCl_4诱导的小鼠肝损伤和大鼠化学性肝纤维化均有显著的治疗作用,但对大鼠免疫性肝纤维化是否有作用尚不清楚。为进一步探讨TFB的药理作用,本文在查阅大量文献和前期研究基础上,采用猪血清诱导的大鼠免疫性肝纤维化模型方法,研究TFB对免疫性肝纤维化的治疗作用和部分机制。
1.TFB对免疫性肝纤维化大鼠的治疗作用
48只大鼠,随机分为正常组、模型组、TFB 160 mg/kg、TFB 80 mg/kg、TFB 40mg/kg等6组,每组8只。除正常组外,其余各组采用腹腔注射猪血清(0.5 ml/只,每周2次)诱导免疫性肝纤维化模型,共12周,病理组织学检查造模情况。检验造模成功后,给药组分别灌服相应的受试药物,正常组和模型组灌服等容量的生理盐水,疗程10周。处死大鼠,常规方法取血、肝脏、脾脏等组织备检。研究发现,与模型组相比,TFB能增加大鼠体重,抑制肝纤维化大鼠肝、脾指数上升;能降低血清中升高的ALT、AST、HA、LN、PCⅢ、CⅣ和肝组织中Hyp含量;病理组织学结果显示TFB组肝脏组织结构明显改善,肝纤维化增生程度减轻。提示TFB对猪血清所致大鼠免疫性肝纤维化有明显的治疗。
2.TFB对免疫性肝纤维化治疗作用的部分机制研究
与模型组比较,TFB能显著降低肝组织中MDA含量,升高肝组织中SOD和GSH-Px活性;免疫组织化学法显示,TFB组显著抑制肝组织中α-SMA、TGF-β1蛋白表达;RT-PCR显示TFB组抑制TGF-β1/Smads通路中TGF-β1,smads2 mRNA表达,升高smads7 mRNA表达;TUNEL和α-SMA双染检验细胞凋亡,显示TFB显著减少活化的HSC数目,可检测到其凋亡。提示TFB治疗实验性肝纤维化的作用可能与其抗脂质过氧化损伤和抑制TGF-β1/Smads通路减少体内HSC活化及诱导体内活化的HSC凋亡有关。
结论:以上实验结果表明,TFB对猪血清诱导的大鼠肝纤维化具有明显的治疗作用,其作用机制可能与抗氧化、抑制TGF-β1/Smads信号通路及诱导体内活化的HSC凋亡有关。
Liver fibrosis is result from the majority of chronic liver,which is characterized by acute liver injury,activating of HSC,increasing and deposition of extracellular matrix in the liver.It is mostly induced by viral hepatitis,alcoholism,iron overload,or drug toxicity. So it is very important clinical significant to control the development and process of liver injury in time.In summary,accumulating evidence suggests that liver fibrosis is reversible and that recovery from cirrhosis may be possible.However,it is still difficult to achieve satisfied therapeutic effect.
Bidens bipinnata L.,a species of the genus Bidens(Compositae),is widely distributed in majority province in China.Bidens bipinnata L.had been traditionally used for many years.It is bitter in taste,neutral in nature and innocuity,and has the effect of heat-clearing, detoxicating and eliminating stasis to subdue swelling.It was largely used to treat hepatitis, inflammation,malaria,hypertension,diabetes,pepticulcer,snake bite,smallpox.Previous report show it has anti-inflammatory,removal of oxygen free radicals and the regulation of the immune.It contains many chemical compositions,such as flavonoid glycoside,saponin,alkaloid, aetherolea.Our previous study show its mainly active composition is total flavones of Bipinnata L (TFB),which is extracted from the leaves of Bidens pilosa L.TFB has been preliminarily assessed to be of protection against acute liver injury and experimental liver fibrosis by CCl_4.To further explore the effect of total flavones of Bidens Bipinnata L(TFB) on immunological liver fibrosis,the immunological model was induced by pig serum in Sprague-Dawley rats.The mechanisms of action of TFB on liver fibrosis by using the methods in vivo and molecular levels were studied.
The main contents were divided into some sections as follows:
1.Therapeutic effects of TFB on pig serum-induced liver fibrosis
The pig serum was injected into abdominal cavity(0.5 ml,twice a week) for 12 weeks so as to induce hepatic fibrosis,and then the rats were treated with TFB daily for 10 weeks and killed at the 22~(nd) week.Compared with model group,TFB increased weight and inhibited the elevation of index of liver and spleen.Furthermore,TFB treatment significantly reduced ALT,AST,HA,LN,PCⅢ,CⅣcontent in serum and Hyp in liver tissue.Liver histopathological examination showed TFB could also ameliorate fibrogenesis and pseudolobule formation by hematoxylin-eosin(HE) staining and masson staining. These results suggest that TFB has positively preventive effects and treatment effects on immunological liver fibrosis by pig serum.
2.The mechanisms of Therapeutic effects of TFB on immunological liver fibrosis
Further study showed that TFB treatment markedly reduced MDA in liver tissue, increased SOD,GSH-Px activity.TFB treatment decreased the expression of protein TGF-β1,α-SMA mRNA in liver by Immunohistochemistry.And then TFB treatment could significantly down-regulated TGF-β1 and Smads2 mRNA expression and up-regulated Smads7 mRNA expression in liver by RT-PCR analysis.In addition TFB treatment decreased the number of activated HSC and increased the quantity of apoptosis HSC by TUNEL andα-SMA staining.
Conclusion:TFB significantly had therapeutical effect on immunological liver fibrosis in rats probably by its free-radical scavenging ability,inhibition of HSC TGF-β1/Smads pathway,suppressive effects on HSC proliferation and collagen production,stimulation of activated HSC apoptosis.
引文
1.汪巧娅.乙型肝炎的流行趋势与预防[J].中华护理杂志.2007,42(4):382-4
2.Urtasun R,Nieto N.Hepatic stellate cells and oxidative stress[J].Rev Esp Enferm Dig.2007,99(4):223-30
3.王连升,陈颖伟,李定国.TGFβ1信号与肝纤维化[J].国外医学消化疾病分册.2004,24(3):142-4
4.Elsharkawy AM,Oakley F,Mann DA.The role and regμlation of hepatic stellate cell apoptosis in reversal of liver fibrosis[J].Apoptosis.2005,10(5):927-39
5.Mas N,Tasci I,Comert B,et al.Ursodeoxycholic acid treatment improves hepatocyte μltrastructure in rat liver fibrosis[J].World J Gastroenterol.2008,14(7):1108-11
6.Ajello A,Freni MA,Spadaro A,et al.Ten year follow-up of patients with chronic hepatitis C treated with interferon[J].Hepatogastroenterology.1999,46(28):2447-50
7.Wright TL.Treatment of patients with hepatitis C and cirrhosis[J].Hepatology.2002,36(5 Suppl 1):S185-94
8.江苏新医学院.中药大辞典(下册)[M].上海科学技术出版社.1986:1694
9.Abajo C,Boffill M A,Del Campo J,et al.In vitro study of the antioxidant and immunomod μ latory activity of aqueous infusion of Bidens pilosa[J].J Ethnopharmacol.2004,93(2-3):319-23
10.李帅,匡海学,冈田嘉仁,等.鬼针草化学成分的研究[J].中草药.2004,25(9):972-5
11.陈飞虎,袁丽萍,钟明媚,等.鬼针草总黄酮抗大鼠肝纤维化的实验研究[J].中国临床药理学与治疗学.2006,12(11):1369-74
12.Zhong MM,Chen FH,Yuan LP,et al.Protective effect of total flavonoids from Bidens bipinnata L.against carbon tetrachloride-induced liver injury in mice[J].J Pharm Pharmacol.2007,59(7):1017-25
13.刘秀英,胡怡秀,胡余明,等.四氯化碳和猪血清肝纤维化模型组织病理比较[J].世界华人消化杂志.2004,12(8):1875-9
14.Wu C S,Piao X X,Piao D M,et al.Treatment of pig serum-induced rat liver fibrosis with Boschniakia rossica,oxymatrine and interferon-α[J].World J Gastroenterol. 2005,11(1):122-6
15.Andrade R G,Gotardo B M,Assis B C.Immunological Tolerance to Pig-serum Partially Inhibits the Formation of Septal Fibrosis of the Liver in Capillaria hepatica infected Rats[J].Mem Inst Oswaldo Cruz.2004,99(7):703-7
16.Nanji AA,Kalle J,Maryam F,et al.Increased severity of alcoholic liver injury in female rats:role of oxidative stress,endotoxin,and chemokines[J].Am J Physiol Gastrointest Liver Physiol.2001,281:1348-56
17.Oh WY,Pyo S,Lee KR,et al.Effect of holotrichia diomphalia larvae on liver fibrosis and hepatotoxicity in rats[J].Journal of Ethnopharmacology.2003,87:175-80.
18.胡义,王庆林.肝纤维化发病机制的研究进展[J].国际病理科学与临床杂志.2007,27(1):48-52
19.Lewindon PJ,Pereira TN,Hoskina AC,et al.Role of hepatic stellate cells and transforming growth factor-β in cystic fibrosis liver disease[J].Am J Pathol.2002,160(5):1705-15
20.程明亮,杨长青.肝纤维化的基础研究及临床[M].人民卫生出版社.2002:126
21.Arthur MJP.Fibrogenesis metalloprotcmase and their inhibitors in liver fibrosis[J].Am J phgsloe Gastrointest Liver Physioe.2000,279:G245-9
22.Liu P,Hu YY,Liu CH,et al.Clinical observation of salvianolic acid B in treatment of liver fibrosis in chronic hepatitis B[J].World J Gastroenterol.2002,89(4):679-85
23.Mandal AK,Das S,Basu MK.Hepatoprotective activity of liposomal flavonoid against arsenite-induced liver fibrosis[J].J Pharmacol Exp Ther.2007,320(3):994-1001
24.陈桂敏,郑文芝,薛贵平,等.芪蚣抗纤方对免疫性肝纤维化大鼠肝组织病理形态的影响[J].河北北方学院学报.2005,22(4):3-6
25.崔春吉,李永宇,金幸,等.肝硬变病人血清AST/ALT比值的变化及其意义[J].中国基层医药.2003,10(5):449-50
26.Li C H,Piao D M,Xu W X,et al.Morphological and serum hyaluronic acid,laminin and type Ⅳ collagen changes in dimethylnitrosamine-induced hepatic fibrosis of rats[J].World J Gastroenterol.2005,11(48):7620-4.
27.刘露,张木坤,何伶俐.肝纤维化血清标志物在肝病诊断中的意义[J].放射免疫 学杂志.2004,17(1):23-5
28.王红.慢性病毒性肝炎患者血清TIMP-1、HA与肝纤维化的关系[J],中国误诊学杂志.2007,18(7):4203-5
29.武昌,赵健康,郭玉娟.慢性乙型肝炎和肝硬化患者血清HA、LN、PCⅢ和Ⅳ-C 水平与肝组织纤维化程度的关系[J].实用肝脏病杂志.2005,8(4):200-2
30.唐惠君.肝病患者220例肝纤维化血清标记物的检测.职业与健康.2008,24(1):27-9
31.刘霖敏.血清HA、PCⅢ、Ⅳ-C、LN和内皮素在慢性肝病肝纤维化中的临床意义[J].江西医药.2007,42(9):832-4
32.Hanauske-Abel HM.Fibrosis of the liver:representative molecμlar elements and their emerging role as anti-fibrotic targets[J].Hepatology:A Textbook of Liver isease.2003,4:347-54
33.Kolios G,Valatas V,Kouroumalis E.Role of Kupffer cells in the pathogenesis of liver disease[J].World J Gastroenterol.2006,12(46):7413-20
34.Tomita K,Tamiya G,Ando S.Tumour necrosis factor alpha signalling through activation of Kupffer cells plays an essential role in liver fibrosis of non-alcoholic steatohepatitis in mice[J].Gut.2006,55(3):415-24
35.韩硬海,李树桐.临床肝脏病学[M].山东:山东科学技术出版社,2005:174
36.Bautista AP.Chronic alcohol intoxication primes Kupffer cells and endothelial cells for enhanced CC-chemokine production and concomitantly suppresses phagocytosis and chemotaxis[J].Front Biosci.2002,7:a117-25
37.Melgert BN,Olinga P,Van Der Laan JM,et al.Targeting dexamethasone to Kupffer cells:effects on liver inflammation and fibrosis in rats[J].Hepatology.2001,34(4 Pt 1):719-28
38.袁丽萍,陈飞虎,夏丽娟,等.鬼针草总黄酮对肝纤维化大鼠细胞因子的影响[J].中国药理学通报.2007,23(7):887-91
39.Liu CH,Hu YY,Wang XL,et al.Effects of salvianolic acid-A on NIH/3T3 fibroblast proliferation,collagen synthesis and gene expression[J].World J Gastroenterol.2000,6(3):361-4
40.马雪梅,王宝恩,尤红.丹参对肝星状细胞增殖和凋亡影响的实验研究[J].中国中医药信息杂志.2000,7(7):25-7
41.Adachi J,Matsushita S,Yoshioka N.Plasma phosphatidylcholine hydroperoxide as a new marker of oxidative stress in alcoholic patients.J Lipid Res.2004,45(5):967-71
42.Hoek JB,Pastorino JG..Ethanol,oxidative stress,and cytokine-induced liver cell injury[J].Alcohol.2002,27:63-8
43.Williams AT,Burk RF.Carbon tetrachloride hepatotoxicity:an example of free radical-mediated injury e[J].Semin Liver Dis.1990,10(4):279-4
44.Kim KS,Lee S,Lee YS,et al.Anti-oxidant activities of the extracts from the herbs of Artemisia apiacea[J].J Ethnopharmacol.2003,85(1):69-72
45.Souchelny TS.Transforming growth factor-signaling and its role in cancer[J].Exp Ocol.2002,24:3-12
46.Logolo AF,Nonogaki S,MiguelR E,et al.Transforming growth factor beta expression in head and neck squamous cell carcinoma patients as related to prognosis[J].J Oroal Pathol Med.2003,32(3):139-45
47.Lewindon PJ,Pereira TN,Hoskina AC,et al.Role of hepatic stellate cells and transforming growth factor-β in cystic fibrosis liver disease[J].Am J Pathol.2002,160(5):1705-15
48.Shi Y,Massagu J.Mechamism of TGF-beta signaling from cell member to the nucleus [J].Cell.2003,113(6):685-700
49.Bedossa P,Peltier E,Terris B,et al.Transforming growth factor-beta 1(TGF-beta 1)and receptors in normal,cirrhotic,and neoplastic human livers[J].Hepatology.1995,21:760-6
50.Chen YW,Li DG,Wu JX,et al.Tetrandrine inhibits activation of rat hepatic stellate cells stimμlated by transforming growth factor-beta in vitro via up-regμlation of Smad 7.J Ethnopharmacol.2005,100(3):299-305
51.权启镇,孙自勤,王要军.新肝脏病学[M].山东:山东科学技术出版社.2003:314-5
52.陈源文,李定国,吴建新,等.粉防己碱上调Smad7表达抑制大鼠肝星状细胞活 化[J].中国药理学通报.2005,21(5):563-7
53.Saile B,Eisenbach C,Dudas J,et al.Interferon-gamma acts proapoptotic on hepatic stellate cells(HSC) and abrogates the antiapoptotic effect of interferon alpha by an HSP70 dependent pathway[J].Eur J Cell Biol.2004,83(9):469-76
54.Par A,Par G.Liver fibrosis:pathophysiology,diagnosis and treatment[J].Orv Hetil.2005,146:3-13
1.高春芳,陆伦根.纤维化疾病的基础和临床[M].上海:上海科学技术出版社,2004:265
2.韩硬海,李树桐.临床肝脏病学[M].山东:山东科学技术出版社,2005:174
3.Zhau XY,Murphy FR,Gehdu N,et al.Engagement of aintegrin regμlates proliferation and apoptosis of hepatic stellate cells[J].J Biol Chem.2004,279(23):23996-4006
4.Freeman TL,Kharbanda KK,Tuma DJ,et al.Inhibition of hepatic stellate cell collagen synthesis by N-(methylamino) isobutyric acid[J].Biochem Pharmacol.2002,63(4):697-706
5.Wake K."Sternzellen"in the liver:Perisinusoidal cells with special reference to storage of vitamin A[J].Am J Anat.1971,132(4):429-62
6.Friedman SL.Molecμlar regμlation of hepatic fibrosis,an integrated cellμlar response to tissue injury[J].J Biol Chem.2000,275(4):2247-50
7.萧树东.胃肠病学和肝脏病学——基础理论与临床研究[M].上海:上海世界图书出版公司出版发行,2004:767
8.权启镇,孙自勤,王要军.新肝脏病学[M].山东:山东科学技术出版社.2003:314-5
9.Lv P,Paμl SC,Xiao Y,et al.Effects of thalidomide on the expression of adhesion molecμles in rat liver cirrhosis[J].Mediators Inflamm.2006,6(4):93253
10.Hellerbrond C,Wang SC,Tsukamotoh,et al.Expression of intracellμlar adhesion molecμle 1 by activated hepatic stellate cells[J].Hepatology.1996,24(3):670-6
11.Shi Y,Massagu J.Mechamism of TGF-beta signaling from cell member to the nucleus [J].Cell.2003,113(6):685-700
12.Chen YW,Li DG,Wu JX,et al.Tetrandrine inhibits activation of rat hepatic stellate cells stimulated by transforming growth factor-beta in vitro via up-regulation of Smad 7[J].J Ethnopharmacol.2005,100(3):299-305
13.Kharbanda KK,Rogers DD,Wyatt TA,et al.Transforming growth factor-beta induces contraction of activated hepatic stellate cells[J].J Hepatol.2004,41(1):60-6
14.蒋明德.肝纤维化发生中的MAPK信号传导通路[J].第四军医大学学报.2005,26(8):766-7
15.Kim WH,Matsumoto K,Bessho K,et al.Growth inhibition and apoptosis in liver myofibroblasts promoted by hepatocyte growth factor leads to resolution from liver cirrhosis[J].Am J Pathol.2005,166(4):1017-28
16.Tsukada S,Parsons CJ,Rippe RA.Mechanisms of liver fibrosis[J].Clin Chim Acta.2006,364(1-2):33-60
17.Jung JO,Gwak GY,Lim YS,et al.Role of hepatic stellate cells in the angiogenesis of hepatoma[J].Korean J Gastroenterol.2003,42(2):142-8
18.Dent P,Yacoub A,Fisher PB,et al.MAPK pathways in radiation responses[J].Oncogene.2003,22(37):5885-96
19.Zhang YP,Yao XX,Zhao X.Interleukin-1 beta up-regμlates tissue inhibitor of matrix metalloproteinase-1 mRNA and phosphorylation of c-jun N-terminal kinase and p38 in hepatic stellate cells[J].World J Gastroenterol.2006,12(9):1392-6
20.Sohn JH,Han KL,Kim JH,et al.Protective Effects of macelignan on cisplatin induced hepatotoxicity is associated with JNK activation[J].Biol Pharm Bμll.2008,31(2):273-7
21.Furukawa F,Matsuzaki K,Mori S,et al.p38 MAPK mediates fibrogenic signal through Smad3 phosphorylation in rat myofibroblasts[J].Hepatology.2003,38(4):879-89
22.Varela RM,Montiel DC,Oses PJA,et al.p38 MAPK mediates the regμlation of alpha 1(Ⅰ) procollagen mRNA levels by TNF-alpha and TGF-beta in a cell line of rat hepatic stellate cells[J].Febs Lett.2002,528(1-3):133-8
23.Reif S,LangA,Lindquist JN,et al.The role of focal adhesion kinase phosphatidylinositol 3-kinase-akt signaling in hepatic stellate cell proliferation and type Ⅰ collagen expression[J].J Biol Chem.2003,278(10):8083-90
24.吴晓玲,曾维政,蒋明德.肝纤维化的信号转导通路[J].世界华人消化杂志.2006,14(22):2223-8
25.Gabele E,Reif S,Tsukada S,et al.The role of p70~(56K) in hepatic stellate cell collagen gene expression and cell proliferation[J].J Biol Chem.2005,280(14):13374-82
26.Saxena NK,Ikeda K,Rockey DC,et al.Leptin in hepatic fibrosis:evidence for increased collagen production in stellate cells and lean littermates of ob/ob mice[J].Hepatology.2002,35(4):762-71
27.Hegyi K,Fμlop K,Kovacs K,et al.Leptin-induced signal transduction pathways[J].Cell Biol Int.2004,28(3):159-61
28.Novitskiy G,Ravi R,Potter JJ,et al.Effects of acetaldehyde and TNF alpha on the inhibitory kappa B-alpha protein and nuclear factor kappa B activation in hepatic stellate cells[J].Alcohol.2005,40(2):96-101
29.刘娟,姚树坤,殷飞.脂肝宁对大鼠脂肪性肝炎肝细胞核因子-κB、肿瘤坏死因子-α表达的影响[J].中国中医基础医学杂志.2007,13(1):38-41
30.Gao R,Brigstock DR.Activation of nuclear factor kappa B(NF-kappa B) by connective tissue growth factor(CCN2) is involved in sustaining the survival of primary rat hepatic stellate cells[J].Cell Commun Signal.2005,22(3):14
31.Sung CK,She H,Xiong S,et al.Tumor necrosis factor-alpha inhibits peroxisome proliferators-activated receptor gamma activity at a posttranslational level in hepatic stellate cells[J].Am J Physiol Gastroinlest Liver Physiol.2004,286(5):G722-9
32.Wang XZ,Zhang SJ,Chen YX,et al.Effects of platelet-derived growth factor and interleukin-10 on Fas/Fas-ligand and Bcl-2/Bax mRNA expression in rat hepatic stellate ceils in vitro[J].World J Gastroenterol.2004,10(18):2706-10
33.Trim N,Morgan S,Evans M,et al.Hepatic stellate cells express the low affinity nerve growth factor receptor P75 and undergo apoptosis in response to nerve growth factor stimμlation[J].Am J Pat hol.2000,156(4):1235-43
34.Lang A,Schoonhoven R,Tuvia S,et al.Nuclear factor kappa B inproliferation,activation,and apoptosis in rat hepatic stellate cells[J].J Hepatol.2000,33(1):49-58
35.Zhou Y,Zheng S,Lin J,et al.The interruption of the PDGF and EGF signaling pathways by curcumin stimμlates gene expression of PPAR gamma in rat activated hepatic stellate cell in vitro[J].Lab Invest.2007,87(5):488-98
36.Sun K,Wang Q,Huang XH.PPAR gamma inhibits growth of rat hepatic stellate cells and TGF beta-induced connective tissue growth factor expression[J].Acta Pharmacol Sin 2006,27(6):715-23
37.Galli A,Crabb DW,Ceni E,et al.Antidiabetic thiazolidinediones inhibit collagen synthesis and hepatic stellate cell activation in vivo and in vitro[J].Gastroenterology.2002,122(7):1924-40
38.Novo E,Marra F,Zamara E,et al.Overexpression of Bcl-2 by activated human hepatic stellate cells:resistance to apoptosis as a mechanism of progressive hepatic fibrogenesis in humans[J].Gut.2006,55(8):1174-82
39.梅玫,陆伟.细胞色素P_(450) 2E1在脂肪性肝病中致病作用研究进展[J].实用肝脏病杂志.2007,10(1):61-4
40.Susin SA,Daugas E,Ravagnan L,et al.Two distinct pathways leading to nuclear apoptosis[J].J Exp Med.2000,192(4):571-80
41.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].J Biol Chem.2002,277(13):11069-76
42.Chang XM,Chang Y,Jia A,et al.Effect s of interferon-alpha on expression of hepatic stellate cell and transforming growth factor-b1 and a-smooth muscle actin in rats with hepatic fibrosis[J].World J Gast roenterol.2005,11(17):2634-6
43.Saile B,Eisenbach C,Dudas J,et al.Interferon-gamma acts proapoptotic on hepatic stellate cells(HSC) and abrogates the antiapoptotic effect of interferon-alpha by an HSP70-dependant pathway[J].Eur J Cell Biol.2004,83(9):469-76
2.Urtasun R,Nieto N.Hepatic stellate cells and oxidative stress[J].Rev Esp Enferm Dig.2007,99(4):223-30
3.王连升,陈颖伟,李定国.TGFβ1信号与肝纤维化[J].国外医学消化疾病分册.2004,24(3):142-4
4.Elsharkawy AM,Oakley F,Mann DA.The role and regμlation of hepatic stellate cell apoptosis in reversal of liver fibrosis[J].Apoptosis.2005,10(5):927-39
5.Mas N,Tasci I,Comert B,et al.Ursodeoxycholic acid treatment improves hepatocyte μltrastructure in rat liver fibrosis[J].World J Gastroenterol.2008,14(7):1108-11
6.Ajello A,Freni MA,Spadaro A,et al.Ten year follow-up of patients with chronic hepatitis C treated with interferon[J].Hepatogastroenterology.1999,46(28):2447-50
7.Wright TL.Treatment of patients with hepatitis C and cirrhosis[J].Hepatology.2002,36(5 Suppl 1):S185-94
8.江苏新医学院.中药大辞典(下册)[M].上海科学技术出版社.1986:1694
9.Abajo C,Boffill M A,Del Campo J,et al.In vitro study of the antioxidant and immunomod μ latory activity of aqueous infusion of Bidens pilosa[J].J Ethnopharmacol.2004,93(2-3):319-23
10.李帅,匡海学,冈田嘉仁,等.鬼针草化学成分的研究[J].中草药.2004,25(9):972-5
11.陈飞虎,袁丽萍,钟明媚,等.鬼针草总黄酮抗大鼠肝纤维化的实验研究[J].中国临床药理学与治疗学.2006,12(11):1369-74
12.Zhong MM,Chen FH,Yuan LP,et al.Protective effect of total flavonoids from Bidens bipinnata L.against carbon tetrachloride-induced liver injury in mice[J].J Pharm Pharmacol.2007,59(7):1017-25
13.刘秀英,胡怡秀,胡余明,等.四氯化碳和猪血清肝纤维化模型组织病理比较[J].世界华人消化杂志.2004,12(8):1875-9
14.Wu C S,Piao X X,Piao D M,et al.Treatment of pig serum-induced rat liver fibrosis with Boschniakia rossica,oxymatrine and interferon-α[J].World J Gastroenterol. 2005,11(1):122-6
15.Andrade R G,Gotardo B M,Assis B C.Immunological Tolerance to Pig-serum Partially Inhibits the Formation of Septal Fibrosis of the Liver in Capillaria hepatica infected Rats[J].Mem Inst Oswaldo Cruz.2004,99(7):703-7
16.Nanji AA,Kalle J,Maryam F,et al.Increased severity of alcoholic liver injury in female rats:role of oxidative stress,endotoxin,and chemokines[J].Am J Physiol Gastrointest Liver Physiol.2001,281:1348-56
17.Oh WY,Pyo S,Lee KR,et al.Effect of holotrichia diomphalia larvae on liver fibrosis and hepatotoxicity in rats[J].Journal of Ethnopharmacology.2003,87:175-80.
18.胡义,王庆林.肝纤维化发病机制的研究进展[J].国际病理科学与临床杂志.2007,27(1):48-52
19.Lewindon PJ,Pereira TN,Hoskina AC,et al.Role of hepatic stellate cells and transforming growth factor-β in cystic fibrosis liver disease[J].Am J Pathol.2002,160(5):1705-15
20.程明亮,杨长青.肝纤维化的基础研究及临床[M].人民卫生出版社.2002:126
21.Arthur MJP.Fibrogenesis metalloprotcmase and their inhibitors in liver fibrosis[J].Am J phgsloe Gastrointest Liver Physioe.2000,279:G245-9
22.Liu P,Hu YY,Liu CH,et al.Clinical observation of salvianolic acid B in treatment of liver fibrosis in chronic hepatitis B[J].World J Gastroenterol.2002,89(4):679-85
23.Mandal AK,Das S,Basu MK.Hepatoprotective activity of liposomal flavonoid against arsenite-induced liver fibrosis[J].J Pharmacol Exp Ther.2007,320(3):994-1001
24.陈桂敏,郑文芝,薛贵平,等.芪蚣抗纤方对免疫性肝纤维化大鼠肝组织病理形态的影响[J].河北北方学院学报.2005,22(4):3-6
25.崔春吉,李永宇,金幸,等.肝硬变病人血清AST/ALT比值的变化及其意义[J].中国基层医药.2003,10(5):449-50
26.Li C H,Piao D M,Xu W X,et al.Morphological and serum hyaluronic acid,laminin and type Ⅳ collagen changes in dimethylnitrosamine-induced hepatic fibrosis of rats[J].World J Gastroenterol.2005,11(48):7620-4.
27.刘露,张木坤,何伶俐.肝纤维化血清标志物在肝病诊断中的意义[J].放射免疫 学杂志.2004,17(1):23-5
28.王红.慢性病毒性肝炎患者血清TIMP-1、HA与肝纤维化的关系[J],中国误诊学杂志.2007,18(7):4203-5
29.武昌,赵健康,郭玉娟.慢性乙型肝炎和肝硬化患者血清HA、LN、PCⅢ和Ⅳ-C 水平与肝组织纤维化程度的关系[J].实用肝脏病杂志.2005,8(4):200-2
30.唐惠君.肝病患者220例肝纤维化血清标记物的检测.职业与健康.2008,24(1):27-9
31.刘霖敏.血清HA、PCⅢ、Ⅳ-C、LN和内皮素在慢性肝病肝纤维化中的临床意义[J].江西医药.2007,42(9):832-4
32.Hanauske-Abel HM.Fibrosis of the liver:representative molecμlar elements and their emerging role as anti-fibrotic targets[J].Hepatology:A Textbook of Liver isease.2003,4:347-54
33.Kolios G,Valatas V,Kouroumalis E.Role of Kupffer cells in the pathogenesis of liver disease[J].World J Gastroenterol.2006,12(46):7413-20
34.Tomita K,Tamiya G,Ando S.Tumour necrosis factor alpha signalling through activation of Kupffer cells plays an essential role in liver fibrosis of non-alcoholic steatohepatitis in mice[J].Gut.2006,55(3):415-24
35.韩硬海,李树桐.临床肝脏病学[M].山东:山东科学技术出版社,2005:174
36.Bautista AP.Chronic alcohol intoxication primes Kupffer cells and endothelial cells for enhanced CC-chemokine production and concomitantly suppresses phagocytosis and chemotaxis[J].Front Biosci.2002,7:a117-25
37.Melgert BN,Olinga P,Van Der Laan JM,et al.Targeting dexamethasone to Kupffer cells:effects on liver inflammation and fibrosis in rats[J].Hepatology.2001,34(4 Pt 1):719-28
38.袁丽萍,陈飞虎,夏丽娟,等.鬼针草总黄酮对肝纤维化大鼠细胞因子的影响[J].中国药理学通报.2007,23(7):887-91
39.Liu CH,Hu YY,Wang XL,et al.Effects of salvianolic acid-A on NIH/3T3 fibroblast proliferation,collagen synthesis and gene expression[J].World J Gastroenterol.2000,6(3):361-4
40.马雪梅,王宝恩,尤红.丹参对肝星状细胞增殖和凋亡影响的实验研究[J].中国中医药信息杂志.2000,7(7):25-7
41.Adachi J,Matsushita S,Yoshioka N.Plasma phosphatidylcholine hydroperoxide as a new marker of oxidative stress in alcoholic patients.J Lipid Res.2004,45(5):967-71
42.Hoek JB,Pastorino JG..Ethanol,oxidative stress,and cytokine-induced liver cell injury[J].Alcohol.2002,27:63-8
43.Williams AT,Burk RF.Carbon tetrachloride hepatotoxicity:an example of free radical-mediated injury e[J].Semin Liver Dis.1990,10(4):279-4
44.Kim KS,Lee S,Lee YS,et al.Anti-oxidant activities of the extracts from the herbs of Artemisia apiacea[J].J Ethnopharmacol.2003,85(1):69-72
45.Souchelny TS.Transforming growth factor-signaling and its role in cancer[J].Exp Ocol.2002,24:3-12
46.Logolo AF,Nonogaki S,MiguelR E,et al.Transforming growth factor beta expression in head and neck squamous cell carcinoma patients as related to prognosis[J].J Oroal Pathol Med.2003,32(3):139-45
47.Lewindon PJ,Pereira TN,Hoskina AC,et al.Role of hepatic stellate cells and transforming growth factor-β in cystic fibrosis liver disease[J].Am J Pathol.2002,160(5):1705-15
48.Shi Y,Massagu J.Mechamism of TGF-beta signaling from cell member to the nucleus [J].Cell.2003,113(6):685-700
49.Bedossa P,Peltier E,Terris B,et al.Transforming growth factor-beta 1(TGF-beta 1)and receptors in normal,cirrhotic,and neoplastic human livers[J].Hepatology.1995,21:760-6
50.Chen YW,Li DG,Wu JX,et al.Tetrandrine inhibits activation of rat hepatic stellate cells stimμlated by transforming growth factor-beta in vitro via up-regμlation of Smad 7.J Ethnopharmacol.2005,100(3):299-305
51.权启镇,孙自勤,王要军.新肝脏病学[M].山东:山东科学技术出版社.2003:314-5
52.陈源文,李定国,吴建新,等.粉防己碱上调Smad7表达抑制大鼠肝星状细胞活 化[J].中国药理学通报.2005,21(5):563-7
53.Saile B,Eisenbach C,Dudas J,et al.Interferon-gamma acts proapoptotic on hepatic stellate cells(HSC) and abrogates the antiapoptotic effect of interferon alpha by an HSP70 dependent pathway[J].Eur J Cell Biol.2004,83(9):469-76
54.Par A,Par G.Liver fibrosis:pathophysiology,diagnosis and treatment[J].Orv Hetil.2005,146:3-13
1.高春芳,陆伦根.纤维化疾病的基础和临床[M].上海:上海科学技术出版社,2004:265
2.韩硬海,李树桐.临床肝脏病学[M].山东:山东科学技术出版社,2005:174
3.Zhau XY,Murphy FR,Gehdu N,et al.Engagement of aintegrin regμlates proliferation and apoptosis of hepatic stellate cells[J].J Biol Chem.2004,279(23):23996-4006
4.Freeman TL,Kharbanda KK,Tuma DJ,et al.Inhibition of hepatic stellate cell collagen synthesis by N-(methylamino) isobutyric acid[J].Biochem Pharmacol.2002,63(4):697-706
5.Wake K."Sternzellen"in the liver:Perisinusoidal cells with special reference to storage of vitamin A[J].Am J Anat.1971,132(4):429-62
6.Friedman SL.Molecμlar regμlation of hepatic fibrosis,an integrated cellμlar response to tissue injury[J].J Biol Chem.2000,275(4):2247-50
7.萧树东.胃肠病学和肝脏病学——基础理论与临床研究[M].上海:上海世界图书出版公司出版发行,2004:767
8.权启镇,孙自勤,王要军.新肝脏病学[M].山东:山东科学技术出版社.2003:314-5
9.Lv P,Paμl SC,Xiao Y,et al.Effects of thalidomide on the expression of adhesion molecμles in rat liver cirrhosis[J].Mediators Inflamm.2006,6(4):93253
10.Hellerbrond C,Wang SC,Tsukamotoh,et al.Expression of intracellμlar adhesion molecμle 1 by activated hepatic stellate cells[J].Hepatology.1996,24(3):670-6
11.Shi Y,Massagu J.Mechamism of TGF-beta signaling from cell member to the nucleus [J].Cell.2003,113(6):685-700
12.Chen YW,Li DG,Wu JX,et al.Tetrandrine inhibits activation of rat hepatic stellate cells stimulated by transforming growth factor-beta in vitro via up-regulation of Smad 7[J].J Ethnopharmacol.2005,100(3):299-305
13.Kharbanda KK,Rogers DD,Wyatt TA,et al.Transforming growth factor-beta induces contraction of activated hepatic stellate cells[J].J Hepatol.2004,41(1):60-6
14.蒋明德.肝纤维化发生中的MAPK信号传导通路[J].第四军医大学学报.2005,26(8):766-7
15.Kim WH,Matsumoto K,Bessho K,et al.Growth inhibition and apoptosis in liver myofibroblasts promoted by hepatocyte growth factor leads to resolution from liver cirrhosis[J].Am J Pathol.2005,166(4):1017-28
16.Tsukada S,Parsons CJ,Rippe RA.Mechanisms of liver fibrosis[J].Clin Chim Acta.2006,364(1-2):33-60
17.Jung JO,Gwak GY,Lim YS,et al.Role of hepatic stellate cells in the angiogenesis of hepatoma[J].Korean J Gastroenterol.2003,42(2):142-8
18.Dent P,Yacoub A,Fisher PB,et al.MAPK pathways in radiation responses[J].Oncogene.2003,22(37):5885-96
19.Zhang YP,Yao XX,Zhao X.Interleukin-1 beta up-regμlates tissue inhibitor of matrix metalloproteinase-1 mRNA and phosphorylation of c-jun N-terminal kinase and p38 in hepatic stellate cells[J].World J Gastroenterol.2006,12(9):1392-6
20.Sohn JH,Han KL,Kim JH,et al.Protective Effects of macelignan on cisplatin induced hepatotoxicity is associated with JNK activation[J].Biol Pharm Bμll.2008,31(2):273-7
21.Furukawa F,Matsuzaki K,Mori S,et al.p38 MAPK mediates fibrogenic signal through Smad3 phosphorylation in rat myofibroblasts[J].Hepatology.2003,38(4):879-89
22.Varela RM,Montiel DC,Oses PJA,et al.p38 MAPK mediates the regμlation of alpha 1(Ⅰ) procollagen mRNA levels by TNF-alpha and TGF-beta in a cell line of rat hepatic stellate cells[J].Febs Lett.2002,528(1-3):133-8
23.Reif S,LangA,Lindquist JN,et al.The role of focal adhesion kinase phosphatidylinositol 3-kinase-akt signaling in hepatic stellate cell proliferation and type Ⅰ collagen expression[J].J Biol Chem.2003,278(10):8083-90
24.吴晓玲,曾维政,蒋明德.肝纤维化的信号转导通路[J].世界华人消化杂志.2006,14(22):2223-8
25.Gabele E,Reif S,Tsukada S,et al.The role of p70~(56K) in hepatic stellate cell collagen gene expression and cell proliferation[J].J Biol Chem.2005,280(14):13374-82
26.Saxena NK,Ikeda K,Rockey DC,et al.Leptin in hepatic fibrosis:evidence for increased collagen production in stellate cells and lean littermates of ob/ob mice[J].Hepatology.2002,35(4):762-71
27.Hegyi K,Fμlop K,Kovacs K,et al.Leptin-induced signal transduction pathways[J].Cell Biol Int.2004,28(3):159-61
28.Novitskiy G,Ravi R,Potter JJ,et al.Effects of acetaldehyde and TNF alpha on the inhibitory kappa B-alpha protein and nuclear factor kappa B activation in hepatic stellate cells[J].Alcohol.2005,40(2):96-101
29.刘娟,姚树坤,殷飞.脂肝宁对大鼠脂肪性肝炎肝细胞核因子-κB、肿瘤坏死因子-α表达的影响[J].中国中医基础医学杂志.2007,13(1):38-41
30.Gao R,Brigstock DR.Activation of nuclear factor kappa B(NF-kappa B) by connective tissue growth factor(CCN2) is involved in sustaining the survival of primary rat hepatic stellate cells[J].Cell Commun Signal.2005,22(3):14
31.Sung CK,She H,Xiong S,et al.Tumor necrosis factor-alpha inhibits peroxisome proliferators-activated receptor gamma activity at a posttranslational level in hepatic stellate cells[J].Am J Physiol Gastroinlest Liver Physiol.2004,286(5):G722-9
32.Wang XZ,Zhang SJ,Chen YX,et al.Effects of platelet-derived growth factor and interleukin-10 on Fas/Fas-ligand and Bcl-2/Bax mRNA expression in rat hepatic stellate ceils in vitro[J].World J Gastroenterol.2004,10(18):2706-10
33.Trim N,Morgan S,Evans M,et al.Hepatic stellate cells express the low affinity nerve growth factor receptor P75 and undergo apoptosis in response to nerve growth factor stimμlation[J].Am J Pat hol.2000,156(4):1235-43
34.Lang A,Schoonhoven R,Tuvia S,et al.Nuclear factor kappa B inproliferation,activation,and apoptosis in rat hepatic stellate cells[J].J Hepatol.2000,33(1):49-58
35.Zhou Y,Zheng S,Lin J,et al.The interruption of the PDGF and EGF signaling pathways by curcumin stimμlates gene expression of PPAR gamma in rat activated hepatic stellate cell in vitro[J].Lab Invest.2007,87(5):488-98
36.Sun K,Wang Q,Huang XH.PPAR gamma inhibits growth of rat hepatic stellate cells and TGF beta-induced connective tissue growth factor expression[J].Acta Pharmacol Sin 2006,27(6):715-23
37.Galli A,Crabb DW,Ceni E,et al.Antidiabetic thiazolidinediones inhibit collagen synthesis and hepatic stellate cell activation in vivo and in vitro[J].Gastroenterology.2002,122(7):1924-40
38.Novo E,Marra F,Zamara E,et al.Overexpression of Bcl-2 by activated human hepatic stellate cells:resistance to apoptosis as a mechanism of progressive hepatic fibrogenesis in humans[J].Gut.2006,55(8):1174-82
39.梅玫,陆伟.细胞色素P_(450) 2E1在脂肪性肝病中致病作用研究进展[J].实用肝脏病杂志.2007,10(1):61-4
40.Susin SA,Daugas E,Ravagnan L,et al.Two distinct pathways leading to nuclear apoptosis[J].J Exp Med.2000,192(4):571-80
41.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].J Biol Chem.2002,277(13):11069-76
42.Chang XM,Chang Y,Jia A,et al.Effect s of interferon-alpha on expression of hepatic stellate cell and transforming growth factor-b1 and a-smooth muscle actin in rats with hepatic fibrosis[J].World J Gast roenterol.2005,11(17):2634-6
43.Saile B,Eisenbach C,Dudas J,et al.Interferon-gamma acts proapoptotic on hepatic stellate cells(HSC) and abrogates the antiapoptotic effect of interferon-alpha by an HSP70-dependant pathway[J].Eur J Cell Biol.2004,83(9):469-76