门冬氨酸鸟氨酸注射液抗肝性脑病的疗效观察

目的观察门冬氨酸鸟氨酸治疗肝性脑病的疗效。方法将60例肝性脑病患者随机分为治疗组30例和对照组30例，治疗组在常规综合治疗的基础上将门冬氨酸鸟氨酸10g～20g加入5％葡萄糖注射液250ml中静脉滴注1次／d，治疗7d。观察治疗前后患者的肝功能、静脉血氨浓度和数字连接试验的改善情况。结果门冬氨酸鸟氨酸治疗肝性脑病临床疗效显著优于对照组，治疗后静脉血氨浓度和数字连接试验的改善均有非常显著性差异（P〈0．05），并无明显毒副作用。结论门冬氨酸鸟氨酸治疗肝性脑病疗效确切，安全性好。     

门冬氨酸鸟氨酸在肝细胞癌肝动脉介入栓塞前后护肝作用的临床观察

目的 探讨对肝癌病人进行介入栓塞治疗前后给予门冬氨酸鸟氨酸的护肝作用。方法 选择经B超、CT、AFP等明确诊断为肝癌并且已为中晚期而不宜手术治疗的病人为研究对象，在对其进行肝动脉化疗和栓塞（TACE）治疗前后给予门冬氨酸鸟氨酸治疗13天。并设立对照组，通过生化检测观察介入治疗同时给予门冬氨酸鸟氨酸治疗的肝功能改变。结果 门冬氨酸鸟氨酸对介入治疗的肝癌病人的肝功能有明显的保护作用，病人介入后丙氨酸转氨酶、天冬氨酸转氨酶和胆红素有所升高，但能较快恢复正常。结论 门冬氨酸鸟氨酸可以防治介入栓塞导致的肝癌病人肝功能的进一步损害，保护和促进肝功能恢复，减少并发症，增加对介入治疗的耐受性。     

门冬氨酸鸟氨酸对鼻咽癌化疗药物致肝损害的保护作用

目的 探讨在鼻咽癌化疗中对肝脏的保护作用。方法 将60例鼻咽癌病人随机分成三组，三组病人均给予氟脲嘧啶＋顺铂方案化疗。对照组20例，化疗前及化疗过程中仅给予一般的葡萄糖盐水水化治疗；2组和3组分别给予肝安组和注射用门冬氨酸鸟氨酸静脉滴注。所有病人在化疗前及化疗后第1、5天检测血生化指标和血氨。结果化疗后对照组病人血清AST、ALT、γ-GT、TBIL及血氨水平明显升高（P〈0．05），而门冬氨酸鸟氨酸组病人血清指标和血氨水平在化疗前后无明显变化（P＞0．05）。结论 门冬氨酸鸟氨酸在鼻咽癌病人化疗过程中起到保护肝功能的作用。     

自拟中药对CCl4诱导的肝纤维化大鼠肝组织Smad3表达的影响

目的研究自拟中药对CCl4诱导的大鼠肝纤维化肝脏Smad3表达的影响，探讨其抗纤维化的作用机制。方法Wistar大鼠40只，随机分成正常对照组、模型组、自拟中药组、鳖甲软肝片组，采用CCl4背部皮下注射构建肝纤维化模型，行HE和VG染色，光镜下观察肝组织肝纤维化程度。同时免疫组化SABC方法检测各组Smad3的表达。结果与正常对照组比，模型组Smad3表达明显增强，自拟中药组大鼠肝脏Smad3的表达（0．279±0．085对0．885±0．904，P〈0．05）显著下调。另外，自拟中药组大鼠肝脏肝纤维化病理变化显著改善。结论自拟中药对CCl4诱导的大鼠肝纤维化模型肝脏Smad3表达有明显的下调作用，可能是其抗肝纤维化的主要作用机制之一。     

肝纤维化大鼠晚期糖基化终末产物变化及氨基胍的干预作用

目的研究四氯化碳诱导的实验性大鼠肝纤维化不同阶段体内晚期糖基化终末产物的变化情况，以及晚期糖基化终末产物抑制剂氨基胍对肝纤维化的干预作用。方法sD大鼠分为3组：对照组、模型组、氨基胍干预组。检测四氯化碳诱导的大鼠肝纤维化及氨基胍干预后不同阶段血清及肝组织匀浆晚期糖基化终末产物含量。血清透明质酸水平，并对照观察肝脏的组织病理学改变进行肝纤维化程度评分。结果血清及肝组织匀浆晚期糖基化终末产物含量、透明质酸水平以及肝纤维化评分，肝纤维化l2周组高于对照组（t值分别为3．26、3．49、4．70和25．4，P值均〈0．01），氨基胍干预组低于肝纤维化组（t值分别为2．11，2．11、2．93和2．47，P值均〈0．05）。血清及肝组织匀浆晚期糖基化终末产物含量与血清透明质酸水平呈线性相关。结论肝纤维化晚期血清及肝组织匀浆晚期糖基化终末产物含量是增高的。一定程度上，体内晚期糖基化终末产物水平可以反映肝纤维化情况。氨基胍对四氯化碳诱导的实验性大鼠肝纤维化有一定的干预作用。     

结缔组织生长因子在大鼠肝纤维化形成中的作用

目的 研究结缔组织生长因子（CTGF）在大鼠肝纤维化形成中的表达及作用机制。方法 雄性SD大鼠32只，体重250～300g，皮下注射四氯化碳（CCl4）制备大鼠肝纤维化模型，分别于注射后1、4、8周处理动物．采用免疫组化、RT—PCR等方法对肝组织中CTGF的表达进行检测。结果 CCl4注射诱导后，大鼠肝组织中CTGF的表达较正常对照明显增强（P〈0．01）．且注射1、4、8周组肝组织中CTGF的表达强度呈逐级递增的趋势（P〈0．01，〈0．05）。CTGF主要表达于肝星状细胞胞质中．CTGF mRNA的表达与其蛋白质水平的改变相一致。结论 CTGF作为一种致纤维化因子，其过表达促进肝星状细胞的活化增殖及细胞外基质的形成，从而促进了大鼠肝纤维化的发生、发展。     

门冬氨酸鸟氨酸的肝病临床应用与研究进展

门冬氨酸鸟氨酸作为一种抗炎保肝药物广泛用于各种肝脏疾病的治疗,如肝性脑病、药物性肝损、脂肪肝、慢性肝炎等。除了三羧酸循环和鸟氨酸循环外,最新的研究显示,门冬氨酸鸟氨酸的抗炎作用可能与N-甲基-D-门冬氨酸(NMDA)受体有关。门冬氨酸鸟氨酸能够促进肝细胞修复,减轻肝脏炎性反应,降低肝细胞损害,临床疗效确切,而新的作用机制也具有进一步的研究价值。     

门冬氨酸鸟氨酸治疗肝硬化伴发肝性脑病68例疗效观察

目的评价门冬氨酸鸟氨酸（瑞甘）在治疗肝硬化伴发肝性脑病中的临床疗效。方法将2004年3月至2012年8月我院消化内科收治的肝硬化并发肝性脑病患者132例,按随机分配的方法分为观察组、对照组。对照组64例给予常规抗肝昏迷治疗,观察组68例在对照组治疗的基础上给予门冬氨酸鸟氨酸（瑞甘）静脉滴注,对比两组患者治疗前及治疗后血清转氨酶、血氨、总胆红素水平及两组的治疗总有效率。结果两组患者血清转氨酶、血氨、总胆红素治疗后与治疗前比较均有明显好转（P〈0．05）,观察组比对照组改善更显著（P〈0．05）;观察组的治疗总有效率明显高于对照组（P〈0．05）。结论门冬氨酸鸟氨酸可显著改善肝硬化伴发肝性脑病患者的生化指标,疗效确切,值得在肝硬化伴发肝性脑病患者的治疗中推广应用。     

抗纤颗粒对肝纤维化大鼠肝组织胶原蛋白及血清TNF-α和γ-IFN含量的影响

目的 观察抗纤颗粒预防大鼠肝纤维化的疗效并探讨作用机理。方法 采用二甲基亚硝胺诱导的大鼠肝纤维化模型，观察抗纤颗粒干预前后肝胶原蛋白含量、血清INF-α和γ-IFN含量的变化。结果 抗纤颗粒预防组较模型组肝胶原蛋白含量、血清INF-α含量下降（P〈0．05），γ-IFN含量上升（P〈0．05）。结论 抗纤颗粒对二甲基亚硝胺诱导的大鼠肝纤维化有预防作用，其部份机理为通过调节细胞因子的含量，而达到抗肝纤维化的目的。     

安珐特与γ-干扰素抗肝纤维化的比较

目的：比较复方牛胎肝提取物片（商品名安珐特）与γ-干扰素（IFN-γ）抗肝纤维化疗效并探讨其作用机制。方法：用四氯化碳（CCl4）诱导形成大鼠肝纤维化模型，设模型组和正常对照组，使用不同剂量安珐特与IFN-γ对该模型肝纤维化大鼠治疗8周，观察各组大鼠肝功能、血清透明质酸（HA）水平、肝组织胶原含量、病理组织学及免疫组织化学多种细胞因子的表达变化，并以透射电镜观察肝组织超微结构的改变。结果：大鼠死亡率与安珐特剂量有明显的量效关系，3种剂量安珐特与IFN-γ治疗组间SSS计分、一些细胞因子表达水平、部分血清学指标和肝胶原含量无明显差异（P〉0．05），但都不同程度低于模型组（P〈0．05或P〈0．01）。结论：安珐特抗肝纤维化作用与IFN-γ相似。     

腱蛋白在四氯化碳大鼠肝纤维化形成过程中的动态表达

目的：探讨腱蛋白（Tenascin,Tn)在肝纤维化形成中的作用。方法：以CCl4诱发大鼠肝损伤期（4周），肝纤维化早期（8周）和肝纤维化晚期（12周）模型；采用免疫组织化学及核酸原位分子杂交技术对大鼠肝组织中Tn mRNA及其蛋白质表达进行观察，并进行计算机图像分析。结果：正常肝组织有少量Tn分布；肝损伤期及肝纤维化早期，Tn的mRNA及蛋白质表达均显著增高。肝纤维化晚期，Tn的mRNA及蛋白质表达相对减少，核酸原位杂交提示肝间质细胞是Tn的主要合成细胞。结论：Tn是肝内重要的细胞外基质成分，参与了肝纤维化的早期形成。     

Minor contribution of hepatocytes to collagen production in normal and early fibrotic rat livers

Hepatocyte contribution to hepatic collagen production in vivo was estimated in rats, based on the fact that ornithine is used for protein synthesis in the liver as arginine after conversion by way of the urea cycle only by hepatocytes. From rats given a mixture of [14C] ornithine and [3H]arginine, hepatic collagen and serum albumin were obtained. The hepatocyte contribution was calculated from the 14C and 3H in arginine purified from collagen and albumin by high performance liquid chromatography. The contribution was less than 10% of total collagen production in normal and early fibrotic livers induced by a single dose of carbon tetrachloride or dimethylnitrosamine. We conclude that hepatocytes may play a minor role in collagen production in normal and early fibrotic rat livers.     

Estrogen reduces CCL4- induced liver fibrosis in rats

AIM：Chronic liver diseasis,such as fibrosis or cirrhosis,are more common in men than in women,This gender difference may be related to the effects of sex hormones on the liver.The aim of the present work was to investigate the effects of estrogen on CCL4-induced fibrosis of the liver in rats.METHODS:Liver fibrosis was induced in male,female and ovariectomized rats by CCL4 administration.All the groups were treated with estradiol(1mg/kg)twice weekly.And tamoxifen was given to male fibrosis model.At the end of 8weeks,all the rats were killed to study serum indicators and the livers.RESULTS:Estradiol treatment reduced aspartate aminotransferase(AST),alanine aminotransferase(ALT),hyaluronic acid(HA)and typeIVcollagen(CIV)in sera,suppressed hepatic collagen content,decreased the areas of hepatic stellate cells(HSC)positive forα-smooth muscle actin(α-SMA).and lowered the synthesis of hepatic typeⅠcollagen significantly in both sexes and ovariectomy fibrotic rats induced byCCL4administration.Whereas.tamoxifen had the opposite effect.The fibrotic response of the female liver to CCL4 treatment was significantly weaker than that of male liver.CONCLUSION:Estadiol reducese CCL4-induced hepatic fibrosis in rats.The antifibrogenic role of estrogen in the liver may be one reason for the sex associated differences in the progression from hepatic fibrosis to cirrhosis.     

原肌球蛋白1在大鼠肝纤维化模型及肝星状细胞中的动态表达及其意义

目的 观察原肌球蛋白1 (TPMl)在大鼠肝纤维化模型及肝星状细胞(HSC)中的动态表达.方法 将SD大鼠随机分为正常对照组(6只)和模型组(24只).二甲基亚硝胺腹腔注射建立大鼠肝纤维化模型,于第2、4、6、8周(每组各6只)门静脉采血及取肝组织标本; HSC-T6细胞设对照组及刺激组,刺激组以5 ng/ml转化生长因子β 1(TGF β 1)作用48h.苏木素-伊红和Masson染色观察肝组织病理变化,RT-PCR、免疫组织化学和Western blot检测组织与细胞中TPMl,TGF β1及α平滑肌肌动蛋白(α-SMA)的mRNA和蛋白的表达,以及TPMl在肝组织中的定位.两样本均数比较采用独立样本t检验;相关性采用Pearson直线相关分析.结果 成功建立肝纤维化模型,TPMl在正常肝组织中低表达于汇管区血管内皮上,在模型组TPMl强表达于增生的肝纤维间隔,TPMl及α-SMA的mRNA及蛋白的表达在肝纤维化过程中均逐渐升高,6周时高于其他各组,8周时下降,与对照组相比,差异均有统计学意义(P＜ 0.05);TGF β 1先升高,4周时高于其他各组,6周时下降(P＜0.05);相关性分析表明TPMl与o-SMA和TGF β 1的表达均呈正相关(rs=0.688和rs=0.692,P＜0.01); HSC-T6细胞中,TGF β 1刺激组TPM1及α- SMA的mRNA表达均升高,差异有统计学意义(P＜0.05).结论 TPMl参与了肝纤维化的发生和发展过程,有望成为肝纤维化诊断与治疗的新靶点.     

大麻素受体1和细胞外信号调节激酶在肝纤维化小鼠肝组织中的表达及意义

目的研究大麻素受体1(CB1)mRNA在肝纤维化形成过程中表达的变化,从基因转录水平探讨其与细胞外信号调节激酶(ERK)的关系。方法采用10%四氯化碳腹腔注射制备肝纤维化模型,分别于造模第2、4、6、8周留取小鼠的肝组织及血清。通过病理对肝组织进行形态学观察,荧光定量RT-PCR检测CB1 mRNA和ERK mRNA水平,生化法检测血清中ALT和AST的含量,放射免疫法检测血清中透明质酸(HA)的含量。结果与正常对照组相比,各模型组小鼠肝组织中CB1 mRNA和ERK mRNA含量显著升高(P<0.05),而且随造模时间的延长,CB1 mRNA和ERK mRNA含量亦逐渐增高,各组之间差异有统计学意义(P<0.05)。各模型组小鼠血清中ALT、AST及HA的水平随造模时间延长而不断升高,各组间差异具有统计学意义(P<0.05)。CB1 mRNA的含量不但与血清中ALT、AST、HA的含量呈显著正相关(r=0.741、0.763、0.769,P均<0.01),而且与肝组织中ERK mRNA含量也呈显著正相关(r=0.789,P均<0.01)。结论CB1可能通过激活ERK,以ERK通路诱导肝星状细胞(HSC)增殖,促进肝纤维化的形成。     

Contribution of immune response to the hepatic fibrosis induced by porcine serum

To investigate whether hepatic fibrosis induced by porcine serum in rats is caused by an immune reaction to porcine serum, rats that were immunologically tolerant exclusively to porcine serum were subjected to the repeated injection of porcine serum over a long period. This porcine serum-tolerant group consisted of 15 Wistar rats that had been injected intraperitoneally with porcine serum twice a week from the first postnatal day for 18 weeks. The control group consisted of 16 Wistar rats, aged 8 weeks, that were injected intraperitoneally with porcine serum twice a week for 10 weeks. Livers were fixed and examined by light microscopy. The serum of each rat was subjected to indirect enzyme-linked immunosorbent assay (ELISA) to measure the level of antibody to porcine albumin. In addition, immunohistochemical staining for ED1 was performed on untreated normal and porcine serum-induced fibrotic rat livers to examine the distribution of macrophages and their precursors, the monocytes. All rats in the tolerant group showed an extremely low antibody level (x = 68.27 +/- 4.53), and none (0/15) developed hepatic fibrosis. The majority of rats in the control group showed a very high antibody level (x = 1242.19 +/- 201.15); 75 percent (12/16) developed hepatic fibrosis. Data indicate that, despite the prolonged, repeated injections of porcine serum, if an immune response to porcine serum does not occur, the rats do not develop hepatic fibrosis. The porcine serum-tolerant rats developed hepatic fibrosis after 4 weeks of CCl4 treatment, indicating that injection of porcine serum into neonatal rats did not cause anergy of fibrogenesis, thereby preventing the animal from developing hepatic fibrosis. In normal rat liver, ED1-positive cells, which include nearly all Kupffer cells, were located pre-dominantly in the periportal area. In fibrotic rat liver, ED1-positive cells aggregated prominently in the newly formed and advanced connective tissue septa developed mainly between the neighboring central veins, and in fibrotic parts of the liver capsule. Aggregation of ED1-positive cells was rarely observed in nonfibrotic parts of the liver capsule. The difference between normal and fibrotic rat liver in distribution of EDl-positive cells suggests an involvement of macrophages in fibrogenesis and septum formation. In conclusion, our study showed a significant contribution by the immune response to porcine serum antigens leading to porcine serum-induced rat hepatic fibrosis--processes in which macrophages may be important. This study may lead to an understanding of the mechanism responsible for this form of experimental hepatic fibrosis. (Hepatology 1996 Apr;23(4):811-7)     

Hepatic mucosal mast cell hyperplasia in rats with secondary biliary cirrhosis

Mast cells have been shown to play a role in many chronic inflammatory and fibrotic disorders. However, their possible contribution to the pathological changes that occur in liver cirrhosis is unknown. To explore this, we examined whether changes in hepatic mast cell number and mediator content were associated with fibrotic changes in experimental biliary cirrhosis. Rats were studied 7, 14, or 21 days after bile duct resection (BDR). Hepatic mast cells were identified by histochemical and immunohistochemical stains. Rat mast cell protease II (RMCP-II), a marker of mast cell degranulation, was measured in liver by enzyme-linked immunosorbent assay. Hepatic collagen deposition was assessed by Sirius Red F3BA staining. In day 21 BDR rats, there was a one- to twofold increase (P < .001) in the number of hepatic mast cells, but this was not observed in day 7 or 14 BDR rats. Mild fibrotic changes were noted in BDR rat livers as early as 7 days after induction of cholestasis. Significant expansion and organization of fibrous tissue had occurred in day 14 BDR rats which progressed to bridging fibrosis by day 21. Liver RMCP-II levels were decreased by 50 percent (P < .05) and mast cell degranulation was apparent as shown by histamine immunostaining. These results suggest that hepatic mast cell hyperplasia and degranulation occur during prolonged cholestasis in the rat. Although these changes do not correlate with the onset of hepatic fibrosis, they do occur at a time during which there is significant deposition and organization extracellular matrix elements. Hepatic mast cells, by releasing profibrogenic mediators, may contribute to fibrotic changes in biliary cirrhosis. (Hepatology 1996 Apr;23(4):888-95)     

Significance of septal fibrosis for disturbance of hepatic circulation.

To examine the significance of fibrous septa of the liver for hepatic circulatory disturbance, haemodynamic changes were investigated in rats with septal fibrosis induced with horse serum injections. The fibrotic liver showed thin fibrous bands originating in the vicinity of the peripheral branches of the hepatic vein connected with each other and partly with the portal triads, without conspicuous periportal, pericentral or perisinusoidal fibrosis. There was no evidence of hepatic cell enlargement, disarrangement of hepatic cell plates or narrowing of the sinusoids in the fibrotic livers. Portal vascular resistance, bile production and hepatic oxygen consumption, which were measured by an isolated liver perfusion method, were much the same in the normal and the fibrotic livers. Moreover, there was no significant difference in in vivo blood pressures of the portal vein, the terminal portal venule, the terminal hepatic venule and the inferior vena cava between the normal and the fibrotic rats. These data suggest that septal fibrosis in itself does not disturb hepatic circulation.     

Antifibrotic effects of green tea on in vitro and in vivo models of liver fibrosis

AIM: To examine the protective effect of green tea extract (GT) on hepatic fibrosis in vitro and in vivo in dimethylnitrosamine (DMN)-induced rats. METHODS: HSC-T6, a rat hepatic stellate cell line, was used as an in vitro assay system. Cell proliferation,collagen content, and type 1 collagen expression were examined in activated HSC-T6 cells. Collagen was determined by estimating the hydroxyproline content.In rats with DMN-induced hepatic fibrosis, serum aspartate aminotransferase and alanine aminotransferase concentrations, liver hydroxyproline and lipid peroxides were determined. Pathologic changes were examined by hematoxylin & eosin staining.RESULTS: GT administration prevented the development of hepatic fibrosis in the rat model of DMN-induced liver fibrosis. These results were confirmed both by liver histology and by quantitative measurement of hepatic hydroxyproline content, a marker of liver collagen deposition. Accordingly, inhibition of proliferation, reduced collagen deposition, and type 1 collagen expression were observed in activated HSC-T6 cells following GT treatment. These results imply that GT reduced the proliferation of activated HSC and down regulated the collagen content and expression of collagen type 1, thereby ameliorating hepatic fibrosis. tea administration can effectively improve liver fibrosis caused by DMN, and may be used as a therapeutic option and preventive measure against hepatic fibrosis.