加味三仁汤治疗乙肝所致慢性肝炎肝作用及机制研究的作用及机制研究
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摘要
肝纤维化,是一种发生于慢性肝病后的可逆性损伤愈合反应,各种慢性肝病向肝硬化发展的所必经病理过程。目前,对于许多慢性肝病的治疗尚无理想的针对治疗措施,如乙型肝炎病毒所导致的病毒性肝炎。从病理变化来说,肝纤维化是可逆的,而肝硬化则是不可逆的,再加上我国是病毒性肝炎流行的高发区,据最近统计资料显示,我国目前有肝病患者已达2000多万,肝纤维化在我国的发病率较高,是我国人民必须严肃对待的一个健康问题。因此,寻找防治肝纤维化的有效方法和有效药物,是我国人民的迫切要求,具有深远的意义和重大的社会价值。
乙型肝炎是由乙型肝炎病毒(HBV)感染所致,全世界约有3亿人是HBV携带者,而HBV携带者发生肝纤维化、肝硬化和肝癌的危险性比非携带者高出上百倍。我国是乙肝高发区,约有1.2亿HBV携带者。但是由于乙型肝炎的临床表现并不明显,再加上大多数病人并不重视而导致迁延失治,往往会让病情发展为慢性肝炎和肝纤维化。
慢性肝炎(HBV所致)的存在是引发肝纤维化的重要原因,单单治疗肝纤维化是无法使之完全治愈的,就算治疗得当也无法排除复发的危险。因此,抗慢性肝炎肝纤维化应作为一个整体进行治疗,方是彻底治愈的有力保证。国内外在对慢性肝炎及肝纤维化的机理研究方面已取得了一定进展。但是在其临床治疗领域,却依然未能取得明显的进步。加上目前临床现有的药物,其疗效并不够理想,而且有些药物普遍存在副作用较大,费用较高的缺点。因此国内外的研究者都在努力寻找疗效确切、价格低廉、毒副作用小的防治肝纤维化药物,以便能阻止慢性肝炎进一步发展,演变为肝纤维化的进程,最终治愈大多数慢性肝炎及肝纤维化。
因此本课题以加味三仁汤作为实验药物,展开针对慢性肝炎及肝纤维化的研究,拟采用免疫组化、细胞培养技术、流式细胞术、分子生物学方法(RealTime-PCR技术)等技术对鸭乙肝、大鼠免疫性肝纤维化、HSC细胞以及2.2.15细胞的影响等方面探讨其抗慢性肝炎及抗肝纤维化的作用及机理,为该方进一步的临床及开发应用提供实验依据。
1.利用DHBV阳性绿头鸭作为研究对象,观察加味三仁汤对其血清中DHBV-DNA水平的影响。结果显示:模型组鸭血清中DHBV-DNA水平升高,与正常组比较有显著性差异(P＜0.01),加味三仁汤水提液大剂量、小剂量以及大剂量醇提液对DHBV-DNA均有明显的抑制作用(P＜0.05或P＜0.01),而加味三仁汤的小剂量醇提液则没有显著的抑制DHBV-DNA作用。
2.以加味三仁汤作用于2.2.15细胞,观察其对2.2.15细胞HbsAg及HbeAg分泌的影响。结果显示,浓度为1、0.5、0.25、0.125、0.625、0.3125mg/mL的加味三仁汤水提液对2.2.15细胞HbsAg和HbeAg分泌抑制率分别为85.36%、79.72%、75.81%、69.65%、62.14%、30.56%以及90.17%、83.26%、76.34%、46.86%、20.32%、0.36%。药物剂量与HbsAg和HbeAg分泌抑制率呈现递增关系,其中随着剂量增加,其中药物对HbsAg的抑制更为明显。
3.观察加味三仁汤对2.2.15细胞HBV-DNA表达的影响。结果表明,加味三仁汤具有明显的抑制2.2.15细胞HBV表达的作用,其中1 mg/mL、0.5 mg/mL及0.25 mg/mL浓度的加味三仁汤水提液效果更优于阳性药物。
4.通过对DMN肝纤维化大鼠模型,观察加味加味三仁汤对肝组织肝HA、LN、IVC、PCIINP及HyP的影响。模型组及各给药组血清HA、LN、IVC、PCⅢ及HyP的水平均升高,与正常组比较,有显著性差异(P＜0.01)。加味三仁汤水提大、小剂量组与模型组比较,血清HA、PCⅢ、LN、CIV及HyP水平均明显下降(P＜0.05或0.01),且随剂量增加效果也相应增强;加味三仁汤醇提大剂量组与模型组比较,血清LN、IVC、PCⅢ及HyP的水平有一定程度下降,但无显著意义(P＞0.05)。加味三仁汤醇提小剂量组与模型组比较,血清PCⅢ、CIV、HyP水平有下降,但无显著意义(P＞0.05)。鳖甲软肝片组血清HA、PCⅢ、CIV水平较模型组无显著差异(P＞0.05)。
5.通过对DMN肝纤维化大鼠模型,观察加味三仁汤对DMN肝纤维化大鼠肝组织形态学的影响:(1)HE染色;(2)α-SMA免疫组化;(3)Ⅰ型胶原免疫组化。本实验表明,从肝小叶破坏、假小叶形成、胶原纤维增生等肝脏结构的客观改变出发,认为加味三仁汤可减轻肝纤维化的程度,改善肝脏结构,促进ECM降解,从而治疗实验性肝纤维化。
6.观察加味三仁汤对大鼠肝组织TGFβ_1及PDGF-B表达抑制的影响。结果显示模型组及各给药组血清TGF-β_1及PDGF表达增加,与正常组比较,有显著性差异(P＜0.01)。加味三仁汤水提液组均能显著抑制TGF-β_1和PDGF的表达(P＜0.05),且优于阳性药物,其中尤以加味三仁汤水提大剂量组最为明显(P＜0.01),且随剂量增加效果也相应增强;加味三仁汤醇提小剂量组剂量组与模型组比较,对于TGF-β_1和PDGF表达抑制的影响有显著意义(P＜0.05)。加味三仁汤醇提组与模型组比较,对血清TGF-β_1的影响无显著意义(P＜0.05)。
7.观察加味三仁汤对肝纤维化大鼠血清TNF、IL-1及IL-6的影响。结果提示,加味三仁汤水提液组均具有显著降低大鼠血清中TNF-α、IL-1以及含量的作用(P＜0.05或P＜0.01)。其中水提液大剂量组的效果更是优于阳性药物组。而加味三仁汤醇提大剂量组对大鼠血清中的TNF-α和IL-1有明显的降低作用,但对IL-6则无明显作用。而小剂量醇提液对大鼠血清中的TNF-α、IL-1和IL-6则无明显作用。
8.探讨加味三仁汤对HSC-T6 TIMP-1和MMP-2表达的影响。结果显示40mg/mL和20mg/mL浓度的加味三仁汤能有效降低TIMP-1和MMP-2mRNA的水平,并随着浓度降低而减弱。
9.观察大鼠肝组织和HSC中的Fas/FasL表达与加味三仁汤的干预作用。实验发现,加味三仁汤能明显上调大鼠肝组织及HSC Fas/FasL基因mRNA的表达,而且其水提液对Fas/FasL的上调作用均优于阳性药物组。
10.探讨体外培养HSC凋亡与加味三仁汤的干预作用。实验提示:加味三仁汤和丹参注射液均可诱导HSC凋亡,其中加味三仁汤水提液40mg/ml和20mg/ml剂量组细胞凋亡明显,并优于丹参注射液组。此外,加味三仁汤组对HSC的凋亡促进还呈剂量依赖。
11.探讨加味三仁汤对肝纤维化大鼠组织纤维酶原激活剂抑制剂、组织型纤维酶原激活剂的影响。结果显示:与细胞对照组比较,加味三仁汤可调节uPA及PAI-1的表达。其中浓度为40mg/mL以及20mg/mL的加味三仁汤水提液对HSC-T6细胞uPA及PAI-1的的表达调节优于其它各组。而在大鼠血清uPA及PAI-1的表达抑制中,加味三仁汤水提液组均优于其他各组。
Liver fibrosis,is a reversible reaction after the chronic liver disease,and the inevitable development of the pathological process for the chronic liver disease to cirrhosis.At present, there hasn't ideal treatment for some chronic liver diseases.such as the virus hepatitis which caused by hepatitis B virus hepatitis. From the pathological change,the liver fibrosis is reversible, and liver cirrhosis is irreversible.China is a high incidence of viral hepatitis epidemic.According to recent statistics,it shows that China has more than 20 million patients with liver disease.The IN of liver fibrosis is very high in our country,so it is a serious healthy problem that the national people must treat to.Therefore,searching for an effective prevention and treatment, for liver fibrosis,is an urgent requirement of national people and have far-reaching significance and important social value.
HB is caused by the hepatitis B virus(HBV).There have about 3 billion HBV carriers all around the world.The HBV carriers is easily to get the risk of liver fibrosis,liver cirrhosis and liver cancer than non-carriers.China is a high incidence of hepatitis B and have about 120 million HBV carriers.However,the obsolete clinical manifestations and the ignoring of hepatitis B to the majority of patients lead to the aggravate of this disease,even the occuring of chronic hepatitis and liver fibrosis.
Chronic hepatitis(HBV-induced) is the caused the important factor of the causing of liver fibrosis.The simple treatment for liver fibrosis can not make it cured completely.even if the well treatment can not rule out the risk of relapse.Therefore, anti-liver fibrosis in chronic hepatitis should be treated as a whole,is the guarantee for the complete cure.The research for the mechanism of chronic hepatitis and liver fibrosis have been some progress all round the world in nowday.However,in the field of clinical treatment,it still can't achieve the significant progress.Add the efficacy of common drugs for liver fibrosis is beyond ideal,and the drug have some disadvantages,for exsample, the obvious side effects and the high cost.So researchers at home and abroad are trying to search for a drug which have the advantage, including the exact effect,cheap and the shortage of toxic side effects.in order to cure the majority of chronic hepatitis and liver fibrosis.
This subject is selecting the JIAWEISANRENTANG as an experimental drug,used for chronic hepatitis and liver fibrosis research.The research adopted immunohistochemist-ry,cell culture,flow cytometry and RealTime-PCR technology for the teatment effect and mechanism of anti-chronic hepatitis and anti-hepatic fibrosis on DHBV model,autoimmune liver fibrosis in rats,HSC cells and 2.2.15 cells.It is supply the clinical and laboratory basis for the further development and application.
1.Use the DHBV-positive subjects to research JIAWEISANRENTANG in their serum DHBV-DNA levels.The results showed that: the model group of duck serum DHBV-DNA levels,compared with the normal group were significantly different(P＜0.01), JIAWEISANRENTANG extract high-dose,low-dose and high dose of alcohol extract of DHBV-DNA were significantly inhibited(P＜0.05 or P＜0.01),and JIAWEISANRENTANG small doses of alcohol did not extract a significant role in inhibiting DHBV-DNA.
2.Used JIAWEISANRENTANG in the role of the 2.2.15 cells were observed on the 2.2.15 cells and HbsAg secretion HbeAg.The results showed that concentration of 1,0.5,0.25,0.125,0.625,0.3125 mg /mL of JIAWEISANRENTANG tothe secretion of HbsAg and HbeAg for 2.2.15 cell inhibition rate was 85.36%,79.72%,75.81%,69.65%, 62.14%,30.56%and 90.17%,83.26%,76.34%,46.86%,20.32%,0.36%. Drug dose and HbsAg and HbeAg show increased secretion of the relationship between inhibition rate,which increased with the dose of which drug to more pronounced inhibition of HbsAg.
3.Observation JIAWEISANRENTANG on 2.2.15 cells,HBV-DNA expression.The results showed that with a flavored soup Sanren 2.2.15 cells inhibited the expression of the role of HBV,of which 1mg/mL,0.5mg/mL and 0.25mg/mL concentration JIAWEISANRENTANG extract more than the positive effect of the drug.
4.Rat model of liver fibrosis by DMN was observed for the action to liver liver tissue HA,LN,IVC,PCIINP and the impact of HyP by JIAWEISANRENTANG.Model group and treatment group in serum HA, LN,IVC,PCIII and water HyP average increase compared with the normal group,the difference was significant(P＜0.01). JIAWEISANRENTANG to large and small dose group compared with the model group,serum HA,PCIII,LN,CIV and HyP were significantly decreased(P＜0.05 or 0.01),and the effect increased with the dose corresponding enhancement;JIAWEISANRENTANG alcohol extract of high-dose group compared with the model group,serum LN,IVC, PCIII and HyP level dropped to a certain extent,but no significant (P＞0.05).JIAWEISAN-RENTANG low-dose group compared with the model group,serum PCIII,CIV,HyP levels decline,but no significant(P＞0.05).Fufangbiejiaruanganpian serum HA,PCIII, CIV level than the model group was no significant difference(P＞0.05).
5.Observed the rat model of liver fibrosis which is induced by DMN insect JIAWEISANRENTANG on DMN hepatic fibrosis of rat liver tissue the effects of morphology:(1) HE staining;(2)α-SMA immunohistochemistry;(3) I type collagen immunohistochemistry. The experiments show that damage from hepatic loble,the formation of false lobules,hyperplasia of collagen fibers,such as objective changes in liver structure,the JIAWEISANRENTANG can reduce the extent of liver fibrosis and improve liver structure, the promotion of ECM degradation and thus the treatment of experimental liver fibrosis.
6.Observed JIAWEISANRENTANG Decoction on rat liver tissue TGFβ1 and PDGF-B Inhibition of the expression.The results showed that the model group and treatment group in serum TGF-β1 and PDGF expression,and the normal group,the difference was significant (P＜0.01).JIAWEISANRENTANG extract group were significantly inhibited TGF-β1 and PDGF expression(P＜0.05),and superior to the positive drug,especially JIAWEISANREN-TANG mention the most obvious high-dose group(P＜0.01),and dose effect with a corresponding increase in enhancement;JIAWEISANRENTANG ethanolic dose low-dose group compared with the model group,the TGF-β1 and PDGF inhibit the effect of the expression of significant (P＜0.05).M JIAWEISANRENTANG decoction group compared with the model group,serum TGF-β1 on the impact of no significant(P＜0.05).
7.Observed JIAWEISANRENTANG Decoction on liver fibrosis serum TNF,IL-1 and the effects of IL-6.The results suggest that JIAWEISANRENTANG extract Sanren group have significantly lower serum TNF-α,IL-1,as well as the role of content(P＜0.05 or P＜0.01).Water extract of which high-dose group was superior to the positive effect of the drug group.The JIAWEISANRENTANG high-dose group in the serum TNF-αand IL-1 significantly reduced the role of IL-6 but no significant effect.While small doses of alcohol extracts of serum TNF-α,IL-1 and IL-6 had no significant effect.
8.Discussion JIAWEISANRENTANG on HSC-T6 TIMP-1 and MMP-2 expression.The results showed that the concentration of 40mg/mL and 20mg/mL JIAWEISANRENTANG can effectively reduce the TIMP-1 and MMP-2mRNA level and decreased with lower concentrations.
9.Observed of rat liver tissue and HSC in the Fas/FasL expression and flavored soup Sanren intervention role.Experiments found that JIAWEISANRENTANG significantly increase rat liver tissue and HSC Fas/FasL gene mRNA expression,and the water extract of the Fas /FasL are better than the increase in the role of drug-positive group.
10.Discussion on HSC apoptosis in vitro and JIAWEISANRENTANG intervention role.Experimental Tip:JIAWEISANRENTANG and Danshen injection can induce apoptosis of HSC,which JIAWEISANRENTANG extract 40mg/ml and 20mg/ml obvious apoptosis dose group,and better than Danshen injection group.In addition, the JIAWEISANRENTANG Decoction group to promote apoptosis of HSC is also a dose-dependent manner.
11.Explore JIAWEISANRENTANG Decoction on liver fibrosis in rat tissue plasminogen activator inhibitor,tissue-type plasminogen activator impact.The results showed that:compared with the cells in the control group,JIAWEISANRENTANG adjustable uPA and PAI-1 expression.Which the concentration of 40mg/mL and 20mg/mL JIAWEISANRENTANG extracts of HSC-T6 cells,uPA and PAI-1 expression and regulation of better than other groups.In serum uPA and PAI-1 expression inhibition in JIAWEISANRENTANG group are better than other groups.
乙型肝炎是由乙型肝炎病毒(HBV)感染所致,全世界约有3亿人是HBV携带者,而HBV携带者发生肝纤维化、肝硬化和肝癌的危险性比非携带者高出上百倍。我国是乙肝高发区,约有1.2亿HBV携带者。但是由于乙型肝炎的临床表现并不明显,再加上大多数病人并不重视而导致迁延失治,往往会让病情发展为慢性肝炎和肝纤维化。
慢性肝炎(HBV所致)的存在是引发肝纤维化的重要原因,单单治疗肝纤维化是无法使之完全治愈的,就算治疗得当也无法排除复发的危险。因此,抗慢性肝炎肝纤维化应作为一个整体进行治疗,方是彻底治愈的有力保证。国内外在对慢性肝炎及肝纤维化的机理研究方面已取得了一定进展。但是在其临床治疗领域,却依然未能取得明显的进步。加上目前临床现有的药物,其疗效并不够理想,而且有些药物普遍存在副作用较大,费用较高的缺点。因此国内外的研究者都在努力寻找疗效确切、价格低廉、毒副作用小的防治肝纤维化药物,以便能阻止慢性肝炎进一步发展,演变为肝纤维化的进程,最终治愈大多数慢性肝炎及肝纤维化。
因此本课题以加味三仁汤作为实验药物,展开针对慢性肝炎及肝纤维化的研究,拟采用免疫组化、细胞培养技术、流式细胞术、分子生物学方法(RealTime-PCR技术)等技术对鸭乙肝、大鼠免疫性肝纤维化、HSC细胞以及2.2.15细胞的影响等方面探讨其抗慢性肝炎及抗肝纤维化的作用及机理,为该方进一步的临床及开发应用提供实验依据。
1.利用DHBV阳性绿头鸭作为研究对象,观察加味三仁汤对其血清中DHBV-DNA水平的影响。结果显示:模型组鸭血清中DHBV-DNA水平升高,与正常组比较有显著性差异(P＜0.01),加味三仁汤水提液大剂量、小剂量以及大剂量醇提液对DHBV-DNA均有明显的抑制作用(P＜0.05或P＜0.01),而加味三仁汤的小剂量醇提液则没有显著的抑制DHBV-DNA作用。
2.以加味三仁汤作用于2.2.15细胞,观察其对2.2.15细胞HbsAg及HbeAg分泌的影响。结果显示,浓度为1、0.5、0.25、0.125、0.625、0.3125mg/mL的加味三仁汤水提液对2.2.15细胞HbsAg和HbeAg分泌抑制率分别为85.36%、79.72%、75.81%、69.65%、62.14%、30.56%以及90.17%、83.26%、76.34%、46.86%、20.32%、0.36%。药物剂量与HbsAg和HbeAg分泌抑制率呈现递增关系,其中随着剂量增加,其中药物对HbsAg的抑制更为明显。
3.观察加味三仁汤对2.2.15细胞HBV-DNA表达的影响。结果表明,加味三仁汤具有明显的抑制2.2.15细胞HBV表达的作用,其中1 mg/mL、0.5 mg/mL及0.25 mg/mL浓度的加味三仁汤水提液效果更优于阳性药物。
4.通过对DMN肝纤维化大鼠模型,观察加味加味三仁汤对肝组织肝HA、LN、IVC、PCIINP及HyP的影响。模型组及各给药组血清HA、LN、IVC、PCⅢ及HyP的水平均升高,与正常组比较,有显著性差异(P＜0.01)。加味三仁汤水提大、小剂量组与模型组比较,血清HA、PCⅢ、LN、CIV及HyP水平均明显下降(P＜0.05或0.01),且随剂量增加效果也相应增强;加味三仁汤醇提大剂量组与模型组比较,血清LN、IVC、PCⅢ及HyP的水平有一定程度下降,但无显著意义(P＞0.05)。加味三仁汤醇提小剂量组与模型组比较,血清PCⅢ、CIV、HyP水平有下降,但无显著意义(P＞0.05)。鳖甲软肝片组血清HA、PCⅢ、CIV水平较模型组无显著差异(P＞0.05)。
5.通过对DMN肝纤维化大鼠模型,观察加味三仁汤对DMN肝纤维化大鼠肝组织形态学的影响:(1)HE染色;(2)α-SMA免疫组化;(3)Ⅰ型胶原免疫组化。本实验表明,从肝小叶破坏、假小叶形成、胶原纤维增生等肝脏结构的客观改变出发,认为加味三仁汤可减轻肝纤维化的程度,改善肝脏结构,促进ECM降解,从而治疗实验性肝纤维化。
6.观察加味三仁汤对大鼠肝组织TGFβ_1及PDGF-B表达抑制的影响。结果显示模型组及各给药组血清TGF-β_1及PDGF表达增加,与正常组比较,有显著性差异(P＜0.01)。加味三仁汤水提液组均能显著抑制TGF-β_1和PDGF的表达(P＜0.05),且优于阳性药物,其中尤以加味三仁汤水提大剂量组最为明显(P＜0.01),且随剂量增加效果也相应增强;加味三仁汤醇提小剂量组剂量组与模型组比较,对于TGF-β_1和PDGF表达抑制的影响有显著意义(P＜0.05)。加味三仁汤醇提组与模型组比较,对血清TGF-β_1的影响无显著意义(P＜0.05)。
7.观察加味三仁汤对肝纤维化大鼠血清TNF、IL-1及IL-6的影响。结果提示,加味三仁汤水提液组均具有显著降低大鼠血清中TNF-α、IL-1以及含量的作用(P＜0.05或P＜0.01)。其中水提液大剂量组的效果更是优于阳性药物组。而加味三仁汤醇提大剂量组对大鼠血清中的TNF-α和IL-1有明显的降低作用,但对IL-6则无明显作用。而小剂量醇提液对大鼠血清中的TNF-α、IL-1和IL-6则无明显作用。
8.探讨加味三仁汤对HSC-T6 TIMP-1和MMP-2表达的影响。结果显示40mg/mL和20mg/mL浓度的加味三仁汤能有效降低TIMP-1和MMP-2mRNA的水平,并随着浓度降低而减弱。
9.观察大鼠肝组织和HSC中的Fas/FasL表达与加味三仁汤的干预作用。实验发现,加味三仁汤能明显上调大鼠肝组织及HSC Fas/FasL基因mRNA的表达,而且其水提液对Fas/FasL的上调作用均优于阳性药物组。
10.探讨体外培养HSC凋亡与加味三仁汤的干预作用。实验提示:加味三仁汤和丹参注射液均可诱导HSC凋亡,其中加味三仁汤水提液40mg/ml和20mg/ml剂量组细胞凋亡明显,并优于丹参注射液组。此外,加味三仁汤组对HSC的凋亡促进还呈剂量依赖。
11.探讨加味三仁汤对肝纤维化大鼠组织纤维酶原激活剂抑制剂、组织型纤维酶原激活剂的影响。结果显示:与细胞对照组比较,加味三仁汤可调节uPA及PAI-1的表达。其中浓度为40mg/mL以及20mg/mL的加味三仁汤水提液对HSC-T6细胞uPA及PAI-1的的表达调节优于其它各组。而在大鼠血清uPA及PAI-1的表达抑制中,加味三仁汤水提液组均优于其他各组。
Liver fibrosis,is a reversible reaction after the chronic liver disease,and the inevitable development of the pathological process for the chronic liver disease to cirrhosis.At present, there hasn't ideal treatment for some chronic liver diseases.such as the virus hepatitis which caused by hepatitis B virus hepatitis. From the pathological change,the liver fibrosis is reversible, and liver cirrhosis is irreversible.China is a high incidence of viral hepatitis epidemic.According to recent statistics,it shows that China has more than 20 million patients with liver disease.The IN of liver fibrosis is very high in our country,so it is a serious healthy problem that the national people must treat to.Therefore,searching for an effective prevention and treatment, for liver fibrosis,is an urgent requirement of national people and have far-reaching significance and important social value.
HB is caused by the hepatitis B virus(HBV).There have about 3 billion HBV carriers all around the world.The HBV carriers is easily to get the risk of liver fibrosis,liver cirrhosis and liver cancer than non-carriers.China is a high incidence of hepatitis B and have about 120 million HBV carriers.However,the obsolete clinical manifestations and the ignoring of hepatitis B to the majority of patients lead to the aggravate of this disease,even the occuring of chronic hepatitis and liver fibrosis.
Chronic hepatitis(HBV-induced) is the caused the important factor of the causing of liver fibrosis.The simple treatment for liver fibrosis can not make it cured completely.even if the well treatment can not rule out the risk of relapse.Therefore, anti-liver fibrosis in chronic hepatitis should be treated as a whole,is the guarantee for the complete cure.The research for the mechanism of chronic hepatitis and liver fibrosis have been some progress all round the world in nowday.However,in the field of clinical treatment,it still can't achieve the significant progress.Add the efficacy of common drugs for liver fibrosis is beyond ideal,and the drug have some disadvantages,for exsample, the obvious side effects and the high cost.So researchers at home and abroad are trying to search for a drug which have the advantage, including the exact effect,cheap and the shortage of toxic side effects.in order to cure the majority of chronic hepatitis and liver fibrosis.
This subject is selecting the JIAWEISANRENTANG as an experimental drug,used for chronic hepatitis and liver fibrosis research.The research adopted immunohistochemist-ry,cell culture,flow cytometry and RealTime-PCR technology for the teatment effect and mechanism of anti-chronic hepatitis and anti-hepatic fibrosis on DHBV model,autoimmune liver fibrosis in rats,HSC cells and 2.2.15 cells.It is supply the clinical and laboratory basis for the further development and application.
1.Use the DHBV-positive subjects to research JIAWEISANRENTANG in their serum DHBV-DNA levels.The results showed that: the model group of duck serum DHBV-DNA levels,compared with the normal group were significantly different(P＜0.01), JIAWEISANRENTANG extract high-dose,low-dose and high dose of alcohol extract of DHBV-DNA were significantly inhibited(P＜0.05 or P＜0.01),and JIAWEISANRENTANG small doses of alcohol did not extract a significant role in inhibiting DHBV-DNA.
2.Used JIAWEISANRENTANG in the role of the 2.2.15 cells were observed on the 2.2.15 cells and HbsAg secretion HbeAg.The results showed that concentration of 1,0.5,0.25,0.125,0.625,0.3125 mg /mL of JIAWEISANRENTANG tothe secretion of HbsAg and HbeAg for 2.2.15 cell inhibition rate was 85.36%,79.72%,75.81%,69.65%, 62.14%,30.56%and 90.17%,83.26%,76.34%,46.86%,20.32%,0.36%. Drug dose and HbsAg and HbeAg show increased secretion of the relationship between inhibition rate,which increased with the dose of which drug to more pronounced inhibition of HbsAg.
3.Observation JIAWEISANRENTANG on 2.2.15 cells,HBV-DNA expression.The results showed that with a flavored soup Sanren 2.2.15 cells inhibited the expression of the role of HBV,of which 1mg/mL,0.5mg/mL and 0.25mg/mL concentration JIAWEISANRENTANG extract more than the positive effect of the drug.
4.Rat model of liver fibrosis by DMN was observed for the action to liver liver tissue HA,LN,IVC,PCIINP and the impact of HyP by JIAWEISANRENTANG.Model group and treatment group in serum HA, LN,IVC,PCIII and water HyP average increase compared with the normal group,the difference was significant(P＜0.01). JIAWEISANRENTANG to large and small dose group compared with the model group,serum HA,PCIII,LN,CIV and HyP were significantly decreased(P＜0.05 or 0.01),and the effect increased with the dose corresponding enhancement;JIAWEISANRENTANG alcohol extract of high-dose group compared with the model group,serum LN,IVC, PCIII and HyP level dropped to a certain extent,but no significant (P＞0.05).JIAWEISAN-RENTANG low-dose group compared with the model group,serum PCIII,CIV,HyP levels decline,but no significant(P＞0.05).Fufangbiejiaruanganpian serum HA,PCIII, CIV level than the model group was no significant difference(P＞0.05).
5.Observed the rat model of liver fibrosis which is induced by DMN insect JIAWEISANRENTANG on DMN hepatic fibrosis of rat liver tissue the effects of morphology:(1) HE staining;(2)α-SMA immunohistochemistry;(3) I type collagen immunohistochemistry. The experiments show that damage from hepatic loble,the formation of false lobules,hyperplasia of collagen fibers,such as objective changes in liver structure,the JIAWEISANRENTANG can reduce the extent of liver fibrosis and improve liver structure, the promotion of ECM degradation and thus the treatment of experimental liver fibrosis.
6.Observed JIAWEISANRENTANG Decoction on rat liver tissue TGFβ1 and PDGF-B Inhibition of the expression.The results showed that the model group and treatment group in serum TGF-β1 and PDGF expression,and the normal group,the difference was significant (P＜0.01).JIAWEISANRENTANG extract group were significantly inhibited TGF-β1 and PDGF expression(P＜0.05),and superior to the positive drug,especially JIAWEISANREN-TANG mention the most obvious high-dose group(P＜0.01),and dose effect with a corresponding increase in enhancement;JIAWEISANRENTANG ethanolic dose low-dose group compared with the model group,the TGF-β1 and PDGF inhibit the effect of the expression of significant (P＜0.05).M JIAWEISANRENTANG decoction group compared with the model group,serum TGF-β1 on the impact of no significant(P＜0.05).
7.Observed JIAWEISANRENTANG Decoction on liver fibrosis serum TNF,IL-1 and the effects of IL-6.The results suggest that JIAWEISANRENTANG extract Sanren group have significantly lower serum TNF-α,IL-1,as well as the role of content(P＜0.05 or P＜0.01).Water extract of which high-dose group was superior to the positive effect of the drug group.The JIAWEISANRENTANG high-dose group in the serum TNF-αand IL-1 significantly reduced the role of IL-6 but no significant effect.While small doses of alcohol extracts of serum TNF-α,IL-1 and IL-6 had no significant effect.
8.Discussion JIAWEISANRENTANG on HSC-T6 TIMP-1 and MMP-2 expression.The results showed that the concentration of 40mg/mL and 20mg/mL JIAWEISANRENTANG can effectively reduce the TIMP-1 and MMP-2mRNA level and decreased with lower concentrations.
9.Observed of rat liver tissue and HSC in the Fas/FasL expression and flavored soup Sanren intervention role.Experiments found that JIAWEISANRENTANG significantly increase rat liver tissue and HSC Fas/FasL gene mRNA expression,and the water extract of the Fas /FasL are better than the increase in the role of drug-positive group.
10.Discussion on HSC apoptosis in vitro and JIAWEISANRENTANG intervention role.Experimental Tip:JIAWEISANRENTANG and Danshen injection can induce apoptosis of HSC,which JIAWEISANRENTANG extract 40mg/ml and 20mg/ml obvious apoptosis dose group,and better than Danshen injection group.In addition, the JIAWEISANRENTANG Decoction group to promote apoptosis of HSC is also a dose-dependent manner.
11.Explore JIAWEISANRENTANG Decoction on liver fibrosis in rat tissue plasminogen activator inhibitor,tissue-type plasminogen activator impact.The results showed that:compared with the cells in the control group,JIAWEISANRENTANG adjustable uPA and PAI-1 expression.Which the concentration of 40mg/mL and 20mg/mL JIAWEISANRENTANG extracts of HSC-T6 cells,uPA and PAI-1 expression and regulation of better than other groups.In serum uPA and PAI-1 expression inhibition in JIAWEISANRENTANG group are better than other groups.
引文
[1]Seeger C,Mason W.Hepatitis B virus biology.Microbiol Mol Biol Rev,2000,64:51-68
[2]Strader DB,Wright T,Thomas DL,and Seeff LB.Diagnosis,management,and treatment of hepatitis C.Hepatology,2004,39:1147-1171
[3]Hu KQ.Occult hepatitis B virus infection and its clinical implications.J Viral Hepat,2002,9:243-257
[4]陈国民,袁平戈.乙型肝炎病毒致病机制的新概念[J].现代医药卫生.2007,23(11):1581
[5]程斌,林松挺,杨玉珍.HBx致肝细胞癌分子机制的研究进展.世界华人消化杂志.2007,15(20):2242-2248
[6]徐道振,巫善明,周霞秋主编.病毒性肝炎临床实践.第1版.北京:人民卫生出版社,2006,140-141
[7]何绮娜.原发性肝癌与病毒性肝炎、肝硬化关系的探讨.河北医药,1986,8:135-136
[8]中华医学会传染病与寄生虫病学分会,肝病学分会.病毒性肝炎的诊断.中西医结合肝病杂志,2001,11:56-60
[9]美国肝病学会,美国感染病学会.美国慢性乙型肝炎病毒感染处理流程.中华传染病杂志,2006,9:2-5
[10]薛蓉,周镇先,王建芳.HBV基因型及P基因变异与拉米夫定耐药的关系.临床肝胆病杂志.2005,21(6):399-340
[11]王晶晶,刘宝芳,桂秀海,等.胃液中乙肝病毒指标检测结果分析[J].山西医学院学报,1995,26(4):334-335
[12]Gunther S,Sommer G,lwaska A,et al.Heterogeneity and common feature 是 of defective hepatitis B virus genomes derived from spliced pregenomic RNA.Virology,1997,238(2):363
[13]Thursz MR,Kwiatkowski D,Allsop CE,et al.Association between an MHC classⅡ allele and cleanrance of hepatitis B virus in the Gambia.N Engl J MED,1995,332:1065
[14]万谟彬.慢性乙型肝炎治疗的现状及前景[J].中华传染病杂志,2002,20(1):57-59
[15]王季午,刘克洲,陈智.人类病毒性疾病[M].北京:人民卫生出版社,2002,489
[16]陈湖光,余春艳,孟雪芹.病毒性肝炎患者血清IL-4、IL-12及IFN-a水平的观察[J].中华传染病杂志,2001,10(5):313
[17]宋瑞楼.肝炎、肝硬化与肝癌[M].台北:橘井文化事业股份有限公司,2006,139
[18]邬祥惠.慢性肝炎的发病机理和治疗.现代实用医学,2001,13(1):5-8
[19]Takano S,Yokosuka O,Imazeki F,Tagawa M,Omata M.Incidence of hepatocellular carcinoma in chronic hepatitis B and C aprospective study of 251 patients.Hepatology 1995,21:650-655
[20]Kagi D,Ledermann B,Burki K,Zinkemagel RM,Hengartner H.M o lecular mechanisms of Iymphocyte-mediated cytotoxicity and their role in immunological protection and pathogenesis in vivo.Annu Rev Immunol 1996,14:207-232
[21]Lohr HF,Krug S,Herr W,Weyer S,Schlaak J,Wo]fel T,Gerken G,Meyer zum Buschenfelde KH.Quantitative and functional analysis of core-specific T-helper cell and CTL activities in acute and chronic hepatitis B.Liver 1998,18:405-413
[22]Chisari FV,Ferrari C,Hepatitis B virus immunopathogenesis.Annu Rev Immunol 1995,13:29-60
[23]张瑞,赵彤言,顾长海.不同类型乙型肝炎病毒感染者体内毒株存在状况与临床转归[J].中华传染病杂志,2001,10(5):313
[24]周光德,赵景民.细胞外基质在肝内的代谢与肝纤维化的形成.世界华人消化杂志,2002,10:57-59
[25]李才.器官纤维化:基础与临床[M].北京:人民卫生出版社,2003:58-62
[26]LAMIREAU T,DESMOULIERE A,BIOULACSAGE P,et al.Mechanisms of hepatic fibrogenesis[J].Arch Pediatr,2002,9(4):392-405
[27]TAUB R.Liver regeneration:from myth to mechanism[J].Nat Rev Mol Cell Biol,2004,5(10):836-847
[28]程明亮,刘三都,主编.肝纤维化的基本概况[M].肝纤维化的基础及临床.第1版.北京:人民卫生出版社,1996.1-16
[29]Bataller R,Brenner D A.Liver fibrosis[J].J Clin Invest,2005,115:209
[30]范建高.非酒精性脂肪肝的临床病学研究[J].中国消化杂志,2002,22(2):106-107
[31]Geert A.History,heterogeneity,developmental biology,and funetion of quiescent hepatic stellate cells[J].Semin Liver Dis,2001,21(3):311-335
[32]Alcolodo R.Pathogenesis of liver fibrosis[J].Clin Sci,1997,92:103
[33]Friedman S L.Molecular regulation of hepatic fibrosis,an integrated cellular response to tissue injury[J].J Biol Chem,2000,275(4):2247-2250
[34]LI D,Fridman SL.Liver fibrogenesis and the role of hepatic atellate cells:new insights and prospects for therapy[J].J Gastroenterol Hepatol,1999,14:618
[35]G-ressner -AM.Cytokines and cellular crosstalk involved in the activation of fat-storing cells.[J]J Hepatol,1995,22(2 suppl):28-36
[36]Friedman S L.Mac the knife? Macrophages-the-double-edged sword of hepatic fibrosis[J].J Clim invest,2005,115(1):29-32
[37]熊伍军,邱德凯.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
[38]许青.转化生长因子B与肝纤维化[J].国外医学·消化疾病分册,1998,18(3):155
[39]Geremias S L,Carvalho M A,Borojevicr,et al.TGF betal and PDGF AA override Collagen type Ⅰ inhibition of proliferation in human liver connective tissue cells.BMC Gastroenterology,2003,4:30
[40]Wang X,Chen YX,Xu CF,Zhao GN,Huang YX,Wang QL.Relationship between tumor necrosis factor-α and liver fibrosis.World J Gastroenteral,1998,4:18
[41]Lamck JW.Wright ST.Cytotoxic mechamisms of tumor necrosis factor-α.FASEB J,1990,4:3215
[42]Sprenger H,Kaufrnann A,Gam H.Differential expression of monocyte chemotactic protein-l(MCP-1) in transforming rat hepatic stellate cells.J Hepatol,1999,30:88-94
[43]Sprenger H,Kaufrnann A,Gam H,Lahme B,Gernsa D,Gressner AM.Induction of neutrophil-attracting chemokines in transforming rat hepatic stellate cells.Gastrventerology,1997,113:277-285
[44]Wang Y J,Sun ZQ,Quan QZ,Yu JJ.Fat-storing cells and liver fibrosis.China Natl J New Gastroenterol,1996,2:58-60
[45]Yoshi ji H,Noguchi R,Kuriyama S,et al.Imatinib mesylate(STI-571)attenuates liver fibrosis development in rat[J].Am J Physiol Gastrointesl Liver Physiol,2005,288(5):G907-13
[46]Amakawa M,Endo Y.The motility of hepatic Ito cells can be acquired by their myofibroblastic transformation[J].Arch Histol Cytol,2002,65(2):169-178
[47]Garloni V,Romanelli RG,Pinzani M,et al.Focal adhesion kinase and phospholipase C gamma involvement in adhesion and migration of human hepatic stellate cells[J].Gastroenterology,1997,112(2):522-531
[48]金伯泉,主编.细胞和分子免疫学[M].第二版.北京科学出版社,2001,:10
[49]赵霞,姚希贤.白介素与肝纤维化[J].中国全科医学,2006,9(10):853-855
[50]Kovalavich K,Deangelis-RA,Li W,et al.Increased toxin-induced liver injury and fibrosis in interleukin-6-deficient mice[J].Hepatology,2000,31:149-159
[51]Stoat DE,Vincent K J,Authur MJPE,et al.Jun D regulates transcription of the tissue inhibitor of metalloproteinase-1 and interleukin-6 genes in actived hepatic stellate cells[J].Bio Chert,2001,276(26):24412-24421
[52]陈治新,王小从,张莉娟,等.IL-10对实验性肝纤维化大鼠血小板衍生生长因子-AA、BB表达的影响[J].临床消化病杂志,2003,15(3):99-101
[53]李光明,李定国.结缔组织生长因子与肝纤维化[J].国外医学.消化系疾病分册,2004,24(4):198-200
[54]Paradis V,Dargere D,Vidaud M,et al.Expression of connective tissue growth factor in wxperimental rat and human lever fibrosis[J].Hepatology,1999,30(4):968-976
[55]王要军,孙自勤,权启镇.参与肝纤维化的细胞因子.中国煤炭工业医学杂志,2000,3(1):4-5
[56]内皮素-1对肝脏的多种作用[J].国外医学·消化系统病,1997,17(3):167
[57]Sanz S,Pucilowska J B,Lin S.Expression of insulin-like growth factor I by activated hepatic stellate cells reduces fibrogenesis and enhances regeneration after liver injury[J].GUT,2005,54(1):134-141
[58]Van Eyken P,Seiot R,Desmet VJ,et al.Expression of the novel extra-cellular matrix component tenascin in normal and Diseased human liver.An immunohisto-chemical study[J].J HePatol,1990,11(1):42-5
[59]李成忠,等.非创伤性诊断指标优势组合对肝纤维化诊断价值的初步研究[J].中华肝脏病杂志,2001,9(5):261
[60]王新.肝硬变患者血清层粘连蛋白水平的变化[J].第四军医大学学报,1997,18(3):254
[61]Murawakai Y,Nishimura Y,Ikuta Y,et al.Plasma transforming growth factor-betal concentrations in patients with chronic viral hepatitis[J].J Gastrolenterol Hepatol,1998,13:680
[62]Kim T,Mars W,Stolz D,et al.Expression and activation of pro-MMP-2and pro-MMP-9 during rat liver regeneration[j].Hepatology,2000,31(1):75-78
[63]刘磊.整合素与肝纤维化[J].国外医学流行病学传染病学分册,2003,30(1):31-33
[64]龚作炯,宋仕玲,黄砚青,等.血管紧张素Ⅱ受体拮抗剂对大鼠肝纤维化的疗效及作用机制[J].肝脏,2004,9(2):97-100
[65]申凤俊,朱跃科,李琴,等.肝纤维化形成过程中肾素-血管紧张素系统的变化[J].肝脏,2003,8(4):24-26.
[66]王会丽,蒋维晟,苑军正.浅谈慢性乙型肝炎肝纤维化病因病机和治疗.江西中医药,2006,3(27):11-12
[67]刘平.现代中医肝脏病学[M].北京:人民卫生出版社,,2001,3
[68]唐智敏,茹清静,张振鄂,等.肝血瘀阻与肝纤维化关系的临床研究[J].中国中西医结合杂志,1997,17(2):81-83
[69]林小田,骆抗先,冯筱榕,等.慢性乙型肝炎临床与病理分级、分期的对比分析.[J]中华内科杂志,1998,37(7):437-439
[70]骆抗先.乙型肝炎临床与活性组织病理[M].第2版.北京:科学出版社,2001:81-86
[71]林小田.慢性肝炎临床诊断标准的探讨[J].广东医学院学报,2001,16(1):52
[72]张淑玲,董继华.慢性肝炎乙型抗病毒的研究进展[J].病毒学杂志,2006,13(6):179
[73]Cooksley WG.Peginterferon-alpha α-2a for the treatment of hepatitisB infection Expect Opin pharmacother,2005,6(8):1373-1380
[74]程有香.慢性肝炎乙型抗病毒治疗[J].中国城乡企业卫生,2007,6(12):48-49
[75]秦成勇,韩国庆.我国乙型肝炎的治病现状及治疗进展[J].医学前沿,2007,36(1):22-24
[76]叶丽红.浅谈慢性乙型肝炎的中医辨证治疗[J].辽宁中医杂志,2002,11(11):661
[77]汪静,杨秀华,谢朝良,等.辨舌分型治疗无临床症状慢性乙型肝炎42例.泸州医学院学报,2003,26(1):25
[78]胡金娣.自拟益气活血汤治疗慢性乙肝的效果观察.中医中药,2007,4(6):59
[79]冯圣林.自拟健脾益肾解毒活血汤治慢性乙肝56例.四川中医,2002,20(9):45
[80]马秀丽,刘耀明,刘霞.丹参在慢性肝炎治疗及复发预防中的作用探讨[J].临床医学,2000,20(5):42-43
[81]范锡伟.苦参素治疗慢性乙肝临床观察[J].山东医药,2005,45(25):72-73
[82]吴沛田.天花粉治疗慢性乙型肝炎[J].中医杂志,2006,47(9):651
[83]吴明,颜开华.灯盏花联合苦参素治疗慢性乙肝50例临床观察[J].哈尔滨医药,2007,27(1):23-24
[84]王宝恩,张定凤,主编.现代肝脏病学[M].第1版.北京:科学出版社,2003,513
[85]骆抗先,主编.乙型肝炎-基础和临床[M].第一版.北京:人民卫生出版社,1997,370
[86]朗江明,主编.临床免疫诊断学[M].第一版.广州:广东科技出版社,2003,61
[87]1995年5月北京第五次全国传染病寄生虫学术会议讨论修订.病毒性肝炎防治方案(试行).中华传染病杂志,1995,13(4):241-247
[88]2000年9月西安中华医学会传染病与寄生虫病学分会、肝病学会分会联合修订.病毒性肝炎防治方案
[89]Scheuer PJ.Classification ofchornic viral hepatitis:a need for reassessment.J Hepatol,1991,13:372
[90]Halfon P,Bourliere M,Penaranda G,et al.Accuracy of hyaluronic acid level for predicting liver fibrosis stages in patients with hepatitis C virus.Comparative hepatology,2005,4:6 dio:10.1 186/1476-5926-4-6
[91]Montazeri G,Estakhri A,Mohamadnejad M,et al.Serum hyaluronatc as a non-invasive marker of hepatic fibrosis and inflammation in HbeAg-negative chronic hepatitis B.BMC gastroenterology,2005;5:32doi:10.1 186/1471-230×/5/32
[92]Plevris JN,Haydon GH,Simpson KL,et al.Serom hualuronan-a non-invasive test for diagnosing liver cirrhosis.European journal of gastroenterology&hepatology,2000,12:121-1127
[93]Desmet Murawaki Y,Iknta Y,Koka M,et al.Clinical significance of serum hyaluronan in patients with chronic viral liver disease.Journal of gastroenterology and hepatoloigy,1996,11:459-465
[94]董永杰,彭彦辉,赵晓云,等.肝纤维化血清学诊断方法的研究进展.医学综述,2007,13(2):1743-1745
[95]Zachariae H,Heickendorff L,Sogaard H.The value of aminoterminal propeptide of type Ⅲ procollagen in routine screening for methotrexate-induced liver fibrosis:a 10-year follow up.Br J Dermato 2001;144:100-103
[96]Hironaka K,Sakaida I,Uchida K,Okita K.Correlation between stellate cell activation and serum fibrosis markrs in choline-deficient L-amino acid-defined diet-induced rat liver fibrosis.Dig Dis Sci 2000;45:1935-1943
[97]Kauschke SG,Knorr A,Heke M,Kohlmeyer J,Schauer M,Theiss G,Waehler R,Burchardt ER.Two assays for measuring fibrosis:reverse transcriptase-polymerase chain reaction of collagen alpha(1)(Ⅲ) mPNA is an early predictor of subsequent collagen deposition while a novel serum N-terminal procollagen(Ⅲ) propeptide assay reflects manifest fibrosis in carbon tetrachloride-treated rats.Anal Biochem 1999;275:131-140
[98]Walsh KM,Fletcher A,Macsween RN,Morris AJ.Comparison of assays for N-amino terminal propeptide of type Ⅲ procollagen in chronic hepatitis C by using receiver operating characteristic analysis.Eur J Gastroenterol Hepatol 1999;11:827-831
[99]Stickel F,Urbaschek R,Schuppan D,Poeschl G,Oesterling C,Conradt C,McCuskey RS,Simanowski UA,Seitz HK.Serum collagen type Ⅵ and ⅩⅣ and hyaluronic acid as early indicators for altered connective tissue turnover in alcoholic liver disease.Dig Dis Sci 2001;46:2025-2032
[100]Serejo F,Costa A,Oliveira AG,Ramalho F,Batista A,De Moura MC.Alpha-interferon improves liver fibrosis in chronic hepatitis C:clinical significance of the serum N-terminal propeptide of procollagen type Ⅲ.Dig Dis Sci 2001;46:1684-1689
[101]李小维,苌新明.血清Ⅳ型胶原在肝纤维化诊断中的意义[J].西安医科大学学报,2000,21(5):431-432
[102]谢仕斌,姚集鲁,郑树森,等.血清肝纤维化指标水平与肝组织纤维图像分析的关系[J].中华肝脏病杂志,2000,8(4):203-205
[103]李永强,蔡伊梅.血清Ⅳ型胶原诊断肝纤维化的价值[J].上海第二医科大学学报,2000,20(5):455-457
[104]柴明胜.肝病诊断新标志-血清Ⅳ型胶原[J].上海医学检验杂志,1995,10(3):182
[105]张世兰,杨永平,李亚洁,等.肝病患者层粘连蛋白的检测及临床意义.第一军医大学学报,2000,20(4):313-314
[106]Castera L,Hartmann DJ,Chapel F,Guettier C,Mall F,Lons T,Richardet JP,Grimbert S,Morassi O,Beaugrand M,Trinchet JC.Serum laminin and type Ⅳ collagen are accurate markers of hitologically severe alcoholic hepatitis in patients with cirrhosis.J Hepatol 2000, 32:412-418
[107]侯振江,张宗英,周秀梅.蛋白标记物在肝纤维化研究中的应用[J].中华肝脏病杂志,1998,14(4):200
[108]郝菁华,石军,任万华,等.血清透明质酸水平与肝脏微循环状况的关系[J].临床肝胆病杂志,2002,18(1):35-37
[109]Okazaki I,Watanabe T,Hozawa S,et al.Molecular mechanism of the reversibility of hepatic fibrosis:with special reference to the role of matrix metalloproteinases[J].J Gastroenterol Hepatol,2000,15:D26-32
[110]黄宇琦,高毅.鼠肝纤维化基质金属蛋白酶及其抑制因子的表达[J].世界华人消化杂志,1999,7(9):795-796
[111]何云,王建宾,王宇明.慢性肝炎肝纤维化程度诊断方法的进展[J].世界华人消化杂志,2001,9(11):1305
[112]何云,王建宾,王宇明.肝纤维化程度诊断方法的评价[J].成都军区医学院学报,2002,4(3):35
[113]张平,李勤光,高永琳.转化生长因子β1与病毒性乙型肝炎患者肝细胞损伤和肝纤维化的关系[J].传染病信息,2004,1(17):29
[114]张立煌,方海林,裘云庆,等.病毒性肝炎患者血清转化因子-β1活性及其与纤维化的关系[J].中华传染病杂志,1997,15(2):82-84
[115]Eghbali-Fatourchi G,Sieck GC,Prakash YS,et al.Type Ⅰprocollagen production and cell proliferation is mediated by transforming growth factor-β in a model of hepatic fibrosis.Endocrinology,1996,137(5):1879-1903
[116]俞海英,杨毅军,陈彦,等.血小板衍生生长因子对慢性重型肝炎预后评估的临床意义[J].临床荟萃,2003,18(16):901-904
[117]张慧芸,吕卉,李新民,等.α-干扰素治疗慢性乙型肝炎纤维化的疗效观察[J].中华肝脏病杂志,2003,11(2):117-118
[118]Cooksley G.The treatment of hepatitis B e antigen-positive chronic hepatitis B with pegylated interferon[J].J Hepatol,2003,39(1):143-145
[119]张岩,白雪帆,李艳红,等.拉米夫定治疗慢性乙型肝炎的疗效及肝组织学改变[J].中国误诊学杂志,2006,5(5):804-806
[120]Bataller R,Brenner DA.Hepatic stellate cells as target for the treatment of liver fibrosis[J].Semin Liver Dis,2001,21(3):437-451
[121]谭海荣,吴谦,潘竞锵,等.水飞蓟素对抗大鼠酒精性脂肪肝作用及机制[J].中国临床药理学与治疗学,2004,9(7):803-806
[122]Boigk G,Stroedter L,Herbst H,et al.Silymarin retards collagen accumulation in early and advanced biliary fibrosis secondary to complete bile duct obliteration in rats[J].Hepatology,1997,26(3):643-649
[123]刘海成,李风华,陈文慧,等.甘草酸二铵对肝纤维化大鼠肝脏脂质过氧化与间质性胶原酶火星的影响[J]..中国病理生理杂志,2005,21(3):2233-2237
[124]许倩,许建娟.腺苷蛋氨酸治疗妊娠肝内胆汁淤积症疗效探讨[J].中国优生与遗传杂志,2004,12(1):83-84
[125]汪余勤,程五凤,李宣海.维生素E与肝纤维化[J].临床肝胆病杂志,2000,16(1):19
[126]Dogru Abbasoglu S,Balkan J,Kanbagli O,et al.Aminoguanidineian inducible nitric oxide synthase inhibitor,plus N-acetylcysteine treatment reduce the lipopolysaccharide-augmented hepatotoxicity in rats with cirrhosis[J].Hum Exp Toxicol,2002,21(7):359-364
[127]Vendemiale G,Grattagliano I,Caruso ML,et al.Increased oxidative stress in dimethylnitrosamine-induced liver fibrosis in the rat:effect of N-acetylcysteine and interferon-alpha[J].Toxicol Appl Pharmacol,2001,175(2):130-139
[128]Kim KY,Rhim T,Choi I,et al.N-acetylcysteine induces cell cycle arrest in hepatic stellate cells through its reducing activity[J].J Biol Chem,2001,276(44):40591-40598
[129]Meurer SK,Lahme B,Tihaa L,et al.N-acetyl-L-cysteine suppresses TGF-beta signsling at distinct molecular steps:the biochemical and biological efficacy of a multifunctional,antifibrotic drug[J].Biochem Pharmacol,2005,70(7):1026-1034
[130]Arrieta O,Rodriguez JL,Rosaa V,et al.Clchicine delays the development of hepatocellular carcinoma in patients with hepatitis virus related liver cirrhosis[J].Cancer,2006,107(8):1852-1858
[131]程书权.肝纤维化的现代药物治疗研究[J].中国处方药,2005,3(5):36-40
[132]阳学风,曾明新,张明亮,等.马洛替酯抑制肝纤维化的实验与临床研究[J].世界华人消化杂志,1999,7(3):224-226
[133]何方平,孙惠蓉,张跃新,等.四种药物对大鼠肝纤维化的实验与临床研究[J].新疆医科大学学报,2003,26(4):338
[134]Keiding S,Badsberg JH,Becket U,et al.The prognosis of patients with alcoholic liver disease.An international randomized placebO-con-trolled trial on the effect of malotilate on survival[J].J.Hepatol,1994,20(4):454-460
[135]Zou WL,Yang Z,Zang YJ,et al.Inhibitory effects of prostaglandin E1 on activation of hepatic stellate cells in rabbits with schistosomiasis[J].Hepatobillary Pancreate Dis Int,2007,6(2):176-181
[136]Hui AY,Dannenberg AJ,Sung JJ,et al.Prostaglandin E2 inhibits transformaing growth factor beta 1 mediated induction of collagen alpha(1) in hepatic stellate cells[J].J Hepatol,2004,41(2):251-258
[137]沃明黔.前列腺素E1-治疗肝纤维化疗效观察[J].航空航天医药,2002,13(4):230
[138]邹卫龙,杨镇,吴健,等.前列腺素E-1抑制血吸虫病家兔肝脏星状细胞活化研究[J].中华实验外科杂志,2004,21(12):1468-1470
[139]Lieber CS.New concepts of the pathogenesis of alcoholic liver disease lead to novel treatments[J].Curr Gastroenterol,2004,6(1):60-65
[140]Austin AS,Mahida YR,Clarke D,et al.A pilotstudy to investigate the use of oxoentifylline and thalidomide in portal hyperten-sion secondary to alcoholic cirrhosis[J].Aliment Pharmacol Ther,2004,19(1):79-88
[141]Isbrucker RA,peterson TC.Platelet-derived growth factor and pentoxifylline modulation od collagen synthesis myofibroblasts[J].Toxico Appl Pharmacol,1998,149(1):120-126
[142]Akriviadis E,Botla R,Briggs W,et al.Pentoxifylline improves short-term survival in severe acute-alcoholichepatitis;double-blind,placebo-con-trolledtrial[J].Gastroenterology,2000,119(6):1637-1648
[143]Matsuda Y,Matsumoto K,Yamada A,et al.Preventive and therapeutic effects in rat of hepatocyte growth factor infusion on liver fibrosis cirrhosis[J].Hepatology,1997,26(1):81-89
[144]吴国春,何忠华,王雄.不同剂量促肝细胞生长素治疗肝硬化血清肝纤维化指标的变化[J].江苏医药,2003,29(6):456-458
[145]刘平,王晓玲,刘成.丹酚酸A对成纤维细胞活力、增生及胶原合成的影响[J].中西医结合肝病杂志,2000,10(1):24-25
[146]张荣华,周子成,洪多伦,等.三七抗肝纤维化的实验研究[J].第三军医大学学报,2000,22(4):307
[147]程鹏,刘索侠.黄芪抗肝纤维化的作用与转化生长因子β1及干扰素γ的关系[J].临床军医杂志,2000,28(3):32
[148]李延昌,孙玉凤,冯志杰,等.赤芍抗肝纤维化的实验研究[J].中国中西医结合杂志,2003,23(10):767
[149]许正锯,黄以群,张启华,等.大黄对慢性肝炎抗肝纤维化的临床研究[J].中华传染病杂志,2004,22(3):202
[150]展玉涛,李定国,王志荣,等.大黄素对大鼠肝纤维化形成的影响[J].中国中西医结合杂志,2000,20(4):276-278
[151]马雄,邱德凯.冬虫夏草多糖脂质体抗纤维化的实验研究[J].中国中医基础医学杂志,1999,5(9):28-30
[152]李旭东,王树槐.扶正化痰中药体外对大鼠纤维肝肝细胞蛋白质合成、分泌的影响[J].中成药,2001,23(4):274-277
[153]茹清静,唐智敏,张振鄂,等.血府逐瘀汤治疗慢性乙型肝炎肝纤维化患者的临床研究[J].中国中西医结合杂志,2004,24(11):983-985
[154]宋家五,李绍白.血府逐瘀汤分解方抗肝纤维化作用的研究[J].中西医结合肝病杂志,1995,5(2):23-25
[155]张晓平,陈建民,强势平.血府逐瘀汤抗血吸虫致小鼠肝纤维化的实验研究[J].中医杂志,2003,44(4):299-300
[156]李宁,吴圣东.大黄蛰虫丸辅助治疗慢性肝病肝纤维化46例[J].中国中西医结合杂志,2002,22(11):866
[157]赵治友,姚真敏,钟庆平,等.鳖甲煎丸对慢性肝病肝纤维化治疗作用的临床研究[J].新中医,2005,37(4):29-30
[158]周光德,李文书,赵景民,等.复方鳖甲软坚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
[159]任小巧,卢跃卿,陈永旭,等.仲景三方对大鼠肝纤维化不同时期血清型前胶原透明质酸及层粘蛋白作用的观察[J].北京中医药大学学报,2001,24(3):35-37
[160]张晓斌.柔肝补肾健脾活血法治疗肝纤维化72例分析[J].实用中医内科杂志,2003,17(5):406-407
[161]陈琰碧,杨宏志,许瑞云,等.补肾益气舒肝凉血活血方对乙型肝纤维化患者免疫功能的影响[J].中国中医基础医学杂志,1998,4(11):30-31
[162]陈爽,贲长恩,杨美娟.柴胡皂甙对肝细胞增殖及基质合成的实验研究[J].中国中医基础医学杂志,1999,5(5):21
[163]贾道全,张正,罗成福,等.甘草甜素逆转肝纤维化及早期肝硬化的作用探讨[J].中华消化杂志,2001,21(12):754-756
[164]陈伟忠,张俊平.苦参碱对大鼠实验性肝纤维化作用的实验研究[J].第二军医大学学报,1996,17(5):424-426
[165]Park PH,Nan JX,ParkE J,et al.Effect of tetrandrine on experimental hepatic fibrosis induced by bile duct ligation and scission in rats[J].Pharmacol Toxicol,2000,87:261-268
[166]陈岳祥,李石,张兴荣,等.牛磺酸对四氯化碳诱导大鼠肝纤维化的抑制作用[J].中华消化杂志,1999,19(3):185
[167]Lee T Y,Wang G J,Chiu J H,et al.Long-term administration of Salvia miltiorrhiza ameliorates carbon tetrachloride-induced hepatic fibrosis in rats[J].J Pharm Pharmacol,2003,55(11):1561-1568
[168]胡晓峰,刘斌,张敏,等.家兔肝纤维化模型的模型的建立及肝功能指标与肝纤维化的相关性[J].实用肝脏病杂志,2007,10(3):152-154
[169]庞荣清,刘建昆,何占龙,等.猕猴肝纤维化模型建立与评价[J].世界华人消化杂志,2005,13(16):1956-1958
[170]Vendemiale G,Grattaagliano I,Caruso M L,et al.Increased oxidative stress in dimethylnitrosamine-induced liver fibrosis in the rat:effect of N-acetylcysteine and interferon-alpha[J].Toxicol Appl Pharmacol,2001,175(2):130-139
[171]吴丽,魏伟.肝纤维化的动物模型及治疗药物研究[J].中国药理学通报,2004,20(5):481-485
[172]Jonker A M,Dijkhuis F,Hardonk M J,et al.Immunohisto-chemical study of hepatic fibrosis induced in rats by multiplegalactosamine injections[J].Hepatology,1994,19(3):775-781
[173]杨文卓,曾民德,范竹萍,等.氧化苦参碱防治半乳糖胺诱导大鼠肝纤维化的实验研究[J].中华肝脏病杂志,2002,10(3):193-196
[174]杨文卓,曾明德.肝纤维化的发病机制及病理生理[J].国外医学·消化系统疾病分册,2000,20(4):216-220
[175]Liebe R C S,DeCarli I M.The feeding of ethanol liquid diets[J].Alcohol Clin Exp Res,1986,10(5):550-553
[176]Tsukamoto H,Reidelberger R D,French S W,et al.Long term cannulation model for blood sampling and intragastric infusion in the rat[J].Am J Physiol,1984,247(3 Pt2):R595-R599
[177]Kamimura S,Sohda T,Shijo H,et al.Hepatic fibrosis in rats fed a liquid diet with ethanol and carbonyl iron[J].Int Hepatol Commu,1995,3(2):70-76
[178]洪洋懿,阳学风,雷军,等.乙酰肝素酶在大鼠酒精肝纤维化中的表达及其意义[J].世界感染杂志,2007,7(3):207-210
[179]丁霞,蒙一纯,责长恩.等.酒精性肝纤维化动物模型的建立[J].中国中医基础医学杂志,1999.5(7):47-48
[180]Haratake J,Hisaoda M,Yamamoto O,et al.Morphological changes of hepatic microcirculation in experimental rat cirrhosis:a scanning electron microscopic study[J].Hepatology,1991.13(5):952-956
[181]Mori T,Okanode T,Sawa Y,et al.Defenestration of the sinusoidal endothelial cell in a rat model of cirrhosis[J].Hepatology,1993,17(5):891-897
[182]朱起贵,方步武.吴贺算,等.牛血清白蛋白致免疫损伤性肝纤维化动物模型的研究[J].中华病理学杂志,1993,22(2):121
[183]Santra A,Chowdhury A,Ghosh A,et al.Development of an animal model of hepatic fibrosis by excretory-secretory antigen of Ascaris suum[J].Indian J Gastroenterol,2000,19(3):119-121
[184]程明亮,杨长青.肝纤维化的基础研究及临床[M].2版.北京:人民卫生出版社,2002:366-367
[185]李培建,梁保忠,王爱民,等.四氯化碳、人血自蛋白所致大鼠肝纤维化动物模型的实验研究[J].实验动物科学与管理,2000,17(2):32-34
[186]Tiegs G,Hentschel J,Wendel A.A T cell—dependent experimental liver injury in mice inducible by concanavalin A[J].J Clin Invest,1992,90(1):196-203
[187]李鸿立,田聆,魏于全,等.刀豆素蛋白A诱导小鼠肝纤维化模型的建立[J].免疫学杂志,2004,20(5):390-392,396.
[188]阴宏,马红,刘乃慧,等.大鼠胆管阻塞性肝纤维化模型的建立[J].实验动物科学与管理,2002,19(2):1-3
[189]陈智.乙型肝炎病毒cccDNA研究现状[J].中华传染病杂志,2003,21(1):8-10
[190]Yang W,Mason WS,Summers J.Covalenfly Closed Circular Viral DNA Formed from Two Types of Linear DNA in Woodchuck Hepatitis Virus-Infected Liver[J].J Virol of Virology,1996,70(7):4567-4575
[191]Chou YC,Jeng KS,Chen ML,et al.Evaluation of transcriptional efficiency of hepatitis B virus covalently closed circular DNA by reverse transcription·-PCR combined with the restriction enzyme digestion method[J].J Virol,2005,79(3):1813-1823
[192]Summers J,Smith PM,Horwich AL.Hepadnavirus envelope proteins regulate covalendy closed circular DNA amplicatlon[J].J Virol,1990,64(6):2819-2824
[193]LeeKS,Lee SJ,ParkHJ,Chung JP,HanKH,Chon CY,Lee SI,Moon YM.Oxidative stress effect on the activation of hepatic stellate cells[J].Yonsef Med,2001;42:1-8
[194]Gressner AM,Pohar B,Lahme B,M annherz HG.Induction of rat liver parenchymal cell apoptosisby hepatic myofibroblasts via transforming growth factor beta[J].HepatoloRy 1996;23:571-581
[195]李莉娜,贾心善.肝脏星状细胞与细胞外基质、金属蛋白酶的研究进展[J].日本医学介绍 2002;23(10):139-141
[196]Greenwel P,Roikind M.Accelerated development of liver fibrosis in CC14-treated rats by the weekly induction of acute phase response episodes:upregulation of alphal(Ⅰ) procollagen and tissue inhibitor of metall-oproteinase-1 mRNAs[J].Biochim Biophvs Acta 1997:1361:177-184
[197]Wells RG.Fibrogenesis.V.TGF—beta signaling pathways[J].Am J Phvsiof Gastrointest Liver Phvsiol 2000:279:G845-G850
[198]Iredale J,Benyon RC,Picketing J,et al.Mechanisms of spontaneous resolution of rat liver fibrosis:Hepatic stellate cell apoptosis and reduced hepatic expression of metalloproteinase inhibitors[J].J Clin Invest,1998,102(3):538-549
[199]Kishibe K,Yamada Y,Ogawa K,et al.Production of nerve growth factor by mouse hepatocellular carcinoma cells and expression of TrkA in tumor —associated arteries in mice[J].GastroenteroIogy,2002,122(7):1978-1986
[200]Fiona Oakley,Nathan Trim,Christothea M,et al.Hepatocytes express nerve growth factor during liver injury[J],Am J Pathol,2003,163(5):1849-1858
[201]Fischer R,Schmltt M,Bode J G,et al.Expression of the peripheral-type benzodiazepine receptor and apoptosis induction in hepatic stellate cells[J].GastroenterOlogy,2001,120(5):1212-1226
[202]Gong WR.Pecci A,Roth S.et al.Transformation-dependent susceptibility of rat hepatic stellate cells to apoptosis induced by soluble fas-ligand[J].Hepatology,1998·28(2):492-502
[203]Salle B,Matthes N,Knittel T,el al.Transforming growth factor beta and tumor necrosis factor alpha inhibit both apoptosis and proliferation of activated rat hepatic stellate cells[J].Hepatology·1999,30(1):196-202
[204]Taimr P,Higuchi H,Kocova E,et al.Activated Stellate cells express the TRAIL receptor-2/death receptor-5 and Undergo TRAIL-mediated apoptosis[J].Hepatology,2003,37(1):87-95
[205]Gressner AM.The up-and-down of hepatic stellate cells in tissue injury:apoptosis restores cellular homeostasis [J].Gastroenterology,2001,120(5):1285-1288
[206]刘建虎.肝窦星状细胞的激活与凋亡[J].实用肝脏病杂志,2003,6(1):50-52
[207]赵东强,姜慧卿,修贺明,等.丹参单体IH764-3对肝星状细胞增殖与凋亡的影响.中华肝脏病杂志,2002,10(4):265-274
[208]Carloni V,Romanelli RG,Pinzani M,et al.Focal adhesiion kinase and phospholipase C gamma involvement in adhesion and migration of human hepatic stellate cells[J].Gastroenterology,1997,112:522-531
[209]张晓岚,姜慧卿,刘丽,等.丹参单体IH764-3诱导肝星状细胞凋亡[J].中华内科杂志,2002,41(9):616-617
[210]田雄英,翁山耕,程协枝,等.苦参碱对大鼠肝星状细胞增殖和凋亡的影响[J].肝脏,2005,10(2):95-97
[211]Araujo CC,Leon LL.Biological activities of Curcuma longa L.Mem 25 Inst Oswaldo Cruz,2001,96:723-728
[212]何雅军,舒建昌,吕霞,等.姜黄素预防肝纤维化作用与肝星状细胞的关系[J].中华肝脏病杂志,2006,14(5):337-340
[213]尤红,王宝恩,王泰龄,等.复方861对肝星状细胞的增殖和凋亡的干预作用[J].中华肝脏杂志,2000,8(2):78-80
[214]尤红,王宝恩,马雪梅.中药复方861对肝星状细胞NF-gB活性的体外研究[J].中华肝脏杂志,2001,9(2):73-74
[215]赵英恒,何兴祥.复方利肝冲剂药物血清对肝星状细胞NF-kB结合活性的抑制作用[J].世界华人消化杂志,2002,10(1):95-96
[216]Olson D,Pollanen J,Hoyer-Hansen G,Ronne E,et al.Internalization of the urokinase-plasminogen activator inhibitor type-1 complex is mediated by the urokinase receptor[J].J Biol Chem,1992,267:9129-9133
[217]陈香美.凝血纤溶系统与细胞外基质调控系统在肾脏疾病中的作用[J].中华肾脏病杂志,2001;17(3):348-349
[218]Brauer PR.M M Ps role in cardiovascular development and disease[J].Front Biosc,2006,11:447-478
[219]Malemud CJ.Matrix metalloproteinases(MMPs) in health and disease:an overview[J].Front Biosc,2006,11:1696-1701
[220]崔红燕,刘成,刘成海.纤溶系统与肝纤维化的研究进展[J].中两医结合肝病杂志,2003;13(2):316-318
[221]Irigoyen JP,M unoz,Canoves P,et al.The plasminogen activator system:biology an d regulation[J].CPl Mol Life Sc,1999,56:104-132
[222]Leyland H,Gentry J,Arthru M,et al.The Plasminogen activating system in hepatic stellate cells[J].Hepatology,1996,24:1172-1178
[223]Murphy G,Atkinson S,Gavrilovic J,et al.The role of plasminogesn activators in the regulation of connective tissue metalloproteinase[J].Amm N Y Acad Sci,1992,667:1-12
[224]Thomton A,Bruzdainski C,Raper S,et al.Plasminogen activator inhibitor-1 is an immediate early response genein regenerating rat liver[J].Cancer Res,1994,54:1337-1343
[225]Li P,Terumi T,Yutaka Y,et al.Increased expression of plasminogen activator and plasminogen activator inhibitor during liver fibrogenesis of rats:role of stellate cells[J].J Hepatol,1999,31:703-711
[226]翟玉祥,杨进,卞慧敏,等.清营汤及其拆方对实验性家兔营热阴伤证模型凝血与纤溶系统的影响[J].中国中医药科技,2001,8(2):81-83
[227]陈志强,赵玉庸,范焕芳,等.红花对实验性局灶节段性肾小球硬化症大鼠纤溶系统的影响[J].中草药,2005,36(12):1847-1849
[228]田耘,胡俊鸿,程小红.安肾方对免疫复合物型肾炎大鼠凝血纤溶系统的影响[J].陕西中医,2007,28(8):1098-1100
[229]Mosmann T.Rapid colorimetric assay for cell growth and survival:Mpdigication to the tetrazolium dye proceduce giving improved sensitivity and reliability,J Immunol Methods,1986;89:271
[230]李定国,陈颖伟.肝纤维化研究现状及展望[J].上海第二医科大学学报.2005,25(2):101
[231]Kobayashi H,Sakahara H,Hosono M,et al.Improved clearance of radiolabeled biotinylated monoclonal antibody following the infusion of avidin as a:"chase" without decreased accumulation in the target tumor[J].J Nucl Med,1994,35:1677
[232]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
[233]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):122-123
[234]DooleyS,Delvoux B,Streekert M,et al.FEBS Lett,2001,502(1-2):4-10
[235]乐小华,李美忠,杨桂林,等.肝星状细胞活化与肝纤维化分期与血清学指标的关系[J].实用医学杂志,2002,18(10):1051
[236]TSUKADA S,PARSONS C J,RIPPER A.Mechanisms of Iiver fibrosis[J].Clin Chim Acta,2006,364(1-2):33-6
[237]Zhang LP,Takahara T,Yata Y,et al.Increased expression of plasminogen activator and plasminogen activator inhibitor during liver fibro genesis of rats:role of stellate cells[J].J Hepatology,1999,31(4):703-711
[238]Murphy G,Atkinson S,Ward R,et al.The role of plasminogen activators in the regulation of connective tissue metalloproteinases[J].Ann N Y Acad Sci,1992,667:1-12
[2]Strader DB,Wright T,Thomas DL,and Seeff LB.Diagnosis,management,and treatment of hepatitis C.Hepatology,2004,39:1147-1171
[3]Hu KQ.Occult hepatitis B virus infection and its clinical implications.J Viral Hepat,2002,9:243-257
[4]陈国民,袁平戈.乙型肝炎病毒致病机制的新概念[J].现代医药卫生.2007,23(11):1581
[5]程斌,林松挺,杨玉珍.HBx致肝细胞癌分子机制的研究进展.世界华人消化杂志.2007,15(20):2242-2248
[6]徐道振,巫善明,周霞秋主编.病毒性肝炎临床实践.第1版.北京:人民卫生出版社,2006,140-141
[7]何绮娜.原发性肝癌与病毒性肝炎、肝硬化关系的探讨.河北医药,1986,8:135-136
[8]中华医学会传染病与寄生虫病学分会,肝病学分会.病毒性肝炎的诊断.中西医结合肝病杂志,2001,11:56-60
[9]美国肝病学会,美国感染病学会.美国慢性乙型肝炎病毒感染处理流程.中华传染病杂志,2006,9:2-5
[10]薛蓉,周镇先,王建芳.HBV基因型及P基因变异与拉米夫定耐药的关系.临床肝胆病杂志.2005,21(6):399-340
[11]王晶晶,刘宝芳,桂秀海,等.胃液中乙肝病毒指标检测结果分析[J].山西医学院学报,1995,26(4):334-335
[12]Gunther S,Sommer G,lwaska A,et al.Heterogeneity and common feature 是 of defective hepatitis B virus genomes derived from spliced pregenomic RNA.Virology,1997,238(2):363
[13]Thursz MR,Kwiatkowski D,Allsop CE,et al.Association between an MHC classⅡ allele and cleanrance of hepatitis B virus in the Gambia.N Engl J MED,1995,332:1065
[14]万谟彬.慢性乙型肝炎治疗的现状及前景[J].中华传染病杂志,2002,20(1):57-59
[15]王季午,刘克洲,陈智.人类病毒性疾病[M].北京:人民卫生出版社,2002,489
[16]陈湖光,余春艳,孟雪芹.病毒性肝炎患者血清IL-4、IL-12及IFN-a水平的观察[J].中华传染病杂志,2001,10(5):313
[17]宋瑞楼.肝炎、肝硬化与肝癌[M].台北:橘井文化事业股份有限公司,2006,139
[18]邬祥惠.慢性肝炎的发病机理和治疗.现代实用医学,2001,13(1):5-8
[19]Takano S,Yokosuka O,Imazeki F,Tagawa M,Omata M.Incidence of hepatocellular carcinoma in chronic hepatitis B and C aprospective study of 251 patients.Hepatology 1995,21:650-655
[20]Kagi D,Ledermann B,Burki K,Zinkemagel RM,Hengartner H.M o lecular mechanisms of Iymphocyte-mediated cytotoxicity and their role in immunological protection and pathogenesis in vivo.Annu Rev Immunol 1996,14:207-232
[21]Lohr HF,Krug S,Herr W,Weyer S,Schlaak J,Wo]fel T,Gerken G,Meyer zum Buschenfelde KH.Quantitative and functional analysis of core-specific T-helper cell and CTL activities in acute and chronic hepatitis B.Liver 1998,18:405-413
[22]Chisari FV,Ferrari C,Hepatitis B virus immunopathogenesis.Annu Rev Immunol 1995,13:29-60
[23]张瑞,赵彤言,顾长海.不同类型乙型肝炎病毒感染者体内毒株存在状况与临床转归[J].中华传染病杂志,2001,10(5):313
[24]周光德,赵景民.细胞外基质在肝内的代谢与肝纤维化的形成.世界华人消化杂志,2002,10:57-59
[25]李才.器官纤维化:基础与临床[M].北京:人民卫生出版社,2003:58-62
[26]LAMIREAU T,DESMOULIERE A,BIOULACSAGE P,et al.Mechanisms of hepatic fibrogenesis[J].Arch Pediatr,2002,9(4):392-405
[27]TAUB R.Liver regeneration:from myth to mechanism[J].Nat Rev Mol Cell Biol,2004,5(10):836-847
[28]程明亮,刘三都,主编.肝纤维化的基本概况[M].肝纤维化的基础及临床.第1版.北京:人民卫生出版社,1996.1-16
[29]Bataller R,Brenner D A.Liver fibrosis[J].J Clin Invest,2005,115:209
[30]范建高.非酒精性脂肪肝的临床病学研究[J].中国消化杂志,2002,22(2):106-107
[31]Geert A.History,heterogeneity,developmental biology,and funetion of quiescent hepatic stellate cells[J].Semin Liver Dis,2001,21(3):311-335
[32]Alcolodo R.Pathogenesis of liver fibrosis[J].Clin Sci,1997,92:103
[33]Friedman S L.Molecular regulation of hepatic fibrosis,an integrated cellular response to tissue injury[J].J Biol Chem,2000,275(4):2247-2250
[34]LI D,Fridman SL.Liver fibrogenesis and the role of hepatic atellate cells:new insights and prospects for therapy[J].J Gastroenterol Hepatol,1999,14:618
[35]G-ressner -AM.Cytokines and cellular crosstalk involved in the activation of fat-storing cells.[J]J Hepatol,1995,22(2 suppl):28-36
[36]Friedman S L.Mac the knife? Macrophages-the-double-edged sword of hepatic fibrosis[J].J Clim invest,2005,115(1):29-32
[37]熊伍军,邱德凯.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
[38]许青.转化生长因子B与肝纤维化[J].国外医学·消化疾病分册,1998,18(3):155
[39]Geremias S L,Carvalho M A,Borojevicr,et al.TGF betal and PDGF AA override Collagen type Ⅰ inhibition of proliferation in human liver connective tissue cells.BMC Gastroenterology,2003,4:30
[40]Wang X,Chen YX,Xu CF,Zhao GN,Huang YX,Wang QL.Relationship between tumor necrosis factor-α and liver fibrosis.World J Gastroenteral,1998,4:18
[41]Lamck JW.Wright ST.Cytotoxic mechamisms of tumor necrosis factor-α.FASEB J,1990,4:3215
[42]Sprenger H,Kaufrnann A,Gam H.Differential expression of monocyte chemotactic protein-l(MCP-1) in transforming rat hepatic stellate cells.J Hepatol,1999,30:88-94
[43]Sprenger H,Kaufrnann A,Gam H,Lahme B,Gernsa D,Gressner AM.Induction of neutrophil-attracting chemokines in transforming rat hepatic stellate cells.Gastrventerology,1997,113:277-285
[44]Wang Y J,Sun ZQ,Quan QZ,Yu JJ.Fat-storing cells and liver fibrosis.China Natl J New Gastroenterol,1996,2:58-60
[45]Yoshi ji H,Noguchi R,Kuriyama S,et al.Imatinib mesylate(STI-571)attenuates liver fibrosis development in rat[J].Am J Physiol Gastrointesl Liver Physiol,2005,288(5):G907-13
[46]Amakawa M,Endo Y.The motility of hepatic Ito cells can be acquired by their myofibroblastic transformation[J].Arch Histol Cytol,2002,65(2):169-178
[47]Garloni V,Romanelli RG,Pinzani M,et al.Focal adhesion kinase and phospholipase C gamma involvement in adhesion and migration of human hepatic stellate cells[J].Gastroenterology,1997,112(2):522-531
[48]金伯泉,主编.细胞和分子免疫学[M].第二版.北京科学出版社,2001,:10
[49]赵霞,姚希贤.白介素与肝纤维化[J].中国全科医学,2006,9(10):853-855
[50]Kovalavich K,Deangelis-RA,Li W,et al.Increased toxin-induced liver injury and fibrosis in interleukin-6-deficient mice[J].Hepatology,2000,31:149-159
[51]Stoat DE,Vincent K J,Authur MJPE,et al.Jun D regulates transcription of the tissue inhibitor of metalloproteinase-1 and interleukin-6 genes in actived hepatic stellate cells[J].Bio Chert,2001,276(26):24412-24421
[52]陈治新,王小从,张莉娟,等.IL-10对实验性肝纤维化大鼠血小板衍生生长因子-AA、BB表达的影响[J].临床消化病杂志,2003,15(3):99-101
[53]李光明,李定国.结缔组织生长因子与肝纤维化[J].国外医学.消化系疾病分册,2004,24(4):198-200
[54]Paradis V,Dargere D,Vidaud M,et al.Expression of connective tissue growth factor in wxperimental rat and human lever fibrosis[J].Hepatology,1999,30(4):968-976
[55]王要军,孙自勤,权启镇.参与肝纤维化的细胞因子.中国煤炭工业医学杂志,2000,3(1):4-5
[56]内皮素-1对肝脏的多种作用[J].国外医学·消化系统病,1997,17(3):167
[57]Sanz S,Pucilowska J B,Lin S.Expression of insulin-like growth factor I by activated hepatic stellate cells reduces fibrogenesis and enhances regeneration after liver injury[J].GUT,2005,54(1):134-141
[58]Van Eyken P,Seiot R,Desmet VJ,et al.Expression of the novel extra-cellular matrix component tenascin in normal and Diseased human liver.An immunohisto-chemical study[J].J HePatol,1990,11(1):42-5
[59]李成忠,等.非创伤性诊断指标优势组合对肝纤维化诊断价值的初步研究[J].中华肝脏病杂志,2001,9(5):261
[60]王新.肝硬变患者血清层粘连蛋白水平的变化[J].第四军医大学学报,1997,18(3):254
[61]Murawakai Y,Nishimura Y,Ikuta Y,et al.Plasma transforming growth factor-betal concentrations in patients with chronic viral hepatitis[J].J Gastrolenterol Hepatol,1998,13:680
[62]Kim T,Mars W,Stolz D,et al.Expression and activation of pro-MMP-2and pro-MMP-9 during rat liver regeneration[j].Hepatology,2000,31(1):75-78
[63]刘磊.整合素与肝纤维化[J].国外医学流行病学传染病学分册,2003,30(1):31-33
[64]龚作炯,宋仕玲,黄砚青,等.血管紧张素Ⅱ受体拮抗剂对大鼠肝纤维化的疗效及作用机制[J].肝脏,2004,9(2):97-100
[65]申凤俊,朱跃科,李琴,等.肝纤维化形成过程中肾素-血管紧张素系统的变化[J].肝脏,2003,8(4):24-26.
[66]王会丽,蒋维晟,苑军正.浅谈慢性乙型肝炎肝纤维化病因病机和治疗.江西中医药,2006,3(27):11-12
[67]刘平.现代中医肝脏病学[M].北京:人民卫生出版社,,2001,3
[68]唐智敏,茹清静,张振鄂,等.肝血瘀阻与肝纤维化关系的临床研究[J].中国中西医结合杂志,1997,17(2):81-83
[69]林小田,骆抗先,冯筱榕,等.慢性乙型肝炎临床与病理分级、分期的对比分析.[J]中华内科杂志,1998,37(7):437-439
[70]骆抗先.乙型肝炎临床与活性组织病理[M].第2版.北京:科学出版社,2001:81-86
[71]林小田.慢性肝炎临床诊断标准的探讨[J].广东医学院学报,2001,16(1):52
[72]张淑玲,董继华.慢性肝炎乙型抗病毒的研究进展[J].病毒学杂志,2006,13(6):179
[73]Cooksley WG.Peginterferon-alpha α-2a for the treatment of hepatitisB infection Expect Opin pharmacother,2005,6(8):1373-1380
[74]程有香.慢性肝炎乙型抗病毒治疗[J].中国城乡企业卫生,2007,6(12):48-49
[75]秦成勇,韩国庆.我国乙型肝炎的治病现状及治疗进展[J].医学前沿,2007,36(1):22-24
[76]叶丽红.浅谈慢性乙型肝炎的中医辨证治疗[J].辽宁中医杂志,2002,11(11):661
[77]汪静,杨秀华,谢朝良,等.辨舌分型治疗无临床症状慢性乙型肝炎42例.泸州医学院学报,2003,26(1):25
[78]胡金娣.自拟益气活血汤治疗慢性乙肝的效果观察.中医中药,2007,4(6):59
[79]冯圣林.自拟健脾益肾解毒活血汤治慢性乙肝56例.四川中医,2002,20(9):45
[80]马秀丽,刘耀明,刘霞.丹参在慢性肝炎治疗及复发预防中的作用探讨[J].临床医学,2000,20(5):42-43
[81]范锡伟.苦参素治疗慢性乙肝临床观察[J].山东医药,2005,45(25):72-73
[82]吴沛田.天花粉治疗慢性乙型肝炎[J].中医杂志,2006,47(9):651
[83]吴明,颜开华.灯盏花联合苦参素治疗慢性乙肝50例临床观察[J].哈尔滨医药,2007,27(1):23-24
[84]王宝恩,张定凤,主编.现代肝脏病学[M].第1版.北京:科学出版社,2003,513
[85]骆抗先,主编.乙型肝炎-基础和临床[M].第一版.北京:人民卫生出版社,1997,370
[86]朗江明,主编.临床免疫诊断学[M].第一版.广州:广东科技出版社,2003,61
[87]1995年5月北京第五次全国传染病寄生虫学术会议讨论修订.病毒性肝炎防治方案(试行).中华传染病杂志,1995,13(4):241-247
[88]2000年9月西安中华医学会传染病与寄生虫病学分会、肝病学会分会联合修订.病毒性肝炎防治方案
[89]Scheuer PJ.Classification ofchornic viral hepatitis:a need for reassessment.J Hepatol,1991,13:372
[90]Halfon P,Bourliere M,Penaranda G,et al.Accuracy of hyaluronic acid level for predicting liver fibrosis stages in patients with hepatitis C virus.Comparative hepatology,2005,4:6 dio:10.1 186/1476-5926-4-6
[91]Montazeri G,Estakhri A,Mohamadnejad M,et al.Serum hyaluronatc as a non-invasive marker of hepatic fibrosis and inflammation in HbeAg-negative chronic hepatitis B.BMC gastroenterology,2005;5:32doi:10.1 186/1471-230×/5/32
[92]Plevris JN,Haydon GH,Simpson KL,et al.Serom hualuronan-a non-invasive test for diagnosing liver cirrhosis.European journal of gastroenterology&hepatology,2000,12:121-1127
[93]Desmet Murawaki Y,Iknta Y,Koka M,et al.Clinical significance of serum hyaluronan in patients with chronic viral liver disease.Journal of gastroenterology and hepatoloigy,1996,11:459-465
[94]董永杰,彭彦辉,赵晓云,等.肝纤维化血清学诊断方法的研究进展.医学综述,2007,13(2):1743-1745
[95]Zachariae H,Heickendorff L,Sogaard H.The value of aminoterminal propeptide of type Ⅲ procollagen in routine screening for methotrexate-induced liver fibrosis:a 10-year follow up.Br J Dermato 2001;144:100-103
[96]Hironaka K,Sakaida I,Uchida K,Okita K.Correlation between stellate cell activation and serum fibrosis markrs in choline-deficient L-amino acid-defined diet-induced rat liver fibrosis.Dig Dis Sci 2000;45:1935-1943
[97]Kauschke SG,Knorr A,Heke M,Kohlmeyer J,Schauer M,Theiss G,Waehler R,Burchardt ER.Two assays for measuring fibrosis:reverse transcriptase-polymerase chain reaction of collagen alpha(1)(Ⅲ) mPNA is an early predictor of subsequent collagen deposition while a novel serum N-terminal procollagen(Ⅲ) propeptide assay reflects manifest fibrosis in carbon tetrachloride-treated rats.Anal Biochem 1999;275:131-140
[98]Walsh KM,Fletcher A,Macsween RN,Morris AJ.Comparison of assays for N-amino terminal propeptide of type Ⅲ procollagen in chronic hepatitis C by using receiver operating characteristic analysis.Eur J Gastroenterol Hepatol 1999;11:827-831
[99]Stickel F,Urbaschek R,Schuppan D,Poeschl G,Oesterling C,Conradt C,McCuskey RS,Simanowski UA,Seitz HK.Serum collagen type Ⅵ and ⅩⅣ and hyaluronic acid as early indicators for altered connective tissue turnover in alcoholic liver disease.Dig Dis Sci 2001;46:2025-2032
[100]Serejo F,Costa A,Oliveira AG,Ramalho F,Batista A,De Moura MC.Alpha-interferon improves liver fibrosis in chronic hepatitis C:clinical significance of the serum N-terminal propeptide of procollagen type Ⅲ.Dig Dis Sci 2001;46:1684-1689
[101]李小维,苌新明.血清Ⅳ型胶原在肝纤维化诊断中的意义[J].西安医科大学学报,2000,21(5):431-432
[102]谢仕斌,姚集鲁,郑树森,等.血清肝纤维化指标水平与肝组织纤维图像分析的关系[J].中华肝脏病杂志,2000,8(4):203-205
[103]李永强,蔡伊梅.血清Ⅳ型胶原诊断肝纤维化的价值[J].上海第二医科大学学报,2000,20(5):455-457
[104]柴明胜.肝病诊断新标志-血清Ⅳ型胶原[J].上海医学检验杂志,1995,10(3):182
[105]张世兰,杨永平,李亚洁,等.肝病患者层粘连蛋白的检测及临床意义.第一军医大学学报,2000,20(4):313-314
[106]Castera L,Hartmann DJ,Chapel F,Guettier C,Mall F,Lons T,Richardet JP,Grimbert S,Morassi O,Beaugrand M,Trinchet JC.Serum laminin and type Ⅳ collagen are accurate markers of hitologically severe alcoholic hepatitis in patients with cirrhosis.J Hepatol 2000, 32:412-418
[107]侯振江,张宗英,周秀梅.蛋白标记物在肝纤维化研究中的应用[J].中华肝脏病杂志,1998,14(4):200
[108]郝菁华,石军,任万华,等.血清透明质酸水平与肝脏微循环状况的关系[J].临床肝胆病杂志,2002,18(1):35-37
[109]Okazaki I,Watanabe T,Hozawa S,et al.Molecular mechanism of the reversibility of hepatic fibrosis:with special reference to the role of matrix metalloproteinases[J].J Gastroenterol Hepatol,2000,15:D26-32
[110]黄宇琦,高毅.鼠肝纤维化基质金属蛋白酶及其抑制因子的表达[J].世界华人消化杂志,1999,7(9):795-796
[111]何云,王建宾,王宇明.慢性肝炎肝纤维化程度诊断方法的进展[J].世界华人消化杂志,2001,9(11):1305
[112]何云,王建宾,王宇明.肝纤维化程度诊断方法的评价[J].成都军区医学院学报,2002,4(3):35
[113]张平,李勤光,高永琳.转化生长因子β1与病毒性乙型肝炎患者肝细胞损伤和肝纤维化的关系[J].传染病信息,2004,1(17):29
[114]张立煌,方海林,裘云庆,等.病毒性肝炎患者血清转化因子-β1活性及其与纤维化的关系[J].中华传染病杂志,1997,15(2):82-84
[115]Eghbali-Fatourchi G,Sieck GC,Prakash YS,et al.Type Ⅰprocollagen production and cell proliferation is mediated by transforming growth factor-β in a model of hepatic fibrosis.Endocrinology,1996,137(5):1879-1903
[116]俞海英,杨毅军,陈彦,等.血小板衍生生长因子对慢性重型肝炎预后评估的临床意义[J].临床荟萃,2003,18(16):901-904
[117]张慧芸,吕卉,李新民,等.α-干扰素治疗慢性乙型肝炎纤维化的疗效观察[J].中华肝脏病杂志,2003,11(2):117-118
[118]Cooksley G.The treatment of hepatitis B e antigen-positive chronic hepatitis B with pegylated interferon[J].J Hepatol,2003,39(1):143-145
[119]张岩,白雪帆,李艳红,等.拉米夫定治疗慢性乙型肝炎的疗效及肝组织学改变[J].中国误诊学杂志,2006,5(5):804-806
[120]Bataller R,Brenner DA.Hepatic stellate cells as target for the treatment of liver fibrosis[J].Semin Liver Dis,2001,21(3):437-451
[121]谭海荣,吴谦,潘竞锵,等.水飞蓟素对抗大鼠酒精性脂肪肝作用及机制[J].中国临床药理学与治疗学,2004,9(7):803-806
[122]Boigk G,Stroedter L,Herbst H,et al.Silymarin retards collagen accumulation in early and advanced biliary fibrosis secondary to complete bile duct obliteration in rats[J].Hepatology,1997,26(3):643-649
[123]刘海成,李风华,陈文慧,等.甘草酸二铵对肝纤维化大鼠肝脏脂质过氧化与间质性胶原酶火星的影响[J]..中国病理生理杂志,2005,21(3):2233-2237
[124]许倩,许建娟.腺苷蛋氨酸治疗妊娠肝内胆汁淤积症疗效探讨[J].中国优生与遗传杂志,2004,12(1):83-84
[125]汪余勤,程五凤,李宣海.维生素E与肝纤维化[J].临床肝胆病杂志,2000,16(1):19
[126]Dogru Abbasoglu S,Balkan J,Kanbagli O,et al.Aminoguanidineian inducible nitric oxide synthase inhibitor,plus N-acetylcysteine treatment reduce the lipopolysaccharide-augmented hepatotoxicity in rats with cirrhosis[J].Hum Exp Toxicol,2002,21(7):359-364
[127]Vendemiale G,Grattagliano I,Caruso ML,et al.Increased oxidative stress in dimethylnitrosamine-induced liver fibrosis in the rat:effect of N-acetylcysteine and interferon-alpha[J].Toxicol Appl Pharmacol,2001,175(2):130-139
[128]Kim KY,Rhim T,Choi I,et al.N-acetylcysteine induces cell cycle arrest in hepatic stellate cells through its reducing activity[J].J Biol Chem,2001,276(44):40591-40598
[129]Meurer SK,Lahme B,Tihaa L,et al.N-acetyl-L-cysteine suppresses TGF-beta signsling at distinct molecular steps:the biochemical and biological efficacy of a multifunctional,antifibrotic drug[J].Biochem Pharmacol,2005,70(7):1026-1034
[130]Arrieta O,Rodriguez JL,Rosaa V,et al.Clchicine delays the development of hepatocellular carcinoma in patients with hepatitis virus related liver cirrhosis[J].Cancer,2006,107(8):1852-1858
[131]程书权.肝纤维化的现代药物治疗研究[J].中国处方药,2005,3(5):36-40
[132]阳学风,曾明新,张明亮,等.马洛替酯抑制肝纤维化的实验与临床研究[J].世界华人消化杂志,1999,7(3):224-226
[133]何方平,孙惠蓉,张跃新,等.四种药物对大鼠肝纤维化的实验与临床研究[J].新疆医科大学学报,2003,26(4):338
[134]Keiding S,Badsberg JH,Becket U,et al.The prognosis of patients with alcoholic liver disease.An international randomized placebO-con-trolled trial on the effect of malotilate on survival[J].J.Hepatol,1994,20(4):454-460
[135]Zou WL,Yang Z,Zang YJ,et al.Inhibitory effects of prostaglandin E1 on activation of hepatic stellate cells in rabbits with schistosomiasis[J].Hepatobillary Pancreate Dis Int,2007,6(2):176-181
[136]Hui AY,Dannenberg AJ,Sung JJ,et al.Prostaglandin E2 inhibits transformaing growth factor beta 1 mediated induction of collagen alpha(1) in hepatic stellate cells[J].J Hepatol,2004,41(2):251-258
[137]沃明黔.前列腺素E1-治疗肝纤维化疗效观察[J].航空航天医药,2002,13(4):230
[138]邹卫龙,杨镇,吴健,等.前列腺素E-1抑制血吸虫病家兔肝脏星状细胞活化研究[J].中华实验外科杂志,2004,21(12):1468-1470
[139]Lieber CS.New concepts of the pathogenesis of alcoholic liver disease lead to novel treatments[J].Curr Gastroenterol,2004,6(1):60-65
[140]Austin AS,Mahida YR,Clarke D,et al.A pilotstudy to investigate the use of oxoentifylline and thalidomide in portal hyperten-sion secondary to alcoholic cirrhosis[J].Aliment Pharmacol Ther,2004,19(1):79-88
[141]Isbrucker RA,peterson TC.Platelet-derived growth factor and pentoxifylline modulation od collagen synthesis myofibroblasts[J].Toxico Appl Pharmacol,1998,149(1):120-126
[142]Akriviadis E,Botla R,Briggs W,et al.Pentoxifylline improves short-term survival in severe acute-alcoholichepatitis;double-blind,placebo-con-trolledtrial[J].Gastroenterology,2000,119(6):1637-1648
[143]Matsuda Y,Matsumoto K,Yamada A,et al.Preventive and therapeutic effects in rat of hepatocyte growth factor infusion on liver fibrosis cirrhosis[J].Hepatology,1997,26(1):81-89
[144]吴国春,何忠华,王雄.不同剂量促肝细胞生长素治疗肝硬化血清肝纤维化指标的变化[J].江苏医药,2003,29(6):456-458
[145]刘平,王晓玲,刘成.丹酚酸A对成纤维细胞活力、增生及胶原合成的影响[J].中西医结合肝病杂志,2000,10(1):24-25
[146]张荣华,周子成,洪多伦,等.三七抗肝纤维化的实验研究[J].第三军医大学学报,2000,22(4):307
[147]程鹏,刘索侠.黄芪抗肝纤维化的作用与转化生长因子β1及干扰素γ的关系[J].临床军医杂志,2000,28(3):32
[148]李延昌,孙玉凤,冯志杰,等.赤芍抗肝纤维化的实验研究[J].中国中西医结合杂志,2003,23(10):767
[149]许正锯,黄以群,张启华,等.大黄对慢性肝炎抗肝纤维化的临床研究[J].中华传染病杂志,2004,22(3):202
[150]展玉涛,李定国,王志荣,等.大黄素对大鼠肝纤维化形成的影响[J].中国中西医结合杂志,2000,20(4):276-278
[151]马雄,邱德凯.冬虫夏草多糖脂质体抗纤维化的实验研究[J].中国中医基础医学杂志,1999,5(9):28-30
[152]李旭东,王树槐.扶正化痰中药体外对大鼠纤维肝肝细胞蛋白质合成、分泌的影响[J].中成药,2001,23(4):274-277
[153]茹清静,唐智敏,张振鄂,等.血府逐瘀汤治疗慢性乙型肝炎肝纤维化患者的临床研究[J].中国中西医结合杂志,2004,24(11):983-985
[154]宋家五,李绍白.血府逐瘀汤分解方抗肝纤维化作用的研究[J].中西医结合肝病杂志,1995,5(2):23-25
[155]张晓平,陈建民,强势平.血府逐瘀汤抗血吸虫致小鼠肝纤维化的实验研究[J].中医杂志,2003,44(4):299-300
[156]李宁,吴圣东.大黄蛰虫丸辅助治疗慢性肝病肝纤维化46例[J].中国中西医结合杂志,2002,22(11):866
[157]赵治友,姚真敏,钟庆平,等.鳖甲煎丸对慢性肝病肝纤维化治疗作用的临床研究[J].新中医,2005,37(4):29-30
[158]周光德,李文书,赵景民,等.复方鳖甲软坚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
[159]任小巧,卢跃卿,陈永旭,等.仲景三方对大鼠肝纤维化不同时期血清型前胶原透明质酸及层粘蛋白作用的观察[J].北京中医药大学学报,2001,24(3):35-37
[160]张晓斌.柔肝补肾健脾活血法治疗肝纤维化72例分析[J].实用中医内科杂志,2003,17(5):406-407
[161]陈琰碧,杨宏志,许瑞云,等.补肾益气舒肝凉血活血方对乙型肝纤维化患者免疫功能的影响[J].中国中医基础医学杂志,1998,4(11):30-31
[162]陈爽,贲长恩,杨美娟.柴胡皂甙对肝细胞增殖及基质合成的实验研究[J].中国中医基础医学杂志,1999,5(5):21
[163]贾道全,张正,罗成福,等.甘草甜素逆转肝纤维化及早期肝硬化的作用探讨[J].中华消化杂志,2001,21(12):754-756
[164]陈伟忠,张俊平.苦参碱对大鼠实验性肝纤维化作用的实验研究[J].第二军医大学学报,1996,17(5):424-426
[165]Park PH,Nan JX,ParkE J,et al.Effect of tetrandrine on experimental hepatic fibrosis induced by bile duct ligation and scission in rats[J].Pharmacol Toxicol,2000,87:261-268
[166]陈岳祥,李石,张兴荣,等.牛磺酸对四氯化碳诱导大鼠肝纤维化的抑制作用[J].中华消化杂志,1999,19(3):185
[167]Lee T Y,Wang G J,Chiu J H,et al.Long-term administration of Salvia miltiorrhiza ameliorates carbon tetrachloride-induced hepatic fibrosis in rats[J].J Pharm Pharmacol,2003,55(11):1561-1568
[168]胡晓峰,刘斌,张敏,等.家兔肝纤维化模型的模型的建立及肝功能指标与肝纤维化的相关性[J].实用肝脏病杂志,2007,10(3):152-154
[169]庞荣清,刘建昆,何占龙,等.猕猴肝纤维化模型建立与评价[J].世界华人消化杂志,2005,13(16):1956-1958
[170]Vendemiale G,Grattaagliano I,Caruso M L,et al.Increased oxidative stress in dimethylnitrosamine-induced liver fibrosis in the rat:effect of N-acetylcysteine and interferon-alpha[J].Toxicol Appl Pharmacol,2001,175(2):130-139
[171]吴丽,魏伟.肝纤维化的动物模型及治疗药物研究[J].中国药理学通报,2004,20(5):481-485
[172]Jonker A M,Dijkhuis F,Hardonk M J,et al.Immunohisto-chemical study of hepatic fibrosis induced in rats by multiplegalactosamine injections[J].Hepatology,1994,19(3):775-781
[173]杨文卓,曾民德,范竹萍,等.氧化苦参碱防治半乳糖胺诱导大鼠肝纤维化的实验研究[J].中华肝脏病杂志,2002,10(3):193-196
[174]杨文卓,曾明德.肝纤维化的发病机制及病理生理[J].国外医学·消化系统疾病分册,2000,20(4):216-220
[175]Liebe R C S,DeCarli I M.The feeding of ethanol liquid diets[J].Alcohol Clin Exp Res,1986,10(5):550-553
[176]Tsukamoto H,Reidelberger R D,French S W,et al.Long term cannulation model for blood sampling and intragastric infusion in the rat[J].Am J Physiol,1984,247(3 Pt2):R595-R599
[177]Kamimura S,Sohda T,Shijo H,et al.Hepatic fibrosis in rats fed a liquid diet with ethanol and carbonyl iron[J].Int Hepatol Commu,1995,3(2):70-76
[178]洪洋懿,阳学风,雷军,等.乙酰肝素酶在大鼠酒精肝纤维化中的表达及其意义[J].世界感染杂志,2007,7(3):207-210
[179]丁霞,蒙一纯,责长恩.等.酒精性肝纤维化动物模型的建立[J].中国中医基础医学杂志,1999.5(7):47-48
[180]Haratake J,Hisaoda M,Yamamoto O,et al.Morphological changes of hepatic microcirculation in experimental rat cirrhosis:a scanning electron microscopic study[J].Hepatology,1991.13(5):952-956
[181]Mori T,Okanode T,Sawa Y,et al.Defenestration of the sinusoidal endothelial cell in a rat model of cirrhosis[J].Hepatology,1993,17(5):891-897
[182]朱起贵,方步武.吴贺算,等.牛血清白蛋白致免疫损伤性肝纤维化动物模型的研究[J].中华病理学杂志,1993,22(2):121
[183]Santra A,Chowdhury A,Ghosh A,et al.Development of an animal model of hepatic fibrosis by excretory-secretory antigen of Ascaris suum[J].Indian J Gastroenterol,2000,19(3):119-121
[184]程明亮,杨长青.肝纤维化的基础研究及临床[M].2版.北京:人民卫生出版社,2002:366-367
[185]李培建,梁保忠,王爱民,等.四氯化碳、人血自蛋白所致大鼠肝纤维化动物模型的实验研究[J].实验动物科学与管理,2000,17(2):32-34
[186]Tiegs G,Hentschel J,Wendel A.A T cell—dependent experimental liver injury in mice inducible by concanavalin A[J].J Clin Invest,1992,90(1):196-203
[187]李鸿立,田聆,魏于全,等.刀豆素蛋白A诱导小鼠肝纤维化模型的建立[J].免疫学杂志,2004,20(5):390-392,396.
[188]阴宏,马红,刘乃慧,等.大鼠胆管阻塞性肝纤维化模型的建立[J].实验动物科学与管理,2002,19(2):1-3
[189]陈智.乙型肝炎病毒cccDNA研究现状[J].中华传染病杂志,2003,21(1):8-10
[190]Yang W,Mason WS,Summers J.Covalenfly Closed Circular Viral DNA Formed from Two Types of Linear DNA in Woodchuck Hepatitis Virus-Infected Liver[J].J Virol of Virology,1996,70(7):4567-4575
[191]Chou YC,Jeng KS,Chen ML,et al.Evaluation of transcriptional efficiency of hepatitis B virus covalently closed circular DNA by reverse transcription·-PCR combined with the restriction enzyme digestion method[J].J Virol,2005,79(3):1813-1823
[192]Summers J,Smith PM,Horwich AL.Hepadnavirus envelope proteins regulate covalendy closed circular DNA amplicatlon[J].J Virol,1990,64(6):2819-2824
[193]LeeKS,Lee SJ,ParkHJ,Chung JP,HanKH,Chon CY,Lee SI,Moon YM.Oxidative stress effect on the activation of hepatic stellate cells[J].Yonsef Med,2001;42:1-8
[194]Gressner AM,Pohar B,Lahme B,M annherz HG.Induction of rat liver parenchymal cell apoptosisby hepatic myofibroblasts via transforming growth factor beta[J].HepatoloRy 1996;23:571-581
[195]李莉娜,贾心善.肝脏星状细胞与细胞外基质、金属蛋白酶的研究进展[J].日本医学介绍 2002;23(10):139-141
[196]Greenwel P,Roikind M.Accelerated development of liver fibrosis in CC14-treated rats by the weekly induction of acute phase response episodes:upregulation of alphal(Ⅰ) procollagen and tissue inhibitor of metall-oproteinase-1 mRNAs[J].Biochim Biophvs Acta 1997:1361:177-184
[197]Wells RG.Fibrogenesis.V.TGF—beta signaling pathways[J].Am J Phvsiof Gastrointest Liver Phvsiol 2000:279:G845-G850
[198]Iredale J,Benyon RC,Picketing J,et al.Mechanisms of spontaneous resolution of rat liver fibrosis:Hepatic stellate cell apoptosis and reduced hepatic expression of metalloproteinase inhibitors[J].J Clin Invest,1998,102(3):538-549
[199]Kishibe K,Yamada Y,Ogawa K,et al.Production of nerve growth factor by mouse hepatocellular carcinoma cells and expression of TrkA in tumor —associated arteries in mice[J].GastroenteroIogy,2002,122(7):1978-1986
[200]Fiona Oakley,Nathan Trim,Christothea M,et al.Hepatocytes express nerve growth factor during liver injury[J],Am J Pathol,2003,163(5):1849-1858
[201]Fischer R,Schmltt M,Bode J G,et al.Expression of the peripheral-type benzodiazepine receptor and apoptosis induction in hepatic stellate cells[J].GastroenterOlogy,2001,120(5):1212-1226
[202]Gong WR.Pecci A,Roth S.et al.Transformation-dependent susceptibility of rat hepatic stellate cells to apoptosis induced by soluble fas-ligand[J].Hepatology,1998·28(2):492-502
[203]Salle B,Matthes N,Knittel T,el al.Transforming growth factor beta and tumor necrosis factor alpha inhibit both apoptosis and proliferation of activated rat hepatic stellate cells[J].Hepatology·1999,30(1):196-202
[204]Taimr P,Higuchi H,Kocova E,et al.Activated Stellate cells express the TRAIL receptor-2/death receptor-5 and Undergo TRAIL-mediated apoptosis[J].Hepatology,2003,37(1):87-95
[205]Gressner AM.The up-and-down of hepatic stellate cells in tissue injury:apoptosis restores cellular homeostasis [J].Gastroenterology,2001,120(5):1285-1288
[206]刘建虎.肝窦星状细胞的激活与凋亡[J].实用肝脏病杂志,2003,6(1):50-52
[207]赵东强,姜慧卿,修贺明,等.丹参单体IH764-3对肝星状细胞增殖与凋亡的影响.中华肝脏病杂志,2002,10(4):265-274
[208]Carloni V,Romanelli RG,Pinzani M,et al.Focal adhesiion kinase and phospholipase C gamma involvement in adhesion and migration of human hepatic stellate cells[J].Gastroenterology,1997,112:522-531
[209]张晓岚,姜慧卿,刘丽,等.丹参单体IH764-3诱导肝星状细胞凋亡[J].中华内科杂志,2002,41(9):616-617
[210]田雄英,翁山耕,程协枝,等.苦参碱对大鼠肝星状细胞增殖和凋亡的影响[J].肝脏,2005,10(2):95-97
[211]Araujo CC,Leon LL.Biological activities of Curcuma longa L.Mem 25 Inst Oswaldo Cruz,2001,96:723-728
[212]何雅军,舒建昌,吕霞,等.姜黄素预防肝纤维化作用与肝星状细胞的关系[J].中华肝脏病杂志,2006,14(5):337-340
[213]尤红,王宝恩,王泰龄,等.复方861对肝星状细胞的增殖和凋亡的干预作用[J].中华肝脏杂志,2000,8(2):78-80
[214]尤红,王宝恩,马雪梅.中药复方861对肝星状细胞NF-gB活性的体外研究[J].中华肝脏杂志,2001,9(2):73-74
[215]赵英恒,何兴祥.复方利肝冲剂药物血清对肝星状细胞NF-kB结合活性的抑制作用[J].世界华人消化杂志,2002,10(1):95-96
[216]Olson D,Pollanen J,Hoyer-Hansen G,Ronne E,et al.Internalization of the urokinase-plasminogen activator inhibitor type-1 complex is mediated by the urokinase receptor[J].J Biol Chem,1992,267:9129-9133
[217]陈香美.凝血纤溶系统与细胞外基质调控系统在肾脏疾病中的作用[J].中华肾脏病杂志,2001;17(3):348-349
[218]Brauer PR.M M Ps role in cardiovascular development and disease[J].Front Biosc,2006,11:447-478
[219]Malemud CJ.Matrix metalloproteinases(MMPs) in health and disease:an overview[J].Front Biosc,2006,11:1696-1701
[220]崔红燕,刘成,刘成海.纤溶系统与肝纤维化的研究进展[J].中两医结合肝病杂志,2003;13(2):316-318
[221]Irigoyen JP,M unoz,Canoves P,et al.The plasminogen activator system:biology an d regulation[J].CPl Mol Life Sc,1999,56:104-132
[222]Leyland H,Gentry J,Arthru M,et al.The Plasminogen activating system in hepatic stellate cells[J].Hepatology,1996,24:1172-1178
[223]Murphy G,Atkinson S,Gavrilovic J,et al.The role of plasminogesn activators in the regulation of connective tissue metalloproteinase[J].Amm N Y Acad Sci,1992,667:1-12
[224]Thomton A,Bruzdainski C,Raper S,et al.Plasminogen activator inhibitor-1 is an immediate early response genein regenerating rat liver[J].Cancer Res,1994,54:1337-1343
[225]Li P,Terumi T,Yutaka Y,et al.Increased expression of plasminogen activator and plasminogen activator inhibitor during liver fibrogenesis of rats:role of stellate cells[J].J Hepatol,1999,31:703-711
[226]翟玉祥,杨进,卞慧敏,等.清营汤及其拆方对实验性家兔营热阴伤证模型凝血与纤溶系统的影响[J].中国中医药科技,2001,8(2):81-83
[227]陈志强,赵玉庸,范焕芳,等.红花对实验性局灶节段性肾小球硬化症大鼠纤溶系统的影响[J].中草药,2005,36(12):1847-1849
[228]田耘,胡俊鸿,程小红.安肾方对免疫复合物型肾炎大鼠凝血纤溶系统的影响[J].陕西中医,2007,28(8):1098-1100
[229]Mosmann T.Rapid colorimetric assay for cell growth and survival:Mpdigication to the tetrazolium dye proceduce giving improved sensitivity and reliability,J Immunol Methods,1986;89:271
[230]李定国,陈颖伟.肝纤维化研究现状及展望[J].上海第二医科大学学报.2005,25(2):101
[231]Kobayashi H,Sakahara H,Hosono M,et al.Improved clearance of radiolabeled biotinylated monoclonal antibody following the infusion of avidin as a:"chase" without decreased accumulation in the target tumor[J].J Nucl Med,1994,35:1677
[232]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
[233]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):122-123
[234]DooleyS,Delvoux B,Streekert M,et al.FEBS Lett,2001,502(1-2):4-10
[235]乐小华,李美忠,杨桂林,等.肝星状细胞活化与肝纤维化分期与血清学指标的关系[J].实用医学杂志,2002,18(10):1051
[236]TSUKADA S,PARSONS C J,RIPPER A.Mechanisms of Iiver fibrosis[J].Clin Chim Acta,2006,364(1-2):33-6
[237]Zhang LP,Takahara T,Yata Y,et al.Increased expression of plasminogen activator and plasminogen activator inhibitor during liver fibro genesis of rats:role of stellate cells[J].J Hepatology,1999,31(4):703-711
[238]Murphy G,Atkinson S,Ward R,et al.The role of plasminogen activators in the regulation of connective tissue metalloproteinases[J].Ann N Y Acad Sci,1992,667:1-12