三草护肝胶囊抗实验性肝纤维化药效学研究

目的:观察三草护肝胶囊对肝纤维化动物血清相关指标(ALT、AST、ALP、TP、Alb、Glb、A/G、LM、HA、PCⅢ)、肝脏羟脯氨酸(Hyp)和肝脏超微结构的影响。方法:以四氯化碳皮下注射复制大鼠化学性肝纤维化模型,与秋水仙碱作比较。结果:三草护肝胶囊能显著降低肝纤维化大鼠血清AST和ALP活性,降低血清HA、LM、PCⅢ及肝组织Hyp含量,超微结构观察亦显示给药组肝纤维化程度较模型组轻。结论:三草护肝胶囊具有较好的抗肝纤维化作用。     

丹参提取物抗CCl_4诱导大鼠肝纤维化的作用(摘要)

目的:研究丹参水溶性提取物抗肝纤维化的作用。方法:采用CCl_4大鼠肝纤维化模型,设立低、中二种不同剂量的丹参提取物组,以秋水仙碱和丹参原生药为对照。观察项目包括:肝脏的病理组织学变化;肝组织羟脯氨酸(Hyp)、一氧化氮(NO)含量;血清丙氨酸氨基转移酶(ALT)活性和白蛋白(A1b)含量。结果:①各丹参提取物组肝纤维化病理     

排钱草总生物碱对实验性肝纤维化动物相关指标的作用

目的 观察排钱草总生物碱对实验性肝纤维化的作用效果及其作用机制。方法 采用四氯化碳（CC14）诱导肝纤维化模型,分别按阻断肝纤维化实验研究方法和治疗肝纤维化实验研究方法,从而清相关指标、肝脏羟脯氨酸含量和病理组织学等观察排钱草总生物碱的疗效,以秋水仙碱作为阳性对照药。结果 排钱草总生物碱能显著降低肝纤维化大鼠血清ALT、HA、γ-球蛋白及肝组织羟脯氨酸含量。肝脏病理组织学检查亦显示良好的作用效果。结论 排钱草总生物碱具有较好的抗肝纤维化作用。     

排钱草总生物碱对免疫性肝纤维化大鼠Ⅰ、Ⅲ、Ⅳ型胶原及TGF-β1表达的影响

目的:观察排钱草总生物碱对免疫性肝纤维化大鼠肝脏胶原沉积和转化生长因子β1(TGF-β1)表达的影响,研究其对肝纤维化形成的抑制作用,并探讨可能的作用机制.方法:设立模型对照组、药物对照组、排钱草总生物碱高、中、低剂量组和正常对照组,以腹腔注射猪血清方法诱导大鼠肝纤维化动物模型.排钱草总生物碱高、中、低剂量组大鼠在注射猪血清的同时分别灌服排钱草总生物碱30mg/kg,20mg/kg,10mg/kg,1次/d,共8周.大鼠肝脏HE染色,观察各组大鼠肝组织的炎性坏死与胶原纤维沉积变化;免疫组化观察大鼠肝纤维化形成过程中腓钱草总生物碱对肝脏表达Ⅰ、Ⅲ、Ⅳ型胶原蛋白及TGF-β1的影响.结果:与正常对照组比较,模型组大鼠肝脏出现典型的肝纤维化表现,肝脏胶原纤维间隔广泛形成,肝小叶与肝窦内胶原增生沉积明显,Ⅰ,Ⅲ,Ⅳ型胶原(1.28±2.59 vs 13.82±6.55,1.00±1.22 vs 14.69±7.16,1.03±1.46 vs 12.44±6.89, P值均＜0.001)及TGF-β1表达明显增多.高、中、低剂量排钱草总生物碱均可以明显减轻大鼠肝脏内胶原纤维增生沉积(P＜0.05),抑制肝脏Ⅰ,Ⅲ,Ⅳ型胶原蛋白(P值均＜0.05)及TGF-β1的合成表达.结论:排钱草总生物碱通过抑制肝纤维化大鼠肝脏Ⅰ,Ⅲ,Ⅳ型胶原蛋白及TGF-β1的合成表达,起到良好地抗肝纤维化作用.     

冷饭团抗肝纤维化的实验研究

目的：探讨冷饭团的抗肝纤维化作用,方法：采用CCl4和高脂低蛋白等复合因素诱导大鼠实验性肝纤维化,以联苯双酯为对照,观察冷饭团对大鼠肝功能和肝组织羟脯氨酸（Hyp)的影响,并作肝脏病理切片,光镜下观察组织学改变,。结果：冷饭团能显著降低实验性肝纤维化大鼠血清谷丙转氨酸（ALT）和谷草转氨酶（AST）活性,升高血清白蛋白（Alb),降低肝组织Hyp含量,并能明显减轻大鼠肝细胞损害,肝脏脂肪变性和胶原纤维增生的程度,结论：冷饭团有较好的降酶,保护肝细胞和抗肝纤维化作用。     

梨头草提取物对四氯化碳致小鼠急性肝损伤的修复作用

目的探讨犁头草提取物对四氯化碳(CCl_4)诱导大鼠急性肝损伤的修复效果和抗氧化作用。方法体外抗氧化评价主要考察对DPPH、ABTS、羟自由基以及还原力的清除率,利用CCl_4诱导昆明小鼠肝损伤后,以不同剂量的犁头草提取物灌胃7 d并且测定血清中天冬氨酸转氨酶(AST)、碱性磷酸酶(ALP)、丙氨酸转氨酶(ALT)、谷氨酰转肽酶(GGT)、总胆红素(TB)和肝肾组织中的超氧化物歧化酶(SOD)、过氧化氢酶(CAT)、谷胱甘肽(GSH)以及丙二醛(MDA)等指标,HE染色观察肝脏病理组织学变化。结果体外抗氧化实验证明犁头草提取物具有较强的抗氧化效果,各剂量组均能降低CCl_4致小鼠急性肝损伤血AST、ALP、ALT、GGT和TB的升高,降低肝肾中MDA含量,增强SOD、CAT和GSH活性,减轻CCl_4对肝组织的病理损伤。结论犁头草提取物对CCl_4致小鼠急性肝损伤具有一定的保护作用。     

林蛙油对大鼠肝纤维化的影响

目的 探讨林蛙油对大鼠肝纤维化的治疗效果.方法 用林蛙油治疗CCl4诱导的肝纤维化模型,观察它对肝细胞实验室检查及氧化和抗氧化能力指标的影响.结果 林蛙油能降低肝纤维化大鼠血清中谷丙转氨酶(ALT)、谷草转氨酶(AST)、碱性磷酸酶(ALP)、γ-谷氨基转移酶(GGT)、羟脯氨酸(Hyp)及丙二醛(MAD),增加超氧化物歧化酶(SOD)及谷胱甘肽过氧化物酶(GSH-Px).结论 林蛙油能改善其肝脏损伤程度,减少肝纤维化大鼠肝组织中胶原的增生,增加抗氧化能力,延缓肝硬化的形成,对大鼠肝纤维化有很好的治疗作用.     

益肝浓缩煎剂与强肝胶囊抗大鼠肝纤维化作用实验研究

目的:研究益肝浓缩煎剂、强肝胶囊对大鼠肝纤维化治疗作用,并对其机制进行初步探讨。方法:CCl_4诱导大鼠肝纤维化模型,造模结束后分别予相应药物进行治疗,持续10周,测定肝组织羟脯氨酸(Hyp)、丙二醛(MDA)含量,光镜观察肝脏病理形态变化。结果:与模型自然恢复组相比,益肝浓缩煎剂、强肝胶囊治疗组Hyp、MDA显著降低,胶原沉积明显减轻。结论:益肝浓缩煎剂、强肝胶囊对大鼠肝纤维化具有明确治疗作用,可促进胶原纤维降解,使早期肝纤维化逆转。其疗效作用机制可能与抗脂质过氧化有关。     

虫草菌丝抗肝纤维化的实验研究

目的:观察人工虫草菌丝对CCl_4中毒性肝纤维化的预防作用。方法:复制大鼠CCl_4中毒性肝纤维化模型,并以秋水仙碱作为阳性治疗对照,采用光镜、电镜观察肝脏组织学改变,测定血清ALT、Alb、G、HA、LN、肝组织Hyp含量。结果:虫草菌丝组肝细胞损害、肝脏脂肪变性、炎性细胞浸润的程度均较模型组轻,但再生肝细胞较多,有假小叶形成;其对肝功能、肝纤维化指标也有明显改善,但秋水仙碱的抗肝纤维化作用优于虫草菌丝。结论:虫草菌丝对肝脏CCl_4损伤具有一定保护作用,有较强促进肝细胞再生修复作用,同时在损伤肝组织中成纤维细胞及胶原纤维也明显增生,其与活血化瘀药有机伍用,可能是防治肝纤维化较理想的组合。     

复方牛胎肝提取物对二甲基亚硝胺致大鼠肝纤维化的干预作用

目的:观察复方牛胎肝提取物(安珐特)对二甲基亚硝胺(DMN)诱导大鼠肝纤维化的干预作用。方法:雄性Wistar大鼠29只,随机分为正常组(9只)、模型组(10只)、安珐特组(10只)。后两组大鼠行腹腔注射4周DMN复制肝纤维化模型。造模结束后,安珐特组大鼠按照成人用药量的8倍剂量灌胃,共4周,正常组和模型组大鼠灌胃等剂量的0.5%羧甲基纤维素钠(CMC)。8周末处死大鼠,留取标本。全自动生化仪检测血清丙氨酸氨基转移酶(ALT)、门冬氨酸氨基转移酶(AST)、总胆红素(TBil)、γ-谷氨酰转肽酶(γ-GT)、血清白蛋白(Alb);检测各组大鼠肝组织羟脯氨酸Hyp的含量;采用HE染色和天狼猩红染色法观察肝组织形态学。结果:与正常组比较,模型组大鼠血清TBi L、ALT、AST、γ-GT水平明显升高(P0.05),Alb水平明显下降(P0.05);大鼠肝组织HE染色可见肝脏内有大量炎性细胞浸润,肝窦狭窄,汇管区扩大,肝细胞排列紊乱,出现肿胀、变性坏死,肝组织内有明显出血现象;天狼猩红染色可见大鼠肝脏胶原增生明显,大量纤维间隔,向肝小叶伸展,分割包绕肝组织,形成假小叶;肝组织Hyp含量明显升高(P0.05)。与模型组比较,安法特组大鼠血清TBi L、ALT、AST均显著降低降低(P0.05),γ-GT水平有所降低,Alb水平有所升高,但差异无统计学意义;肝组织HE染色可见肝细胞变性坏死、出血、炎症细胞浸润等病理变化有不同程度的改善;天狼猩红染色可见纤维化程度有明显改善;肝组织Hyp含量明显降低(P0.05)。结论:安珐特对DMN诱导的大鼠肝纤维化形成有显著的抑制作用。     

冷饭团抗肝纤维化的实验研究

探讨冷饭团的抗肝纤维化作用。方法采用CCl     

Effect of Danshao Huaxian capsule on expression of matrix metalloproteinase-1 and tissue inhibitor of metalloproteinase-1 in fibrotic liver of rats

AIM: To investigate the effects of Danshao Huaxian (DSHX) capsules, a preparation of traditional Chinese medicine, on the expression of matrix metalloproteinase-1 (MMP-1), and tissue inhibitor of metalloproteinase-1 (TIMP-1) in the fibrous livers of rats. METHODS: Eighty male Wistar rats were randomly divided into normal control group (group A), CCl4-induced hepatic fibrosis group (group B), non-DSHX-treated group (group C), low dose-treated group (group D), and high dose-treated group (group E). Fibrous liver models in rats were induced by subcutaneous injection of CCl4, oral administration of alcohol and high-lipid/low-protein diet for 8 wk. After the models were established, the rats in groups D and E were orally given a low dose (0.5 g/kg) and a high dose (1.0 g/kg) of DSHX daily for 8 wk, respectively. Then, the liver indexes, serum hyaluronic acid (HA) and alanine aminotransferase (ALT) were examined. The degree of hepatic fibrosis was evaluated by optical microscopy. Hydroxyproline (Hyp) in the urine was determined, and the expression of MMP-1 and TIMP-1 was detected by immunohistochemical techniques. RESULTS: In groups D and E, the liver indexes, levels of serum HA and ALT reduced and development of hepatic fibrosis weakened significantly. The urinary Hyp and expression of MMP-1 in the liver tissues elevated, but the expression of TIMP-1 decreased obviously, as compared to groups B and C. CONCLUSION: DSHX enhances the expression of MMP-1 but decreases that of TIMP-1 in liver tissues of CCl4-induced hepatic fibrotic rats, which may result in its elevated activity that contributes to fighting against hepatic fibrosis.     

绞股蓝总皂苷对四氯化碳诱导大鼠肝纤维化的防治作用

目的:观察绞股蓝总皂苷对四氯化碳( CCl4)诱导的大鼠肝纤维化的防治作用.方法:采用CCl4诱导的大鼠肝纤维化模型,分为正常组(Z,n=6)、模型组(M,n=8)、绞股蓝总皂苷组(J,n=8)、秋水仙碱(Q,n=8).造模6周末开始给药(股蓝总皂苷200mg/kg体重、秋水仙碱0.1mg/kg体重),给药3周.观察:①大鼠体重、肝脾比值的变化;②血清丙氨酸氨基转移酶(ALT)、门冬氨酸氨基转移酶(AST)、谷氨酰转肽酶(GGT)活性、白蛋白( Alb)、总胆红素(TBil)含量、肝组织羟脯氨酸(Hyp)含量;③肝组织超氧化物歧化酶(SOD)活性及丙二醛(MDA)、还原型谷胱甘肽(GSH)、谷胱甘肽过氧化物酶(GSH-Px)含量;④肝组织病理及胶原沉积情况.结果:①M组大鼠血清ALT、AST、GGT、TBil显著升高,Alb显著降低;J和Q组大鼠血清ALT、AST、GGT、TBil显著下降,Alb显著升高;②M组大鼠肝组织Hyp含量显著升高,J组及Q组大鼠肝组织Hyp含量显著下降;③肝组织HE染色显示:M组大鼠肝细胞脂肪变性,大量纤维结缔组织增生,假小叶形成.J组及Q组大鼠肝细胞脂肪变性减轻,纤维增生减少,少见完整假小叶结构.天狼星红染色显示:M组大鼠肝窦周胶原沉积明显,形成较厚汇管区和中央静脉间的纤维间隔,J组和Q组大鼠肝脏汇管区胶原纤维染较M组明显减轻;④M组大鼠肝组织SOD活性及GSH含量明显降低,MDA含量显著升高.J组大鼠肝组织SOD活性显著提高.结论:绞股蓝总皂苷具有显著抗CCl4诱导的大鼠肝纤维化及氧化损伤的作用.     

Inhibitory effect of Huangqi Zhechong decoction on liver fibrosis in rat

AIM: To assess the inhibitory effect of Huangqi Zhechong decoction on hepatic fibrosis in rats induced by CCl(4) plus alcohol and high fat low protein diet. METHODS: Male SD rats were randomly divided into hepatic fibrosis model group, control group and 3 treatment groups consisting of 12 rats in each group. Except for the normal control group, all the rats were subcutaneously injected with CCl(4) at a dosage of 3 mL/kg. In 3 treated groups, either high-dose group (9 mL/kg), or medium-dose group (6 mL/kg), or low-dose group (3 mL/kg) was daily gavaged with Huangqi Zhechong decoction, and saline vehicle was given to model and normal control rats. Enzyme-linked immunosorbent assay (ELISA) and biochemical examinations were used to determine the changes of alanine aminotransferase (ALT), aspartate aminotransferase (AST), hyaluronic acid (HA), laminin (LN), type-III-procollagen-N-peptide (PIIIP), and type IV collagen content in serum, and hydroxyproline (Hyp) content in liver after sacrificing the rats. Pathologic changes, particularly fibrosis were examined by hematoxylin and eosin (HE) and Van Gieson staining. RESULTS: Compared with the model control group, serum ALT, AST, HA, LN, PIIIP and type IV collagen levels dropped markedly in Huangqi Zhechong decoction groups, especially in the medium-dose Huangqi Zhechong decoction group (1 954+/-576 U/L vs 759+/-380 U/L, 2 735+/-786 U/L vs 1 259+/-829 U/L, 42.74+/-7.04 ng/mL vs 20.68+/-5.85 ng/mL, 31.62+/-5.84 ng/mL vs 14.87+/-1.45 ng/mL, 3.26+/-0.69 ng/mL vs 1.47+/-0.46 ng/mL, 77.68+/-20.23 ng/mL vs 25.64+/-4.68 ng/mL, respectively) (P<0.05). The Hyp content in liver tissue was also markedly decreased (26.47+/-11.24 mg/mgprot vs 9.89+/-3.74 mg/mgprot) (P<0.01). Moreover, the stage of the rat liver fibrosis in Huangqi Zhechong decoction groups was lower than that in model group, and more dramatic drop was observed in medium-dose Huangqi Zhechong decoction group (P<0.01). CONCLUSION: Huangqi Zhechong decoction can inhibit hepatic fibrosis resulted from chronic liver injure, retard the development of cirrhosis, and notably ameliorate the liver function. It may be a safe and effective therapeutic drug for patients with fibrosis.     

Effect of Losartan, an Angiotensin II Antagonist, on Hepatic Fibrosis Induced by CCl4 in Rats

In addition to regulating blood pressure and body fluid homeostasis, the renin-angiotensin system (RAS) is also involved in hepatic fibrogenesis. We aimed to investigate the effect of losartan, an angiotensin II (Ang II) antagonist, on CCl4-induced hepatic fibrosis in rats. Hepatic fibrosis was induced by a subcutaneous injection with 50% CCl4 in Sprague-Dawley rats. The amount of CCl4 administered was 1 mg/kg. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels in plasma and hydroxyproline (Hyp) contents in liver tissue were assayed by spectrophotometry. Hyaluronic acid (HA) and procollagen III (PC III) were assessed by radioimmunoassay. Tumor necrosis factor-alpha (TNF-alpha) and transforming growth factor-beta1 (TGF-beta1) levels in culture supernatants of Kupffer cells (KCs) stimulated with Ang II was determined by ELISA. Liver samples collected after 12 weeks of CCl4 treatment were stained with hematoxylin and eosin, then scored. Losartan (2.5, 5, and 10 mg x kg(-1), ig) and captopril (100 mg x kg(-1), ig) significantly decreased liver and spleen indexes, serum transaminase (AST, ALT) activities, HA and PC III levels, and Hyp contents in liver tissue in rats of hepatic fibrosis. Histopathological scores showed that losartan had an inhibitory effect on the progression of hepatic fibrosis. In in vitro experiments, losartan (1 x 10(-9) - 1 x 10(-5) M) significantly reduced TNF-alpha and TGF-beta1 levels in culture supernatants of KCs, but captopril (1 x 10(-5) M) did not. The results showed that losartan significantly inhibited the progression of hepatic fibrosis induced by CCl4, and the inhibitory effect of losartan on hepatic fibrosis might be associated with its ability to inhibit the production of TNF-alpha and TGF-beta1 by activated KCs.     

Protective effects of 5,4''-dihydroxy-3'',5''- dimethoxy-7-O-β-D -glucopyranosyloxy-flavone on experimental hepatic injury

AIM: To investigate the pharmacological effects of rice flavone (5,4'-dihydroxy-3',5'-dimethoxy-7-O-β-D-glucopyranosyloxy-flavone, RF) separated from panicledifferentiating to flowing rice on rat experimental hepatic injury.METHODS: Models of rat acute hepatic injury induced by carbon tetrachloride (CCl4) administration, rat hepatic fibrosis induced by thioacetamide, injury of primary cultured rat hepatocytes induced by CCl4, respectively,were established. After treated with RF, content of serum alanine transaminase (ALT), aspartate aminotransferase (AST) and albumin (Alb), hyaluronic acid (HA), the activity of glutathione peroxidase (GSH-Px), superoxide dismutase (SOD), and hydroxyproline (Hyp) were measured and liver tissue was observed pathologically by hematoxylin-eosin (HE) staining. Effects of RF on pathological changes,function index, enzyme of scavenging free radicals and blood rheology were evaluated.RESULTS: In model of rat acute hepatic injury induced by CCl4, RF can significantly decrease the contents of serum ALT, AST, increase the content of Alb, improve the dropsy and fat denaturalization of hepatocytes. In model of rat hepatic fibrosis induced by thioacetamide,RF can inhibit the increase of HA, Hyp and whole blood viscosity, and improve the activities of GSH-Px and SOD,and inauricular microcirculation.CONCLUSION: RF has apparent protective effects on hepatic injury by increasing activity of GSH-Px and SOD,scavenging free radicals produced by CCl4, reducing blood viscosity, and improving microcirculation and blood supply.     

二甲基亚硝胺肝硬化大鼠血清元素含量变化及其意义

目的　探讨二甲基亚硝胺 (DMN)肝硬化大鼠血清元素含量变化与肝功能损伤的关系及其在肝纤维化形成与发展中的意义。方法　用 0 .5 %DMN 生理盐水 2ml/kg给大鼠腹腔注射 ,共 4周 12次 ,分别于造模第 2周与第 4周结束后获取大鼠肝组织与血清 ,作肝病理组织学、肝组织羟脯氨酸 (Hyp)含量、肝功能及血清元素含量测定。 结果　( 1)造模第 2周时大鼠的血清ALT活性和TBIL显著升高 ,为同期正常组的 1.7倍 (P <0 .0 1)和 7.2倍 (P <0 .0 5 ) ;造模第 4周时为同期正常大鼠的 3 .4倍 (P <0 .0 1)和 3 4.6倍 (P <0 .0 1) ;第 4周模型大鼠Alb含量显著低于同期正常大鼠(P <0 .0 1)。 ( 2 )造模第 2周时大鼠的肝组织Hyp含量是同期正常组的 1.8倍 (P >0 .0 5 ) ,第 4周时较同期正常组增高了 3 .8倍 (P <0 .0 1)。 ( 3 )造模第 2周时血清元素主要表现为Cu含量显著增高 (P <0 .0 5 ) ,Cu/Zn比值也显著升高 (P <0 .0 1) ;第 4周时模型大鼠的血清Fe含量显著增高 (P >0 .0 5 ) ,Zn含量显著降低 (P <0 .0 1) ;血清Se含量较第 2周时模型大鼠进一步下降 ;Cu/Zn比值显著升高 (P <0 .0 1) ;Zn/Fe比值、Se/Fe比值均显著降低 (P <0 .0 1)。 ( 4 )以第 4周正常组和模型大鼠血清元素含量与肝组织Hyp含量及肝功能各指标作相关分析 ,血清     

Effects of salviainolic acid A (SA-A) on liver injury: SA-A action on hepatic peroxidation

BACKGROUND/AIMS: This study aimed to investigate the actions of salviainolic acid A (SA-A), an antiperoxidative component of Salvia miltiorrhiza (Sm), on rat liver injury and fibrosis. METHODS: Acute and chronic rat liver injury models were established using carbon tetrachloride (CCl4). After 48 h (acute) or during 6 weeks of CCl4 injection, rats were further divided and treated with biphenyl dimethyl-dicarboxylate (BDD) or colchicine, as a control antifibrotic treatment, with Sm, a herbal compound, or SA-A, a water-soluble extract of Sm. Liver function was investigated by assessing alanine transaminase (ALT) and aspartate transaminase (AST) activities, histological analysis, hydroxyproline (Hyp) and malondiadehyde (MDA) content. In vitro, isolated cultured hepatocytes were injured with CCl4 gas for 24 h, followed by treatment with either vitamin E or various concentrations of SA-A. The extent of hepatocyte injury was monitored by analyzing various lipid peroxidative parameters such as superoxide dismutase (SOD), glutathione (GSH), catalase (CAT), lactase dehydrogenase (LDH), and glutathione peroxidase (GSH-PX) levels in hepatocyte supernatants. RESULTS: SA-A significantly decreased abnormal serum ALT activity both in acutely and chronically injured rat livers, decreased abnormal serum AST activity, Hyp and MDA content and attenuated hepatic collagen deposition. After CCl4 incubation and injury, the activities of AST, ALT CAT, GSH-PX and LDH and MDA content in hepatocyte supernatants increased significantly, but GSH levels decreased significantly. SA-A markedly improved these pathological changes in a dose-dependent manner. 10(-4) mol/l SA-A had stronger inhibitory action than vitamin E. CONCLUSIONS: Our studies suggest that SA-A has antiperoxidative effects on injured hepatocytes in liver injury and fibrosis induced by CCl4.     

Melatonin ameliorates experimental hepatic fibrosis induced by carbon tetrachloride in rats

AIM： To investigate the protective effects of melatonin on carbon tetrachloride （CCl4）-induced hepatic fibrosis in experimental rats.
METHODS： All rats were randomly divided into normal control group, model control group treated with CCl4 for 12 wk, CCl4 ＋ NAC group treated with CCl4 ＋ NAC （100 mg/kg, i.p.） for 12 wk, CCl4 ＋ MEL-1 group treated with CCl4 ＋ melatonin （2.5 mg/kg） for 12 wk, CCl4 ＋ MEL-2 group treated with CCl4 ＋ melatonin （5.0 mg/kg） for 12 wk, and CCl4 ＋ MEL-3 group treated with CCl4 ＋ melatonin （10 mg/kg）. Rats in the treatment groups were injected subcutaneously with sterile CCl4 （3 mL/kg, body weight） in a ratio of 2：3 with olive oil twice a week. Rats in normal control group received hypodermic injection of olive oil at the same dose and frequency as those in treatment groups. At the end of experiment, rats in each group were anesthetized and sacrificed. Hematoxylin and eosin （HE） staining and Van Gieson staining were used to examine changes in liver pathology. Serum activities of alanine aminotransferase （ALT）, aspartate aminotransferase （AST） and protein concentration weremeasured with routine laboratory methods using an autoanalyzer. Hydroxyproline （HYP） content in liver and malondialdehyde （MDA） and glutathione peroxidase （GPx） levels in liver homogenates were assayed by spectrophotometry. Serum hyaluronic acid （HA）, laminin （LN）, and procollagen Ⅲ N-terminal peptide （PⅢNP） were determined by radioimmunoassay.
RESULTS： Pathologic grading showed that the fibrogenesis was much less severe in CCl4 ＋ MEL3 group than in model control group （u = 2.172, P 〈 0.05）, indicating that melatonin （10 mg/kg） can significantly ameliorate CCl4-induced hepatic fibrotic changes. The serum levels of ALT and AST were markedly lower in CCl4 ＋ MEL treatment groups （5, 10 mg/kg） than in model control group （ALT： 286.23 ± 121.91 U/L vs 201.15 ± 101.16 U/L and 178.67 ± 103.14 U/L, P = 0.028, P = 0.007; AST： 431.00 ± 166.35 U/L vs 321.23 ± 162.48 U/L and 292.42 ± 126.23 U/L, P = 0.043, P = 0.013）. Similarly, the serum laminin （LN） and hyaluronic acid （HA） levels and hydroxyproline （HYP） contents in liver were significantly lower in CCl4 ＋ MEL-3 group （10 mg/kg） than in model control group （LN： 45.89 ± 11.71 μg/L vs 55.26 ± 12.30 μg/L, P = 0.012; HA： 135.71±76.03 μg/L vs 201.10 ± 68.46 μg/L, P = 0.020; HYP： 0.42 ± 0.08 mg/g tissue vs 0.51 ± 0.07 mg/g tissue, P = 0.012）. Moreover, treatment with melatonin （5, 10 mg/kg） significantly reduced the MDA content and increased the GPx activity in liver homogenates compared with model control group （MDA： 7.89 ± 1.49 noml/mg prot vs 6.29 ±1.42 noml/mg prot and 6.25 ±2.27 noml/mg prot, respectively, P = 0.015, P = 0.015; GPx： 49.13 ±8.72 U/mg prot vs 57.38 ±7.65 U/mg prot and 61.39 ±13.15 U/mg prot, respectively, P = 0.035, P = 0.003）.
CONCLUSION： Melatonin can ameliorate CCl4 -induced hepatic fibrosis in rats. The protective effect of melatonin on hepatic fibrosis may be related to its antioxidant activities,