健脾活血方体内外抗肝纤维化的作用研究
|
摘要
肝纤维化是多种慢性肝病向肝硬化发展的必经之路。不同原因(炎症、中毒、慢性淤胆、代谢障碍、血液循环障碍、营养障碍等)引起肝细胞(HC)慢性损伤(肝细胞发生炎症坏死,肝内纤维结缔组织异常增生),使枯否细胞(KC)激活,分泌多种细胞因子,随同血小板、窦内皮细胞(SEC)和HC等分泌的细胞因子,和某些化学介质共同激活肝星状细胞(HSC),使其转化为肌成纤维细胞(MFB),再通过旁分泌和自分泌作用,大量合成、增殖以胶原为主的细胞外间质(ECM),而降解相对不足,使ECM在肝内过多沉积,肝窦基底膜形成,肝窦毛细血管化,导致肝纤维化的形成和发展。若进一步引起肝小叶改建,假小叶和结节形成,则致肝硬化。因此,肝纤维化是肝脏对各种原因所致肝损伤的代偿修复反应,又是肝损害的促进因素,这种动态演变过程是各种慢性肝病向肝硬化发展的必经阶段,是肝病慢性化的共同特征。
肝纤维化是现代医学病理形态学概念,中医并无此称谓,根据其病因、病机以及临床表现,可归属于“胁痛”、“臌胀”、“黄疸”、“积聚”等病范畴。从中医学角度看,本病多因外感湿热之邪或感染疫毒,或饮酒过度,酿生湿热,羁留不去,再加情志不遂等因素,渐致肝、脾、肾功能失调,气血、津液搏结,以致气滞血瘀,肝络瘀阻。
目前,治疗肝纤维化尚无特效药,西医药在针对肝纤维化发生的各个环节进行抗肝纤维化治疗上已取得了一些进展,很多药物在体外和动物实验中均显示有较强的抗纤维化作用,但由于这些药物或疗效不够稳定,或毒副作用较大,临床应用者尚少。因此,从天然药物中发掘抗纤维化药物,已成为国内外研究的热点。应用单味中药、有效单体、复方、中西药联用等多种治疗方法进行抗纤维化的研究表明,中药在抗纤维化方面有广阔的应用前景,中医中药在治疗肝纤维化上面有着多部位、多靶点、毒副作用小的优势。
为了挖掘更好的抗肝纤维化的中医药,造福人类,本课题研究以肝纤维化的发病机制为依据,以肝纤维化的中西医结合治疗为基础,以中药复方健脾活血方为实验药物,探讨其体内外抗肝纤维化的作用机制。健脾活血方由太子参、茯苓、白术、赤芍、丹参、田七、珍珠草、红花等组成,具有健脾益气,活血祛瘀,清热解毒的功效。
本课题研究体内实验采用DMN肝纤维化大鼠模型。大鼠造模成功后,以健脾活血方为实验药物,给药4个月。通过检测DMN肝纤维化大鼠的肝指数和脾指数、镜下观察肝组织的病理切片,以及放射免疫法测定大鼠血清的肝纤四项,探讨健脾活血方体内抗肝纤维化作用。
体外实验以肝星状细胞为细胞模型,以健脾活血方含药血清为实验药物,含药血清作用于HSC-T6后,貂肺上皮细胞(Mv-1-Lu)生长抑制MTT法检测HSC-T6分泌的TGF-β1的活性及其总量；ELISA法检测PDGF诱导的HSC-T6的Ⅰ型胶原含量,RT-PCR法检测PDGF诱导HSC-T6的TGF-β1mRNA,Ⅰ型胶原mRNA的表达水平,以探讨健脾活血方体外抗肝纤维化的作用。
体内实验结果表明,健脾活血方高、中剂量组可以显著降低肝脾指数(P<0.01);同时,病理切片结果显示健脾活血方高、中、低剂量组均可减轻DMA肝纤维化大鼠肝脏的病变程度,以高、中剂量组为佳。另外,健脾活血方高、中剂量组还可降低DMN肝纤维化大鼠血清的HA、PCⅢ、LN, IV-C的水平(P<0.01),提示健脾活血方可以改善肝组织的病理形态,降低血清肝纤维化指标,具有良好的抗肝纤维化作用。
体外实验结果表明,健脾活血方含药血清高剂量组可明显减少HSC TGF-β1的分泌总量(P<0.01),高剂量组及中剂量组可抑制TGF-β1的活性(P<0.01),高剂量组可降低TGF-β1mRNA的表达；同时健脾活血方含药血清还可降低Ⅰ型胶原的分泌,降低Ⅰ型胶原mRNA的表达,无剂量依赖效应(P<0.01),提示健脾活血方能够抑制HSC-T6增殖活化,干预胶原的合成,具有良好的抗肝纤维化作用。
The hepetic fibrosis is the road taken by many kinds of chronic liver diseases that develop into liver cirrhosis. Different reasons (inflammation, toxicant, chronic silt gallbladder, metabolic block, blood circulation barrier, trophopathy, et al) cause chronic damage of the hepetic cell (HC) (HC have inflammation necrosis; fibrous connective tissue in liver proliferates abnormaly), makes Kupffer Cell (KC) activate, and secrete many kinds of cytokines which accompany cytokines of the blood platelet, sinusoidal endothelial cell (SEC) and HC to activate hepatic stellate cell (HSC) together with certain chemical mediator, causes it to transform into myofibroblast (MFB), then through paracrine and autocrine, the extracellular matrix(ECM), primarily the collagen, synthesize, proliferate massively, while degrading relatively insufficient, thus ECM in the liver excessively depositing, basilar membrane in hepetic sinusoid appearing, capillarity in hepetic sinusoid vascularizing, causes the formation and developmen of hepetic fibrosis. If it further causes the hepatic lobe reconstruction, pseudolobuli and tubercle take shape, then comes the liver cirrhosis. Obviously, the liver fibrosis is not only the liver's compensation and restoration reaction to the damages caused by different reasons but also the contributing factor to the liver injure. this kind of dynamic successional variation process is the stage that each kind of chronic liver disease must pass through in order to develop into liver cirrhosis, and also the common characteristic for chronic liver diseases.
The hepetic fibrosis is the modern medicine's pathological and morphological concept, the Chinese medicine does not have this name. According to its cause, the pathogenesis as well as the clinical manifestation, we can clarify it to the sickness such as "costal pleurisy", "the abdominal distension", "the jaundice", "the agglomeration" and so on. Looking from the traditional Chinese medicine angle, this sickness is mostly caused by hot and damp evil or infected by epidemic disease, or drinking wine excessively, hot and damp ferments, which cannot stop over, plus other factors such as bad mood, gradually makes the function of liver, spleen and kidney out of balance, the vitality, the body fluids wrestles the knot, so that the stagnation of vital energy and blood stasis, stagnation of the liver channels take shape.
At present, the treatment of hepetic fibrosis still have no specific medicine. West medicine, aiming at each link which the hepetic fibrosis occurs, has made some progress in the anti-liver fibrosis treatment, many medicines demonstrate strong anti-fibrosis function in vitro and the animal experimentation.But these medicines are still few in the clinical practice because their curative effect is not very stable, or the poisonous side effect is big. Therefore, excavateing the anti-fibrosis medicine from natural medicine, has become the hot spot of the domestic and foreign research. The research, using the single traditional Chinese medicine, the effective component monomer, the compound prescription, the combination of Chinese and western drugs, many such kinds of methods of treatment carrying on the anti-fibrosis, indicates that the traditional Chinese medicine has the broad application prospect in the anti-fibrosis aspect, the traditional Chinese medicine has superiorities such as multi-spots, multi-targets, small poisonous side effect in treating hepetic fibrosis.
In order to unearth better anti-liver fibrosis Chinese medicine, benefit the humanity, this topic research, taking the hepetic fibrosis's pathogenesis as the basis, the hepetic fibrosis's cooperation treatment of Chinese and Western medicine as the foundation, the traditional Chinese medicine compound prescription:spleen-tonifying and blood-invigorating compound as the tested medicine, investigates its anti-liver fibrosis function mechanism in vivo and vitro. Spleen-tonifying and blood-invigorating compound which is mainly composed of radix pseudostellariae, poria cocos, white atractylodes rhizome, radix paeoniae rubra, salvia miltiorrhiza, radix notoginseng, phyllanthus urinaria, safflower, is able to strengthen the spleen and replenish qi, promote blood circulation and remove blood stasis, clearing away heat and toxic material.
This topic research in vivo experiment use the DMN hepetic fibrosis rats as animal model, the spleen-tonifying and blood-invigorating compound as the tested medicine. After making the mold successfully, through examining the DMN hepetic fibrosis rats'liver index and spleen index, observing the pathological section of hepetic tissue with electron microscope, as well as determineing the rat blood serum's liver filament four items with radioimmunoassay, we explore spleen-tonifying and blood-invigorating compound's anti-liver fibrosis function in vivo.
For the purpose of investigating spleen-tonifying and blood-invigarating compound's anti-liver fibrosis function in vitro, experimens in vitro take the hepetic stellate cell as the cell model, spleen-tonifying and blood-invigorating compound blood serum as the tested medicine. After the blood serum acting on HSC-T6, the TGF-β1's activity and total content in the supernatant of culture was measured by mink lung epithelial cell(Mv-1-Lu) proliferation inhibition MTT assay. And type I collagen was measured by ELISA.the RT-PCR assay examines TGF-β1mRNA, type I collagen mRNA of HSC-T6 induced by PDGF. Experimental results in vivo indicate that the high-dosed and mid-dosed group of spleen-tonifying and blood-invigorating compound can obviously reduce the liver and spleen index (P<0.01). At the same time, the pathological section result shows that all the high-dosed, mid-dosed and low-dosed group of spleen-tonifying and blood-invigorating compound can reduce the DMA hepetic fibrosis rat liver's pathological change, especially the high and middle dose group. Besides, the high-dosed and mid-dosed group of spleen-tonifying and blood-invigorating compound also can reduce DMN hepetic fibrosis rat blood serum's HA, PCIII, LN, IV-C level (P<0.01), suggesting that spleen-tonifying and blood-invigorating compound can not only improve the pathomorphism of hepetic tissue, but also reduce the sera markers for heptic fibrosis, and has good anti-liver fibrosis function.
Experimental results in vitro indicate that the high-dosed group of spleen-tonifying and blood-invigorating compound blood serum can reduce the HSC TGF-β1 secretion total quantity obviously (P<0.01), the high-dosed and mid-dosed group can suppress TGF-β1 activeness (P<0.01), and the high-dosed group can reduce TGF-β1 mRNA expression; Simultaneously spleen-tonifying and blood-invigorating compound blood serum also can reduce the secretion of type I collagen, and reduce type I collagen mRNA the expression, without dosage dependence effect (P<0.01). The results suggest the spleen-tonifying and blood-invigorating compound blood serum is able to suppress the multiplication and activation of HSC-T6, intervene type I collagen's synthesis, and has good anti-liver fibrosis function.
肝纤维化是现代医学病理形态学概念,中医并无此称谓,根据其病因、病机以及临床表现,可归属于“胁痛”、“臌胀”、“黄疸”、“积聚”等病范畴。从中医学角度看,本病多因外感湿热之邪或感染疫毒,或饮酒过度,酿生湿热,羁留不去,再加情志不遂等因素,渐致肝、脾、肾功能失调,气血、津液搏结,以致气滞血瘀,肝络瘀阻。
目前,治疗肝纤维化尚无特效药,西医药在针对肝纤维化发生的各个环节进行抗肝纤维化治疗上已取得了一些进展,很多药物在体外和动物实验中均显示有较强的抗纤维化作用,但由于这些药物或疗效不够稳定,或毒副作用较大,临床应用者尚少。因此,从天然药物中发掘抗纤维化药物,已成为国内外研究的热点。应用单味中药、有效单体、复方、中西药联用等多种治疗方法进行抗纤维化的研究表明,中药在抗纤维化方面有广阔的应用前景,中医中药在治疗肝纤维化上面有着多部位、多靶点、毒副作用小的优势。
为了挖掘更好的抗肝纤维化的中医药,造福人类,本课题研究以肝纤维化的发病机制为依据,以肝纤维化的中西医结合治疗为基础,以中药复方健脾活血方为实验药物,探讨其体内外抗肝纤维化的作用机制。健脾活血方由太子参、茯苓、白术、赤芍、丹参、田七、珍珠草、红花等组成,具有健脾益气,活血祛瘀,清热解毒的功效。
本课题研究体内实验采用DMN肝纤维化大鼠模型。大鼠造模成功后,以健脾活血方为实验药物,给药4个月。通过检测DMN肝纤维化大鼠的肝指数和脾指数、镜下观察肝组织的病理切片,以及放射免疫法测定大鼠血清的肝纤四项,探讨健脾活血方体内抗肝纤维化作用。
体外实验以肝星状细胞为细胞模型,以健脾活血方含药血清为实验药物,含药血清作用于HSC-T6后,貂肺上皮细胞(Mv-1-Lu)生长抑制MTT法检测HSC-T6分泌的TGF-β1的活性及其总量；ELISA法检测PDGF诱导的HSC-T6的Ⅰ型胶原含量,RT-PCR法检测PDGF诱导HSC-T6的TGF-β1mRNA,Ⅰ型胶原mRNA的表达水平,以探讨健脾活血方体外抗肝纤维化的作用。
体内实验结果表明,健脾活血方高、中剂量组可以显著降低肝脾指数(P<0.01);同时,病理切片结果显示健脾活血方高、中、低剂量组均可减轻DMA肝纤维化大鼠肝脏的病变程度,以高、中剂量组为佳。另外,健脾活血方高、中剂量组还可降低DMN肝纤维化大鼠血清的HA、PCⅢ、LN, IV-C的水平(P<0.01),提示健脾活血方可以改善肝组织的病理形态,降低血清肝纤维化指标,具有良好的抗肝纤维化作用。
体外实验结果表明,健脾活血方含药血清高剂量组可明显减少HSC TGF-β1的分泌总量(P<0.01),高剂量组及中剂量组可抑制TGF-β1的活性(P<0.01),高剂量组可降低TGF-β1mRNA的表达；同时健脾活血方含药血清还可降低Ⅰ型胶原的分泌,降低Ⅰ型胶原mRNA的表达,无剂量依赖效应(P<0.01),提示健脾活血方能够抑制HSC-T6增殖活化,干预胶原的合成,具有良好的抗肝纤维化作用。
The hepetic fibrosis is the road taken by many kinds of chronic liver diseases that develop into liver cirrhosis. Different reasons (inflammation, toxicant, chronic silt gallbladder, metabolic block, blood circulation barrier, trophopathy, et al) cause chronic damage of the hepetic cell (HC) (HC have inflammation necrosis; fibrous connective tissue in liver proliferates abnormaly), makes Kupffer Cell (KC) activate, and secrete many kinds of cytokines which accompany cytokines of the blood platelet, sinusoidal endothelial cell (SEC) and HC to activate hepatic stellate cell (HSC) together with certain chemical mediator, causes it to transform into myofibroblast (MFB), then through paracrine and autocrine, the extracellular matrix(ECM), primarily the collagen, synthesize, proliferate massively, while degrading relatively insufficient, thus ECM in the liver excessively depositing, basilar membrane in hepetic sinusoid appearing, capillarity in hepetic sinusoid vascularizing, causes the formation and developmen of hepetic fibrosis. If it further causes the hepatic lobe reconstruction, pseudolobuli and tubercle take shape, then comes the liver cirrhosis. Obviously, the liver fibrosis is not only the liver's compensation and restoration reaction to the damages caused by different reasons but also the contributing factor to the liver injure. this kind of dynamic successional variation process is the stage that each kind of chronic liver disease must pass through in order to develop into liver cirrhosis, and also the common characteristic for chronic liver diseases.
The hepetic fibrosis is the modern medicine's pathological and morphological concept, the Chinese medicine does not have this name. According to its cause, the pathogenesis as well as the clinical manifestation, we can clarify it to the sickness such as "costal pleurisy", "the abdominal distension", "the jaundice", "the agglomeration" and so on. Looking from the traditional Chinese medicine angle, this sickness is mostly caused by hot and damp evil or infected by epidemic disease, or drinking wine excessively, hot and damp ferments, which cannot stop over, plus other factors such as bad mood, gradually makes the function of liver, spleen and kidney out of balance, the vitality, the body fluids wrestles the knot, so that the stagnation of vital energy and blood stasis, stagnation of the liver channels take shape.
At present, the treatment of hepetic fibrosis still have no specific medicine. West medicine, aiming at each link which the hepetic fibrosis occurs, has made some progress in the anti-liver fibrosis treatment, many medicines demonstrate strong anti-fibrosis function in vitro and the animal experimentation.But these medicines are still few in the clinical practice because their curative effect is not very stable, or the poisonous side effect is big. Therefore, excavateing the anti-fibrosis medicine from natural medicine, has become the hot spot of the domestic and foreign research. The research, using the single traditional Chinese medicine, the effective component monomer, the compound prescription, the combination of Chinese and western drugs, many such kinds of methods of treatment carrying on the anti-fibrosis, indicates that the traditional Chinese medicine has the broad application prospect in the anti-fibrosis aspect, the traditional Chinese medicine has superiorities such as multi-spots, multi-targets, small poisonous side effect in treating hepetic fibrosis.
In order to unearth better anti-liver fibrosis Chinese medicine, benefit the humanity, this topic research, taking the hepetic fibrosis's pathogenesis as the basis, the hepetic fibrosis's cooperation treatment of Chinese and Western medicine as the foundation, the traditional Chinese medicine compound prescription:spleen-tonifying and blood-invigorating compound as the tested medicine, investigates its anti-liver fibrosis function mechanism in vivo and vitro. Spleen-tonifying and blood-invigorating compound which is mainly composed of radix pseudostellariae, poria cocos, white atractylodes rhizome, radix paeoniae rubra, salvia miltiorrhiza, radix notoginseng, phyllanthus urinaria, safflower, is able to strengthen the spleen and replenish qi, promote blood circulation and remove blood stasis, clearing away heat and toxic material.
This topic research in vivo experiment use the DMN hepetic fibrosis rats as animal model, the spleen-tonifying and blood-invigorating compound as the tested medicine. After making the mold successfully, through examining the DMN hepetic fibrosis rats'liver index and spleen index, observing the pathological section of hepetic tissue with electron microscope, as well as determineing the rat blood serum's liver filament four items with radioimmunoassay, we explore spleen-tonifying and blood-invigorating compound's anti-liver fibrosis function in vivo.
For the purpose of investigating spleen-tonifying and blood-invigarating compound's anti-liver fibrosis function in vitro, experimens in vitro take the hepetic stellate cell as the cell model, spleen-tonifying and blood-invigorating compound blood serum as the tested medicine. After the blood serum acting on HSC-T6, the TGF-β1's activity and total content in the supernatant of culture was measured by mink lung epithelial cell(Mv-1-Lu) proliferation inhibition MTT assay. And type I collagen was measured by ELISA.the RT-PCR assay examines TGF-β1mRNA, type I collagen mRNA of HSC-T6 induced by PDGF. Experimental results in vivo indicate that the high-dosed and mid-dosed group of spleen-tonifying and blood-invigorating compound can obviously reduce the liver and spleen index (P<0.01). At the same time, the pathological section result shows that all the high-dosed, mid-dosed and low-dosed group of spleen-tonifying and blood-invigorating compound can reduce the DMA hepetic fibrosis rat liver's pathological change, especially the high and middle dose group. Besides, the high-dosed and mid-dosed group of spleen-tonifying and blood-invigorating compound also can reduce DMN hepetic fibrosis rat blood serum's HA, PCIII, LN, IV-C level (P<0.01), suggesting that spleen-tonifying and blood-invigorating compound can not only improve the pathomorphism of hepetic tissue, but also reduce the sera markers for heptic fibrosis, and has good anti-liver fibrosis function.
Experimental results in vitro indicate that the high-dosed group of spleen-tonifying and blood-invigorating compound blood serum can reduce the HSC TGF-β1 secretion total quantity obviously (P<0.01), the high-dosed and mid-dosed group can suppress TGF-β1 activeness (P<0.01), and the high-dosed group can reduce TGF-β1 mRNA expression; Simultaneously spleen-tonifying and blood-invigorating compound blood serum also can reduce the secretion of type I collagen, and reduce type I collagen mRNA the expression, without dosage dependence effect (P<0.01). The results suggest the spleen-tonifying and blood-invigorating compound blood serum is able to suppress the multiplication and activation of HSC-T6, intervene type I collagen's synthesis, and has good anti-liver fibrosis function.
引文
[1]程明亮,刘三都.肝纤维化的基础研究与临床[M].北京：人民卫生出舨杜,1996。
[2]戴希真.酒精性肝损伤[J].中华消化杂志,1993,13(2)：125
[3]Friedman S L, Roll F J, Boyles J, et al. Hepatic lipocytes:the principal collagen-producing cells of normal rat liver ProcNatl[J]. Acad Sci。 1985, 82:8681
[4]王润平,等.肝纤维化形成过程中肝星状细胞激活的旁分泌机制[J].中华肝脏病杂志,1997,5(3)：84
[5]Gressner AM Cytokines and cellular crosstalk involved in the activation of fat-storing cells. [J]J Hepatol,1995,22, (2 suppl):28-36
[6]熊伍军,等.肝窦内皮细胞在肝纤维化中的作用[J].国外医学·消化病分册,2000,8(4)：197
[7]杜卫东.等.实验性肝纤维化肝内胶原生成细胞的研究[J].中华肝脏病杂志,1998,6(4)：238
[8]许翠萍.肥大细胞与肝脏[J].国外医学·消化疾病分册,1997,17(2)：77
[9]许青.转化生长因子8与肝纤维化[J].国外医学·消化疾病分册,1998,18(3)：155
[10]王萍.血小板衍生生长因子与肝纤维化[J].国外医学·消化疾病分册,2000,20(1)： 40
[11]Perlmamn T, Evnas RM. Nuclear receptors in Sicily:all in the famiglia[J]. Cell,1997,90:391-397.
[12]Blom IE, Goldschmeding R, Leask A. Gene regulation of connective tissue growth factor:new targets for antifibrotictherapy[J]?Matrix Biol,2002, 21(6):473-482.
[13]Leask A, Abraham DJ. The role of connective tissue growth factor, a multifunctional matricellular protein, in fibroblast biology [J]. Biochem Cell Biol,2003,81(6):355-363.
[14]Paradis V, Dargere D, Bonvoust F, et al. Efects and regulation of connective tissue growth factor on hepatic stellate cells [J]. Lab Invest,2002,82(6): 767-774
[15]Saile B, Nlatthes N, Knittel T, et al. Transforming growth factor beta and tumor necrosis factor alpha inhibit both apoptosis and proliferation of activated rat hepatic stellate cells. Hepatology,1999。 30:196-202.
[16]刘小菁,吴红斌,刘芳,等.肿瘤坏死因子a对肝星状细胞表达结缔组织生长因子的影响.中华肝脏病杂志,2001,9：15—17.
[17]姜慧卿,赵东强.肿瘤坏死因子-a对肝星状细胞增殖与凋亡的影响.中国病理生理杂志,2003,19：1353—1356.
[18]Thomson K, Maltby J, Fallowfield J, et al. Interleukin-10 expression and function experiment murine liver inflammation and fibrosis. Hepatology, 1998,28:1597-1606.
[19]陈治新,张莉娟,陈运新,等.胰岛素样生长因子-1受体在实验性肝纤维化中的表达及IL-10的干预作用.福建医科大学学报,2002,36：134—136.
[20]刘学松,李定国,陆汉明.肝细胞的胶原合成与肝纤维化[J].中华消化杂志,1994,14(1)：53
[21]王红蓓,等.硫酸软骨素与肝纤维化[J].国外消学·消化疾病分册,1995,(3)：137
[22]Iredale J P. Tissue inhibitors of metalloproteinases in liver fibrosis[J]. Int J Biochem Cell Biol,1997,29:43.
[23]Murawakai Y,Nishimura Y, Ikuta Y, et al. Plasma transforming growth fator-betal concentrations in patients with chronic viral hepatitis [J]. J Gastrolenterol Hepatol,1993,13:680
[24]Denhardt D T, Feng B, Edwards D R, et al. Tissue inhibitor of metalloproteinases(TIMP, aka EPA):structure, control of expression and biological funtions[J]. Pharmacolther,1993,59:329.
[25]粱治学,王晓萍肝纤维化的中医病因病机研究概况甘肃中医,2006,4(19)：43-45
[26]张俊富,崔丽安,范淑芳,等.乙肝2号治慢性乙型肝炎的临床研究[J].中医杂志1993,34(11)：674
[27]李晓良.慢性乙型肝炎中医辨证与病理、病毒指标的关系[J].中西医结合肝病杂志,1996,6(2)：4—5.
[28]唐智镀,茹清静,朱起贵.论肝血瘀阻与肝纤维化的关系[J].中国中医基础医学杂志,1996,2(3)：14—18.
[29]刘宏元,刘作恩.慢性乙肝早期纤维化的治疗研究[J].天津中医,1997,14(3)：101-102.
[30]曾民德,陆伦根,茅益民.肝纤维化的诊断方法及其评估(下),临床肝胆病杂志,2006,11：181～183
[31]张文胜,王宝恩,王泰龄,等.慢性乙型肝炎纤维化无创性诊断模型的建立.中华肝脏病杂志,2006,14：169-173
[32]谢青, 桂红莲肝纤维化诊断标准的现今认识诊断学理论与实践,2009,2(8)：133-136
[33]向志勇,郑勇肝纤维化的诊断方法进展农垦医学,2008,6(30)：496-498
[34]Pinzani M. Non—invasive evaluation of hepatic fibrosis:don't count your chickens before they're hatched. Gut,2006,55:310-312.
[35]Roekey DC, Bissell DM. Noninvasive measures of liver fibrosis. Hepatology 2006,43(2 Sappl):S113 S120.
[36]Huwart L, Peeter F, Sinkus R, et al. Liver fibrosis:non invasive assessment with M R elastography. NM R Biomed,2006,9:173 179.
[37]Diensta JL, Goldin RD, Heatheote EJ, et al. Histologiealouteome during long-term lamivudine therapy[J]. Gastroenterology,2003,124(1):105-117.
[38]Bataller R, Brenner DA. Liver fibrosis [J]. J Clin Invest,2005,115(2): 209-218.
[39]Haluzik M, Haluzikova D. The role of resistin in obesity-induced insulin resistance[J]. Current Opinion in Investigational Drugs,2006,7(4): 306-311.
[40]Hasegawa G, Ohta M, Ichida Y, et al. Increased serum resistin levels in patients with type 2 diabetes are not linked with markers of insulin resistance and adiposity[J]. Acta Diabetol,2005,42(2):104-109.
[41]Yoshiji H, Kufiyama S, Fukui H. Angiotensin—I—converting enzyme inhibitors may be an alternative anti-angiogenic strategy in the treatment of liver fibrosis and hepatocellular carcinoma. Possible role of vascular endothelial grow factor[J]. Tumor Biol,2002,23(2):348-356.
[42]Yoshiji H, Kuriyama S, Toshii J, et al. Angiotensin—Ⅱ type 1 receptor interaction is a major regulator for liver fibrosis development in rats[J]. Hepatology,2001,34(1):745-750.
[43]Pan Q, Li DG, Lu HM, et al. Antiproliferative and proapoptotie effects of somatostatin on activated hepatic stellate cells[J]. World J Gastroenterol,2004,10(2):1015-1018.
[44]Jiang W, Yang CQ, Liu WB, et al. Blockage of transforming growth factor beta recaptors prevents progression of pig serum induced rat liver fibrosis[J]. World J Gastroenterol,2004,10:1634-1638.
[45]Iimuro Y, Fujimoto J. Strategy of gene therapy for liver cirhosis and hepatocellular carcinoma[J]. J Hepatobiliary Pancreat Surg,2003,10:
45-47.
[46]Zhang L, Mi J, YuY, et.al. IFN-gamma gene therapy by intrasplenic hepatocyte transplantation:a novel strategy for reversing hepatic fibrosis in Schistosoma japonicum-infected mice[J]. ParasiteImmunol,2001,23:11-17.
[47]Tsuruta S, Nakamuta M, Enjoji M, et al. Anti-monocyte chemoattractant protein-1 gene therapy prevents dimethylnitrosamine induced hepatic fibrosis in rats[J]. Int J Mol Med,2004,14:837-842.
[48]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[J].中国1晦床药理学与治疗学,2000。5(1)：49—51.
[49]Wasser S, Ho JM, Ang HK, et al. Salvia miltiorrhiza reduces experimentally induced hepatic fibrosis in rats[J]. J Hepatol,1998,29(5):760-771.
[50]张荣华,周子成, 洪多伦,等。三七抗肝纤维化的实验研究第三军医大学学报,2000,4(22)：307-309
[51]李延昌,孙玉凤,冯志杰,等。赤芍抗肝纤维化的实验研究中国中西医结合杂志,2003,10(23)：767-768
[52]刘玉侃,沈薇,张霞.虫草菌丝对实验性肝纤维化的防治作用及其机制研究[J].中国新药与临床杂志,2004,23(3)：139—143.
[53]Lee SJ, Kim YG, Kang KW, et al, Effects of colchicine on liver functions of cirrhotic rats:stellate cell inactivation and inhibition of TGF betal expression [J], Chem Biol Interact,2004,147(1):9-21.
[54]石小枫,刘杞,刘林,等.三七总苷抗实验性肝纤维化的研究[J].中药药理与临床,2004,20(1)：12—14.
[55]薛冬英,洪嘉禾,徐列明.丹参酚酸B对大鼠肝星状细胞中丝裂原激活的蛋白激酶通路的抑制作用[J].中华肝病杂志,2004,12(8)：471-474.
[56]Muriel P, Moreno MG. Effects of silymarin and vitamins E and C on liver damage induced by prolonged biliary obstruction in the rat[J]. Basic Clin Pharmacol Toxicol,2004,94(2):99-104.
[57]韦新,梁健,毛德文,等.牛磺酸对大鼠肝纤维化形成的影响[J].中国中西医结合消化杂志,2004,12(1)：6—7.
[58]黄古叶 健肝散治疗慢性乙型肝炎肝纤维化35例[J].中国中西医结合杂志,2005,7(1)：24
[59]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[J].解放军医学杂志,2004,29(7)：563-564.
[60]冯继红,贾玉杰肝复康抗肝纤维化机制临床疗效的初步观察[J]。中华临床医学
实践杂志,2004,3(6)：495
[61]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研究中西医结合学报2003,7(1)：24
[62]张媛辉,刘俊田 中药抗肝纤维化作用机制的研究进展中国实验方剂学杂志2006,12(6)：66-70
[63]Iwama H, Amagaya S, Ogihara Y, et al. Effect of shosaikoto a Japanese and Chinese traditional herbal medical mixture on the mitogentic activity of lipopolysaccharid:a new pharmacological testing model [J]. J Ethonpharmacol,1987,21(1):45.
[64]薛洁,谢梅林 中药血清药理学的方法学研究近况 中草药2003;34(6)：9-11
[65]阴赦宏,李兰芳,金亚宏等.当归补血汤肝损伤小鼠含药血清抑制肝组织LPO生成的作用[J].中国实验方剂学杂志2000,6(5)：32.
[66]赵保胜,李兰芳,马悦颖,等.参苏饮含药血清对小鼠巨噬细胞Toll样受体及下游信号转导通路的影响[J].中国中药杂志,2007,32(4)：327—331.
[67]窦志华,丁安伟,王陆军,等.复方五仁醇胶囊含药血清指纹图谱研究[J].中国药学杂志,2007,42(12)：892—895.
[68]俞仲毅,汪鸿宇,胡月娟,等.小青龙汤整体给药和含药血清作用的比较研究.中国中医药科技,2001,8(4)：233—234.
[69]张斌,王灵台,陈建杰.抗纤复方影响大鼠肝贮脂细胞生成Ⅰ、Ⅲ型胶原的比较研究. 中国实验方剂学杂志,2000,6(1)：33—35.
[70]凌云彪邱万寿褚忠华,等。不同途径制备的中药复方“肝纤方”含药血清对大鼠肝星状细胞的不同影响[J].中华实验外科杂志,2004,10(21)：1165-1167
[71]张彩华,崔晓栋,姜妙娜,等。肝复康不同浓度含药血清对肝星状细胞工、III型胶原及细胞基质的影响[J]。中国组织工程研究与临床康复,2008,12(33)：6496-6499[72]胡义扬,刘平,刘成,等.丹参提取物对CCL4和DMN诱导的大鼠肝纤维化的影响[J].上海中医药杂志,1999,33：1 0.
[72]阴桢宏,马红,马雪梅,等.复方861含药血清对HSC—T6细胞I型胶原、III型胶原mRNA表达影响的研究中国实验方剂学杂志2002,8(5)：21-23
[73]阴桢宏,马红,马雪梅,等.复方861含药血清对HSC-T6细胞I型胶原、基质金属蛋白酶组织抑制因子1mRNA表达的影响中西医结合肝病杂志2002,12(5)：286-289
[74]谈博,张奉学,刘妮,等.丹参含药血清对肝星状细胞增生的抑制作用世界华人消化杂志2004,12(6)：1357-1360
[75]Ping Liu, Yi-Yang Hu, Cheng Liu, et al. Clinical observation of salvianolic acid B in treatment of liver f ibroses in chronic hepatitis B[J]. World J Gastroenterol,2002,8:679-685.
[76]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影响[J].中华医学杂志,2002,82：1267—1272.
[77]胡义扬,王润平,张学军,等.体外四氯化碳损伤肝细胞对肝星状细胞活化的影响及其丹酚酸A的干预效果[J].中华肝脏病杂志,2000,8：299—301.
[78]彭小东.三七总皂甙、黄芪、黄芩甙和丹参素抗实验性肝纤维化的疗效对比及作用机制探讨[D].重庆：重庆医科大学,2006,5.
[79]刘庆生,王小奇,蔡丹莉,等.三七对酒精性肝病大鼠肝组织NF—-κB／IκB表达的影响[J].中国药学杂志,2007,42(18)：1372—1375.
[80]王恰,薛绍礼,张菁,等.三七总皂苷对传代肝星状细胞增殖的影响[J].淮海医药,2008,26(1)：1—3.
[81]李仪奎,姜名瑛.中药药理[M].北京：中国中医药出版社,1992：147-150.
[82]戚心广,稻垣璺.丹参、赤芍对实验性肝损伤肝细胞保护作用的机理研究.中西医结合杂志1991；11(2)：102—104
[83]杨大国,王林杰,宋为云,等.重用赤芍治疗慢性肝炎纤维化前后肝穿组织学的比较.中国中西医结合杂志1994；14(1)：207—209.
[84]李之清,肖琳,明安萍,等.叶下珠制剂对大鼠慢性肝损伤的保护作用及防止肝纤维化的实验研究.中国中医药科技1999；6(1)：24-25
[85]黄远媛叶下珠汤治疗乙肝肝纤维化50例临床观察.中国中医药信息杂志2003：10(9)：55-56
[87]徐珊,包剑锋,周敏,等。 中国中医药科技2009,2(16)：81-83
[88]Iredale JP, Benyon RC, Pickering J, et al. Mechanisms of spontaneous resolution of rat liver fibrosis:hepatic stellate cell apoptosis and reduced hepatic expression of metalloproteinase inhibitors. J Clin Invest,1998,102(3):538-549.
[89]Hammel P, Couvelard A, O'Toole D, et al. Regression Of liver fibrosis after biliary drainage in patients with chronic pancreatitis and stenosis Of the common bile duct. N Engl J Med,2001,344(6):418-423.
[90]杨柳,刘海林.血管紧张素原在肝纤维化形成和自发逆转过程中的表达.中华肝脏病杂志,2006,14(11)：845—846.
[91]张斌,王灵台.抗纤复方对大鼠肝贮脂细胞产生转化生长因子β1的影响.胃肠病学和肝病学杂志,1998,8(1)：16—18.
[92]程书权,张自富,赵永伟.血清HA、 PLD、 PCⅢ、 LN、 CIV联合检测对慢性肝病的诊断价值探讨.中国实用内科杂志,1999,19(1)：28-30
[93]刘仁才,刘龙秀,张德远,等.血清HA、LN、 CIV、 PCⅢ含量与慢性肝炎炎症活动度及纤维化程度的关系.中国传染病杂志,1999,17(2)：122-123Li CZ, wan MB, Zeng MD, et al. A preliminary study of the conibination of noninvasire parameters in the diagnosis of liver fibrosis 1 Jj. Chin J Hepatol,2001,9 (5):261-2635
[94]Dooley S, Delvoux B, Streekert M, et al. FEBS Lett,2001,502(1-2): 4-10
[95]Friedman SL, Lalazar A, Cmng L, et al. HSC-T6 cells. an immoralized rat hepatic stellate cell line. Hepatology.1997,26 (4Pt):338A
[96]Zavadil J, Bottinger EP. TGF-beta and epithelial-to-mesenchymal transitions. Oncogene 2005; 24:5764.5774
[97]Dooley s, Delvoux B, Lahme B, Mangasser-StephanK, Gressner AM. Modulation of transforming growth factor beta response and signaling during transdifferentiation of rat hepatic stellate cells myofibroblasts. Hepatology 2000; 31:1094-1106
[98]Sentie-Gomez MD, Galvez-Gastelum FJ, Meza-Garcia E, Armendariz-Borunda T. Hepatic fibrosis:role of matrix metalloproteases and TGFbeta. Gac Med Mex 2005; 141:315-322
[99]Knittel T, Mehde M, Kobold D, Saile B, Dinter C, Ramadori G. Expression paterns of matrix metallo. proteinases and their inhibitors in parenchymal and non-parenchymal cells of rat liver:regulation by TNF-alpha and TGF-betal., Hepatof 1999; 30:48-60
[100]Gressner AM, Weiskirchen R. Modern pathogenetic concepts of liver fibrosis suggest stellate cells and TGF-beta as major players and therapeutic targets. J Cell Mol Med 2006; 10:76-99
[101]Breitkopf K, Godoy P, Ciuclan L,Singer MV, Dooley S. TGF-beta/Smad signaling in the]n{uredliver. Z Gastroenterol 2006; 4:57-66
[102]Okuno M, Moriwaki H, Muto Y, et al. Protease inhibitors suppress TGF-B1 generation by hepatic stellate cells. J hepatol,1998,29:1031-1032
[103]Campbell JS, Hughes SD, Gilbertson DG, et al. Platelet derived growth factor C induces liver fibrosis, steatosis, and hepatocellular carcinma[J]. Proc Natl Acad'Sci,2005。 102(9):3389-3393.
[104]Heldin CH. Westermark B. Mechanism of action and in vivo role of platelet derived growth factor[J]. Physiol Rev,1999,79 (4):1283-1316.
[2]戴希真.酒精性肝损伤[J].中华消化杂志,1993,13(2)：125
[3]Friedman S L, Roll F J, Boyles J, et al. Hepatic lipocytes:the principal collagen-producing cells of normal rat liver ProcNatl[J]. Acad Sci。 1985, 82:8681
[4]王润平,等.肝纤维化形成过程中肝星状细胞激活的旁分泌机制[J].中华肝脏病杂志,1997,5(3)：84
[5]Gressner AM Cytokines and cellular crosstalk involved in the activation of fat-storing cells. [J]J Hepatol,1995,22, (2 suppl):28-36
[6]熊伍军,等.肝窦内皮细胞在肝纤维化中的作用[J].国外医学·消化病分册,2000,8(4)：197
[7]杜卫东.等.实验性肝纤维化肝内胶原生成细胞的研究[J].中华肝脏病杂志,1998,6(4)：238
[8]许翠萍.肥大细胞与肝脏[J].国外医学·消化疾病分册,1997,17(2)：77
[9]许青.转化生长因子8与肝纤维化[J].国外医学·消化疾病分册,1998,18(3)：155
[10]王萍.血小板衍生生长因子与肝纤维化[J].国外医学·消化疾病分册,2000,20(1)： 40
[11]Perlmamn T, Evnas RM. Nuclear receptors in Sicily:all in the famiglia[J]. Cell,1997,90:391-397.
[12]Blom IE, Goldschmeding R, Leask A. Gene regulation of connective tissue growth factor:new targets for antifibrotictherapy[J]?Matrix Biol,2002, 21(6):473-482.
[13]Leask A, Abraham DJ. The role of connective tissue growth factor, a multifunctional matricellular protein, in fibroblast biology [J]. Biochem Cell Biol,2003,81(6):355-363.
[14]Paradis V, Dargere D, Bonvoust F, et al. Efects and regulation of connective tissue growth factor on hepatic stellate cells [J]. Lab Invest,2002,82(6): 767-774
[15]Saile B, Nlatthes N, Knittel T, et al. Transforming growth factor beta and tumor necrosis factor alpha inhibit both apoptosis and proliferation of activated rat hepatic stellate cells. Hepatology,1999。 30:196-202.
[16]刘小菁,吴红斌,刘芳,等.肿瘤坏死因子a对肝星状细胞表达结缔组织生长因子的影响.中华肝脏病杂志,2001,9：15—17.
[17]姜慧卿,赵东强.肿瘤坏死因子-a对肝星状细胞增殖与凋亡的影响.中国病理生理杂志,2003,19：1353—1356.
[18]Thomson K, Maltby J, Fallowfield J, et al. Interleukin-10 expression and function experiment murine liver inflammation and fibrosis. Hepatology, 1998,28:1597-1606.
[19]陈治新,张莉娟,陈运新,等.胰岛素样生长因子-1受体在实验性肝纤维化中的表达及IL-10的干预作用.福建医科大学学报,2002,36：134—136.
[20]刘学松,李定国,陆汉明.肝细胞的胶原合成与肝纤维化[J].中华消化杂志,1994,14(1)：53
[21]王红蓓,等.硫酸软骨素与肝纤维化[J].国外消学·消化疾病分册,1995,(3)：137
[22]Iredale J P. Tissue inhibitors of metalloproteinases in liver fibrosis[J]. Int J Biochem Cell Biol,1997,29:43.
[23]Murawakai Y,Nishimura Y, Ikuta Y, et al. Plasma transforming growth fator-betal concentrations in patients with chronic viral hepatitis [J]. J Gastrolenterol Hepatol,1993,13:680
[24]Denhardt D T, Feng B, Edwards D R, et al. Tissue inhibitor of metalloproteinases(TIMP, aka EPA):structure, control of expression and biological funtions[J]. Pharmacolther,1993,59:329.
[25]粱治学,王晓萍肝纤维化的中医病因病机研究概况甘肃中医,2006,4(19)：43-45
[26]张俊富,崔丽安,范淑芳,等.乙肝2号治慢性乙型肝炎的临床研究[J].中医杂志1993,34(11)：674
[27]李晓良.慢性乙型肝炎中医辨证与病理、病毒指标的关系[J].中西医结合肝病杂志,1996,6(2)：4—5.
[28]唐智镀,茹清静,朱起贵.论肝血瘀阻与肝纤维化的关系[J].中国中医基础医学杂志,1996,2(3)：14—18.
[29]刘宏元,刘作恩.慢性乙肝早期纤维化的治疗研究[J].天津中医,1997,14(3)：101-102.
[30]曾民德,陆伦根,茅益民.肝纤维化的诊断方法及其评估(下),临床肝胆病杂志,2006,11：181～183
[31]张文胜,王宝恩,王泰龄,等.慢性乙型肝炎纤维化无创性诊断模型的建立.中华肝脏病杂志,2006,14：169-173
[32]谢青, 桂红莲肝纤维化诊断标准的现今认识诊断学理论与实践,2009,2(8)：133-136
[33]向志勇,郑勇肝纤维化的诊断方法进展农垦医学,2008,6(30)：496-498
[34]Pinzani M. Non—invasive evaluation of hepatic fibrosis:don't count your chickens before they're hatched. Gut,2006,55:310-312.
[35]Roekey DC, Bissell DM. Noninvasive measures of liver fibrosis. Hepatology 2006,43(2 Sappl):S113 S120.
[36]Huwart L, Peeter F, Sinkus R, et al. Liver fibrosis:non invasive assessment with M R elastography. NM R Biomed,2006,9:173 179.
[37]Diensta JL, Goldin RD, Heatheote EJ, et al. Histologiealouteome during long-term lamivudine therapy[J]. Gastroenterology,2003,124(1):105-117.
[38]Bataller R, Brenner DA. Liver fibrosis [J]. J Clin Invest,2005,115(2): 209-218.
[39]Haluzik M, Haluzikova D. The role of resistin in obesity-induced insulin resistance[J]. Current Opinion in Investigational Drugs,2006,7(4): 306-311.
[40]Hasegawa G, Ohta M, Ichida Y, et al. Increased serum resistin levels in patients with type 2 diabetes are not linked with markers of insulin resistance and adiposity[J]. Acta Diabetol,2005,42(2):104-109.
[41]Yoshiji H, Kufiyama S, Fukui H. Angiotensin—I—converting enzyme inhibitors may be an alternative anti-angiogenic strategy in the treatment of liver fibrosis and hepatocellular carcinoma. Possible role of vascular endothelial grow factor[J]. Tumor Biol,2002,23(2):348-356.
[42]Yoshiji H, Kuriyama S, Toshii J, et al. Angiotensin—Ⅱ type 1 receptor interaction is a major regulator for liver fibrosis development in rats[J]. Hepatology,2001,34(1):745-750.
[43]Pan Q, Li DG, Lu HM, et al. Antiproliferative and proapoptotie effects of somatostatin on activated hepatic stellate cells[J]. World J Gastroenterol,2004,10(2):1015-1018.
[44]Jiang W, Yang CQ, Liu WB, et al. Blockage of transforming growth factor beta recaptors prevents progression of pig serum induced rat liver fibrosis[J]. World J Gastroenterol,2004,10:1634-1638.
[45]Iimuro Y, Fujimoto J. Strategy of gene therapy for liver cirhosis and hepatocellular carcinoma[J]. J Hepatobiliary Pancreat Surg,2003,10:
45-47.
[46]Zhang L, Mi J, YuY, et.al. IFN-gamma gene therapy by intrasplenic hepatocyte transplantation:a novel strategy for reversing hepatic fibrosis in Schistosoma japonicum-infected mice[J]. ParasiteImmunol,2001,23:11-17.
[47]Tsuruta S, Nakamuta M, Enjoji M, et al. Anti-monocyte chemoattractant protein-1 gene therapy prevents dimethylnitrosamine induced hepatic fibrosis in rats[J]. Int J Mol Med,2004,14:837-842.
[48]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[J].中国1晦床药理学与治疗学,2000。5(1)：49—51.
[49]Wasser S, Ho JM, Ang HK, et al. Salvia miltiorrhiza reduces experimentally induced hepatic fibrosis in rats[J]. J Hepatol,1998,29(5):760-771.
[50]张荣华,周子成, 洪多伦,等。三七抗肝纤维化的实验研究第三军医大学学报,2000,4(22)：307-309
[51]李延昌,孙玉凤,冯志杰,等。赤芍抗肝纤维化的实验研究中国中西医结合杂志,2003,10(23)：767-768
[52]刘玉侃,沈薇,张霞.虫草菌丝对实验性肝纤维化的防治作用及其机制研究[J].中国新药与临床杂志,2004,23(3)：139—143.
[53]Lee SJ, Kim YG, Kang KW, et al, Effects of colchicine on liver functions of cirrhotic rats:stellate cell inactivation and inhibition of TGF betal expression [J], Chem Biol Interact,2004,147(1):9-21.
[54]石小枫,刘杞,刘林,等.三七总苷抗实验性肝纤维化的研究[J].中药药理与临床,2004,20(1)：12—14.
[55]薛冬英,洪嘉禾,徐列明.丹参酚酸B对大鼠肝星状细胞中丝裂原激活的蛋白激酶通路的抑制作用[J].中华肝病杂志,2004,12(8)：471-474.
[56]Muriel P, Moreno MG. Effects of silymarin and vitamins E and C on liver damage induced by prolonged biliary obstruction in the rat[J]. Basic Clin Pharmacol Toxicol,2004,94(2):99-104.
[57]韦新,梁健,毛德文,等.牛磺酸对大鼠肝纤维化形成的影响[J].中国中西医结合消化杂志,2004,12(1)：6—7.
[58]黄古叶 健肝散治疗慢性乙型肝炎肝纤维化35例[J].中国中西医结合杂志,2005,7(1)：24
[59]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[J].解放军医学杂志,2004,29(7)：563-564.
[60]冯继红,贾玉杰肝复康抗肝纤维化机制临床疗效的初步观察[J]。中华临床医学
实践杂志,2004,3(6)：495
[61]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研究中西医结合学报2003,7(1)：24
[62]张媛辉,刘俊田 中药抗肝纤维化作用机制的研究进展中国实验方剂学杂志2006,12(6)：66-70
[63]Iwama H, Amagaya S, Ogihara Y, et al. Effect of shosaikoto a Japanese and Chinese traditional herbal medical mixture on the mitogentic activity of lipopolysaccharid:a new pharmacological testing model [J]. J Ethonpharmacol,1987,21(1):45.
[64]薛洁,谢梅林 中药血清药理学的方法学研究近况 中草药2003;34(6)：9-11
[65]阴赦宏,李兰芳,金亚宏等.当归补血汤肝损伤小鼠含药血清抑制肝组织LPO生成的作用[J].中国实验方剂学杂志2000,6(5)：32.
[66]赵保胜,李兰芳,马悦颖,等.参苏饮含药血清对小鼠巨噬细胞Toll样受体及下游信号转导通路的影响[J].中国中药杂志,2007,32(4)：327—331.
[67]窦志华,丁安伟,王陆军,等.复方五仁醇胶囊含药血清指纹图谱研究[J].中国药学杂志,2007,42(12)：892—895.
[68]俞仲毅,汪鸿宇,胡月娟,等.小青龙汤整体给药和含药血清作用的比较研究.中国中医药科技,2001,8(4)：233—234.
[69]张斌,王灵台,陈建杰.抗纤复方影响大鼠肝贮脂细胞生成Ⅰ、Ⅲ型胶原的比较研究. 中国实验方剂学杂志,2000,6(1)：33—35.
[70]凌云彪邱万寿褚忠华,等。不同途径制备的中药复方“肝纤方”含药血清对大鼠肝星状细胞的不同影响[J].中华实验外科杂志,2004,10(21)：1165-1167
[71]张彩华,崔晓栋,姜妙娜,等。肝复康不同浓度含药血清对肝星状细胞工、III型胶原及细胞基质的影响[J]。中国组织工程研究与临床康复,2008,12(33)：6496-6499[72]胡义扬,刘平,刘成,等.丹参提取物对CCL4和DMN诱导的大鼠肝纤维化的影响[J].上海中医药杂志,1999,33：1 0.
[72]阴桢宏,马红,马雪梅,等.复方861含药血清对HSC—T6细胞I型胶原、III型胶原mRNA表达影响的研究中国实验方剂学杂志2002,8(5)：21-23
[73]阴桢宏,马红,马雪梅,等.复方861含药血清对HSC-T6细胞I型胶原、基质金属蛋白酶组织抑制因子1mRNA表达的影响中西医结合肝病杂志2002,12(5)：286-289
[74]谈博,张奉学,刘妮,等.丹参含药血清对肝星状细胞增生的抑制作用世界华人消化杂志2004,12(6)：1357-1360
[75]Ping Liu, Yi-Yang Hu, Cheng Liu, et al. Clinical observation of salvianolic acid B in treatment of liver f ibroses in chronic hepatitis B[J]. World J Gastroenterol,2002,8:679-685.
[76]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影响[J].中华医学杂志,2002,82：1267—1272.
[77]胡义扬,王润平,张学军,等.体外四氯化碳损伤肝细胞对肝星状细胞活化的影响及其丹酚酸A的干预效果[J].中华肝脏病杂志,2000,8：299—301.
[78]彭小东.三七总皂甙、黄芪、黄芩甙和丹参素抗实验性肝纤维化的疗效对比及作用机制探讨[D].重庆：重庆医科大学,2006,5.
[79]刘庆生,王小奇,蔡丹莉,等.三七对酒精性肝病大鼠肝组织NF—-κB／IκB表达的影响[J].中国药学杂志,2007,42(18)：1372—1375.
[80]王恰,薛绍礼,张菁,等.三七总皂苷对传代肝星状细胞增殖的影响[J].淮海医药,2008,26(1)：1—3.
[81]李仪奎,姜名瑛.中药药理[M].北京：中国中医药出版社,1992：147-150.
[82]戚心广,稻垣璺.丹参、赤芍对实验性肝损伤肝细胞保护作用的机理研究.中西医结合杂志1991；11(2)：102—104
[83]杨大国,王林杰,宋为云,等.重用赤芍治疗慢性肝炎纤维化前后肝穿组织学的比较.中国中西医结合杂志1994；14(1)：207—209.
[84]李之清,肖琳,明安萍,等.叶下珠制剂对大鼠慢性肝损伤的保护作用及防止肝纤维化的实验研究.中国中医药科技1999；6(1)：24-25
[85]黄远媛叶下珠汤治疗乙肝肝纤维化50例临床观察.中国中医药信息杂志2003：10(9)：55-56
[87]徐珊,包剑锋,周敏,等。 中国中医药科技2009,2(16)：81-83
[88]Iredale JP, Benyon RC, Pickering J, et al. Mechanisms of spontaneous resolution of rat liver fibrosis:hepatic stellate cell apoptosis and reduced hepatic expression of metalloproteinase inhibitors. J Clin Invest,1998,102(3):538-549.
[89]Hammel P, Couvelard A, O'Toole D, et al. Regression Of liver fibrosis after biliary drainage in patients with chronic pancreatitis and stenosis Of the common bile duct. N Engl J Med,2001,344(6):418-423.
[90]杨柳,刘海林.血管紧张素原在肝纤维化形成和自发逆转过程中的表达.中华肝脏病杂志,2006,14(11)：845—846.
[91]张斌,王灵台.抗纤复方对大鼠肝贮脂细胞产生转化生长因子β1的影响.胃肠病学和肝病学杂志,1998,8(1)：16—18.
[92]程书权,张自富,赵永伟.血清HA、 PLD、 PCⅢ、 LN、 CIV联合检测对慢性肝病的诊断价值探讨.中国实用内科杂志,1999,19(1)：28-30
[93]刘仁才,刘龙秀,张德远,等.血清HA、LN、 CIV、 PCⅢ含量与慢性肝炎炎症活动度及纤维化程度的关系.中国传染病杂志,1999,17(2)：122-123Li CZ, wan MB, Zeng MD, et al. A preliminary study of the conibination of noninvasire parameters in the diagnosis of liver fibrosis 1 Jj. Chin J Hepatol,2001,9 (5):261-2635
[94]Dooley S, Delvoux B, Streekert M, et al. FEBS Lett,2001,502(1-2): 4-10
[95]Friedman SL, Lalazar A, Cmng L, et al. HSC-T6 cells. an immoralized rat hepatic stellate cell line. Hepatology.1997,26 (4Pt):338A
[96]Zavadil J, Bottinger EP. TGF-beta and epithelial-to-mesenchymal transitions. Oncogene 2005; 24:5764.5774
[97]Dooley s, Delvoux B, Lahme B, Mangasser-StephanK, Gressner AM. Modulation of transforming growth factor beta response and signaling during transdifferentiation of rat hepatic stellate cells myofibroblasts. Hepatology 2000; 31:1094-1106
[98]Sentie-Gomez MD, Galvez-Gastelum FJ, Meza-Garcia E, Armendariz-Borunda T. Hepatic fibrosis:role of matrix metalloproteases and TGFbeta. Gac Med Mex 2005; 141:315-322
[99]Knittel T, Mehde M, Kobold D, Saile B, Dinter C, Ramadori G. Expression paterns of matrix metallo. proteinases and their inhibitors in parenchymal and non-parenchymal cells of rat liver:regulation by TNF-alpha and TGF-betal., Hepatof 1999; 30:48-60
[100]Gressner AM, Weiskirchen R. Modern pathogenetic concepts of liver fibrosis suggest stellate cells and TGF-beta as major players and therapeutic targets. J Cell Mol Med 2006; 10:76-99
[101]Breitkopf K, Godoy P, Ciuclan L,Singer MV, Dooley S. TGF-beta/Smad signaling in the]n{uredliver. Z Gastroenterol 2006; 4:57-66
[102]Okuno M, Moriwaki H, Muto Y, et al. Protease inhibitors suppress TGF-B1 generation by hepatic stellate cells. J hepatol,1998,29:1031-1032
[103]Campbell JS, Hughes SD, Gilbertson DG, et al. Platelet derived growth factor C induces liver fibrosis, steatosis, and hepatocellular carcinma[J]. Proc Natl Acad'Sci,2005。 102(9):3389-3393.
[104]Heldin CH. Westermark B. Mechanism of action and in vivo role of platelet derived growth factor[J]. Physiol Rev,1999,79 (4):1283-1316.