肝损伤小鼠肝组织氧化/抗氧化平衡的变化及其与TXA_2/PGI_2平衡的关系

目的:探讨氧自由基(OFR)及TXA_2-PGI_2在实验性肝损伤中的作用。方法:检测肝损伤小鼠肝组织过氧化脂质(LPO)、超氧化物歧化酶(SOD)含量以及血浆TXA_2和PGI_2浓度。结果:与对照组比较肝损伤小鼠LPO明显升高,SOD明显降低,当归可逆转LPO和SOD的变化;肝损伤小鼠血浆TXB_2高于对照组,其浓度与肝组织LPO含量呈正相关(r=0.95,P<0.01)。结论:OFR与TXA_2/PGI_2平衡失调相互作用,共同引起实验性肝损伤。     

乙肝Ⅱ号方对免疫性慢性肝损伤小鼠血栓素、前列环素代谢的影响

目的 :研究乙肝Ⅱ号方对免疫性慢性肝损伤小鼠氧自由基 (OFR ) ,血栓素A2 (TXA2 )和前列环素(PGI2 )代谢的影响。方法 :将小鼠分为正常组、模型组和乙肝Ⅱ号方治疗组。对后两组小鼠用异种动物的肝提取物作为抗原 ,免疫纯系小鼠产生抗肝抗体 ,造成慢性实验性免疫性肝损伤模型。检测 3组小鼠肝组织丙二醛 (MDA)、超氧化物歧化酶 (SOD)含量及血浆TXA2 和PGI2 代谢产物的浓度。结果 :与正常组比较 ,免疫性慢性肝损伤小鼠肝组织MDA含量明显升高 ,且与血浆TXB2 变化呈正相关 (r =0 976,P <0 0 0 1)。肝组织SOD含量下降 ,血浆TXA2 明显升高 ,PGI2 明显下降 ;而乙肝Ⅱ号方治疗组小鼠肝组织MDA和血浆TXA2 较模型组低 ,SOD和PGI2 则较模型组高。结论 :乙肝Ⅱ号方对小鼠免疫性肝损伤有明显的防治作用     

鬼针草水提物对脂多糖诱导肝损伤小鼠肿瘤坏死因子-α、白细胞介素-6的影响

目的研究鬼针草水提物对脂多糖(LPS)诱导小鼠肝损伤的保护作用及对小鼠细胞因子的影响。方法一次性腹腔注射LPS(400μg/kg)建立小鼠化学性肝损伤模型,鬼针草水提物灌胃,测定血清谷丙转氨酶(ALT)、谷酰转肽酶(GGT)、肿瘤坏死因子(TNF)-α和白细胞介素(IL)-6的水平和肝匀浆中丙二醛(MDA)、超氧化物歧化酶(SOD)、谷胱甘肽过氧化物酶(GSH-Px)的含量,肝组织HE染色作病理切片分析。结果鬼针草水提物可明显改善LPS引起的小鼠肝组织病理损伤,降低LPS致小鼠血浆ALT、GGT、TNF-α和IL-6的水平,GSH-Px活性明显增高,肝细胞水肿、变性等损伤程度明显减轻。结论鬼针草水提物能够明显降低急性肝损伤小鼠TNF-α、IL-6水平,减轻氧化应激损伤,具有较强的保肝作用。     

四氯化碳诱导小鼠急性肝损伤模型的建立和优化

目的通过单次腹腔注射不同剂量的四氯化碳(CCl4)致小鼠急性肝损伤,检测小鼠血浆转氨酶水平的变化,建立适合本研究的小鼠模型。方法采用6~8周龄雄性C57BL/6小鼠单次腹腔注射CCl4诱导急性肝损伤。比较不同剂量的CCl4诱导急性肝损伤小鼠的血浆转氨酶水平。将182只小鼠随机分出32只。32只小鼠随机分为3组CCl4实验组(每组8只)和正常对照组(8只),分别腹腔注射0.1%、0.2%、0.3%的CCl4橄榄油溶液(10 ml/kg)或等体积橄榄油。注射12小时后取血,检测血浆丙氨酸转氨酶(ALT)、天冬氨酸转氨酶(AST)的水平。比较0.1%和0.2%剂量组小鼠不同时间点血浆转氨酶水平的变化。将剩余150只小鼠随机分为正常对照组(10只)、实验Ⅰ组(0.1%剂量,70只)、实验Ⅱ组(0.2%剂量,70只),实验组小鼠在造模6、12、16、20、24、48、72小时后取血,检测血浆ALT、AST的水平。结果与正常对照组相比,分别用0.1%、0.2%、0.3%CCl4处理后12小时小鼠血浆ALT、AST均明显升高(P0.05),并呈剂量依赖性。与正常对照组相比,0.1%和0.2%剂量组小鼠血浆ALT、AST的水平在早期均呈上升趋势,并分别在16小时和20小时达到高峰,随后逐渐下降,在72小时接近至正常水平。结论单次腹腔注射CCl4诱导小鼠急性肝损伤呈剂量依赖性。0.1%剂量的CCl4以及该剂量处理后16小时是建立C57BL/6小鼠急性轻度肝损伤的合适剂量与检测转氨酶水平的合适时间点。     

乙肝Ⅰ号方对急性肝损伤小鼠的防护作用

目的:观察乙肝1号方治疗小鼠急性肝损伤的效果。方法:采用乙肝1号方大小剂量组灌胃,并与乙肝灵对照。治疗D-氨基半乳糖(D-Galn)所致急性肝损伤小鼠。结果:治疗组小鼠肝损伤明显减轻,肝匀浆超氧化物岐化酶(SOD)的含量上升,上升程度呈明显的量效关系,并优于乙肝灵治疗组。血清谷丙转氨酶(ALT)降低,降低程度呈明显的量效关系,且优于乙肝灵治疗组。结论:乙肝1号方对小鼠急性肝损伤有明显防护作用。     

血浆联合复方甘草酸苷注射液对LPS/D-GalN诱发的小鼠肝损伤的影响

目的:探讨血浆联合复方甘草酸苷注射液对肝损伤小鼠模型肝损伤的影响。方法:将40只清洁型ICR雄性小鼠随机分为4组(n=10):对照组:仅用生理盐水处理;LPS/D-galN组:仅用LPS/D-GalN处理(LPS50mg/ml,D-GalN 500mg/ml);LPS/DgalN+复方甘草酸苷(CG)组:在LPS/D-GalN诱导后2,4,8h腹腔注射5mg/ml的CG注射液3次;LPS/DgalN+复方苷草酸苷和血浆(CG和Plamsa)组:在LPS/D-GalN诱导后2,4,8h尾静脉注射150μl血浆3次,并腹腔注射CG注射液3次。12h后牺牲小鼠,收集血清和肝组织样本,利用AST和ALT检测试剂盒检测血清中AST和ALT的水平,ELISA法检测肝组织中IL-6、TNF-α和NF-κB的表达变化;肝组织进行HE染色,显微镜下观察肝组织病理学变化。结果:与LPS/D-GalN组对比,LPS/D-GalN+CG组和LPS/D-GalN+CG和Plasma组能够显著降低血清中AST和ALT水平(P0.05);炎症相关因子IL-6和TNF-α,转录因子NF-κB水平也明显降低(P0.05)。结论:血浆联合复方甘草酸苷注射液通过抑制炎症相关因子IL-6和TNF-α,并降低转录因子NF-κB的表达,改善LPS/D-GalN诱发的小鼠肝损伤。     

维生素C和维生素E对小鼠化学性肝损伤的预防性保护作用

目的:探讨维生素C(VC)和维生素E(VE)对CCl_4引起化学性肝损伤的预防性保护作用.方法:昆明种小鼠60只随机分5组,设正常对照组、病理模型组、VC保护组、VE保护组、VC VE保护组,饲养10 d,除正常对照组外,其余各组ip 1.5 mL/L CCl_4致小鼠化学性肝损伤,测定小鼠血清中ALT,AST及肝细胞中MDA,GSH,SOD,HE染色光镜下观察肝细胞形态变化.结果:VC和VE保护组能显著降低血清中ALT和AST(2277.12±1187.90,2163.76±1412.11 nkat/L vs 4527.07±1019.37 nkat/L,P<0.01)以及肝细胞中脂质过氧化物MDA的含量(4.37±0.49,3.26±0.71μmol/g vs 9.25±2.74μmol/g,P<0.01).镜下观查肝损伤明显减轻,体外抗氧化实验能显著性的抑制脂质过化物MDA生成,联合应用有协同效应.结论:VC和VE对化学性肝损伤有预防性保护作用.     

白术莪术提取物对小鼠急性肝损伤的保护作用

目的 研究白术莪术提取物对四氯化碳(CCl4)诱导的小鼠急性肝损伤的影响.方法 给予小鼠白术莪术提取物灌胃,连续7d,腹腔注射CCl4-花生油溶液造模急性肝损伤,16 h后测定血清丙氨酸氨基转移酶(ALT)、天冬氨酸氨基转移酶(AST)含量、肝组织中超氧化物歧化酶(SOD)活性及其肝脏、脾脏指数.结果 白术莪术提取物能显著降低急性肝损伤小鼠血清中ALT、AST含量及提高肝组织中SOD活性,减小肝脏指数(P＜0.01).结论 白术莪术提取物对CCl4诱导的小鼠急性肝损伤具有很好的保护作用.     

EGCG对刀豆蛋白A诱导肝损伤小鼠CXCR3表达的影响

目的观察EGCG对刀豆蛋白A(Con A)诱导的肝损伤小鼠肝组织中CXCR3表达的影响。方法 C57BL/6小鼠分成4组:正常对照组、表没食子儿茶素酸酯(EGCG)对照组、Con A模型组,EGCG+Con A模型组。EGCG对照组及EGCG+Con A模型组小鼠造模前给予EGCG口服(5 mg/kg),10 d后两组模型组小鼠通过静脉注射Con A(15 mg/kg)建造肝损伤模型,采血及留取肝组织,HE法检测肝组织病理变化,ELISA法检测肿瘤坏死因子(TNF)α,干扰素(IFN)-γ及CXCR3的水平,免疫组化法检测肝组织中CXCR3的表达。结果 Con A模型组小鼠肝损伤明显,TNF-α、IFN-γ及CXCR3的表达明显增多,与其他组比较有差异显著(P0.05);EGCG干预的模型组肝损伤减轻伴TNF-α、IFN-γ及CXCR3的表达下降,与Con A模型组比较差异明显(P0.05)。免疫组化结果同样显示Con A模型组CXCR3的表达明显增多,EGCG治疗后表达减少。结论 EGCG对Con A诱导的免疫性肝损伤小鼠有保护作用,其机制可能与调节CXCR3的表达有关。     

石榴多酚对小鼠急性肝损伤的保护作用

目的观察石榴多酚对小鼠肝损伤的防护作用。方法用四氯化碳(CCl4)致小鼠急性肝损伤模型,观察石榴多酚(200、400、600mg/kg)对小鼠血清丙氨酸转氨酶(ALT)、天门冬氨酸转氨酶(AST)活性和肝脏组织超氧化物歧化酶(SOD)活性及丙二醛(MDA)含量的影响。结果石榴多酚能明显降低急性肝损伤小鼠血清ALT、AST水平;并可使肝脏中MDA含量降低,SOD活性升高。各实验组小鼠的肝体比值均低于肝损伤模型组。结论石榴多酚对肝损伤具有保护作用,其作用可能与抗氧化有关。     

Serum cholesterol and lipid peroxidation are decreased by melatonin in diet-induced hypercholesterolemic rats

The purpose of this study was to investigate the effect of melatonin, at pharmacological doses, on serum lipids of rats fed with a hypercholesterolemic diet. Therefore, different groups of animals were fed with either the regular Sanders Chow diet or a diet enriched in cholesterol. Moreover, animals were treated with or without melatonin in the drinking water for 3 months. We show that melatonin treatment did not affect the levels of cholesterol or triglycerides in rats fed with a regular diet. However, the increase in total cholesterol and low-density lipoprotein (LDL)-cholesterol induced by a cholesterol-enriched diet was reduced significantly by melatonin administration. On the other hand, melatonin administration prevented the decrease in high-density lipoprotein (HDL)-cholesterol induced by the same diet. No differences in the levels of very low-density lipoprotein (VLDL)-cholesterol and triglycerides were found. We also found that melatonin administration slightly decreased serum uric, bilirubin and increased serum glucose levels. Other biochemical parameters, including total proteins, creatinine, urea, phosphorus, calcium, glutamic oxalacetic transaminase (GOT), glutamic pyruvic transaminase (GPT), gamma-glutamyltranspeptidase (gamma-GT), acetyl cholinesterase (AcCho), and alkaline phosphatase (ALP) were not modified by melatonin treatment. Finally, lipid peroxidation (LPO) was studied in membranes of liver, brain, spleen, and heart as an index of membrane oxidative damage. Results show that hypercholesterolemic diet did not modify the LPO status in any of the tissues studied. However, chronic melatonin administration significantly decreased LPO. Results confirm that melatonin participates in the regulation of cholesterol metabolism and in the prevention of oxidative damage to membranes.     

Hepatocyte membrane stabilization by prostaglandins E1 and E2: favorable effects on rat liver injury.

When prostaglandin (PG) E1 was continuously administered to rats from 24 hours before giving a dose of carbon tetrachloride, deranged serum glutamic pyruvic transaminase levels and prothrombin time were significantly reduced 12 hours after intoxication compared with controls. A similar effect of PGE1 was seen at 24 hours in D-galactosamine-intoxicated rats. Liver histology showed a comparable attenuation of injury in these rats. These results were consistent with reported effects of PGE2, suggesting that both prostaglandins may share a common pathway in protection against liver injury. When PGE1 or 16,16'-dimethyl PGE2 was added to the medium of primary cultured rat hepatocytes, lipid peroxidation-dependent killing of the cells by tert-butyl hydroperoxide was significantly attenuated without affecting the extent of malondialdehyde accumulation compared with controls. Both prostaglandins significantly reduced the extent of increased plasma membrane microviscosity of these cells assessed by 1-[4-(trimethyl-ammonio)phenyl]-6-phenyl-1,3,5-hexatriene. PGE1 and PGE2 may possess cytoprotective effects on liver parenchymal cells through stabilization of membrane microviscosity, which may contribute to protection against liver injury.     

A case of allergic liver injury induced by tegafur

A 51-year-old woman constitutionally susceptible to allergy presented with acute allergic liver injury. She was taking tegafur for treatment of carcinoma of the uterus. The acute liver injury appeared 3 weeks after the first drug administration. She had marked elevation of glutamic oxaloacetic transaminase (GOT) and glutamic pyruvic transaminase (GPT), moderate jaundice, and eosinophilia. The virus markers revealed hepatitis B surface antigen (HBsAg) (-) antibody to hepatitis B surface antigen (HBsAb) (+), and immunoglobulin M HA antibody (IgM HA Ab) (-). The laparoscopic and histologic findings were compatible with drug-induced liver injury. Further, the results of the lymphocyte stimulation test (LST) and challenge test by tegafur were positive. From the above findings, the liver injury was diagnosed to be an allergic reaction induced by tegafur. The hepatic function returned to normal about 20 days after tegafur administration was suspended. Allergic liver injury induced by tegafur is very rare. We report the case with a short review of the literature.     

A comparison of the effects of corticosterone and cortisol on intermediary metabolism of Calotes versicolor.

Corticosterone and cortisol administered to Calotes versicolor significantly increased the concentrations of blood glucose and urea (liver and kidney), the specific activities of glucose-6-phosphatase (liver and kidney), and glutamic oxaloacetic transaminase (liver and heart); they markedly reduced hepatic cholesterol level and did not change the activities of acid phosphatase (liver and kidney) and glutamic pyruvic transaminase (liver), when compared to vehicle-treated controls.     

Lysyl oxidase and collagenase in experimental acute and chronic liver injury

Lysyl oxidase and collagenase activities were measured in experimental acute and chronic liver injury in mice and rats, and correlated with collagen synthesis and accumulation. Acute liver injury was induced in mice and rats by a single dose of carbon tetrachloride given by gavage, and also in mice by a single injection of murine hepatitis virus. Chronic liver injury was induced in rats by repeated injections of carbon tetrachloride. Elevated plasma glutamic oxaloacetic transaminase levels, increased hepatic prolyl hydroxylase activity, and increased synthesis of collagen-bound hepatic hydroxyproline occurred in animals with acute as well as with chronic liver injury. However, only chronic liver injury appeared to be associated with fibrosis, increased collagen-bound hydroxyproline content, increased hepatic lysyl oxidase and collagenase activities, as well as with increased serum lysyl oxidase activity. These data suggest that lysyl oxidase and collagenase may play an important role in the collagen accumulation associated with hepatic fibrosis.     

The effect of whiskey and low-protein diets on hepatic enzymes in rats

Conclusions Chronic administration of whiskey to adult female rats reduced hepatic alcohol dehydrogenase activity. Isocitric dehydrogenase and glutamic pyruvic transaminase activities were also decreased.When a low-protein diet was given in addition to whiskey, the activity of the hepatic alcohol dehydrogenase and mean activity of isocitric dehydrogenase decreased even more.Animals subjected to a low-protein diet only did not experience changes in alcohol dehydrogenase activity, but activities of isocitric dehydrogenase and of the transaminases were reduced.Results obtained in these experiments indicate that whiskey given to rats affects the liver cells directly, altering the alcohol-dehydrogenase system, the isocitric dehydrogenase system, the glutamic pyruvic transaminase system, and glutamic oxalacetic transaminase system.Depression of AD occurred more rapidly with whiskey than with ethanol.This investigation was supported in part by PHS Research Grant A-3104 (Cl) Met. and PHS Training Grant 2A-5213 from the National Institute of Arthritis and Metabolic Diseases, U. S. Public Health Service.     

Laboratory assessment of severe chronic active liver disease during and after corticosteroid therapy: correlation of serum transaminase and gamma globulin levels with histologic features

Serum glutamic oxaloacetic transaminase and gamma globulin levels were correlated with morphologic findings during and after corticosteroid therapy of severe chronic active liver disease to assess ability to monitor histologic change. Morphologic features were interpreted by a single observer from 441 coded biopsy specimens obtained from 69 patients. Serum glutamic oxaloacetic transaminase values were more predictive of histologic findings than gamma globulin levels (p less than 0.02), correctly reflecting morphologic status in 67% of instances during treatment and 80% after treatment. Abnormalities in either test identified chronic active liver disease with similar accuracy, but serum glutamic oxaloacetic transaminase determinations were more sensitive to active inflammation. Serum glutamic oxaloacetic transaminase elevations of more than twice normal during and after therapy were reliably associated with chronic active liver disease. Normal laboratory studies, however, did not detect chronic active liver disease in 55% of cases during treatment and 19% after therapy. The majority of lesions undetected by laboratory investigations comprised periportal necrosis while confluent necrosis was rarely missed. We conclude that serum glutamic oxaloacetic transaminase determinations provide a useful mechanism for monitoring chronic active liver disease. During therapy, serum glutamic oxaloacetic transaminase levels reliably discount resolution, but do not predict histologic inactivity. After treatment, laboratory surveillance inconsistently detects periportal necrosis, but rarely misses severe inflammation of potentially greater prognostic significance.     

Contribution of no-reflow phenomenon to hepatic injury after ischemia-reperfusion: evidence for a role for superoxide anion.

Controversy exists as to the role of oxygen-derived free radicals in tissue injury and the no-reflow phenomenon in reperfusion injury after ischemia. In this study using an experimental rat model, left hepatic lobar ischemia followed by reperfusion resulted in an increase of serum glutamic pyruvic transaminase at 30 min with concomitant histological evidence of hepatocellular necrosis at 24 hr. In the in vivo liver microcirculation, reperfusion after ischemia resulted in an initial transient return of blood flow, but stasis of blood flow later developed in the liver sinusoids. Thus a no-reflow phenomenon in the microcirculation was demonstrated. Intravenous administration of a long-acting form of superoxide dismutase (half-life 6 hr, dose 4 or 8 mg/kg) significantly decreased the hepatocellular necrosis and reduced the microcirculatory stasis in the liver sinusoids. These studies established the important contribution of the no-reflow phenomenon in ischemia-reperfusion injury to the liver and the participation of superoxide anions in mediating the no-reflow phenomenon.     

Specific type IV phosphodiesterase inhibitor ameliorates thioacetamide-induced liver injury in rats

BACKGROUND AND AIMS: Rolipram is a specific type IV phosphodiesterase inhibitor that suppresses the activity of immune cells and the production of pro-inflammatory cytokines. In this study, we assessed the effect of rolipram on acute liver injury using thioacetamide (TAA)-induced liver injury in rats as a model. METHODS: Rats were treated with rolipram (0.5-5 mg/kg, intraperitoneally) or vehicle and injected 30 min later with TAA (100 mg/kg, subcutaneously). Serum transaminase concentrations and tumor necrosis factor-alpha (TNF-alpha), interleukin 1beta (IL-1beta) and growth related oncogene/cytokine-induced neutrophil chemoattractant-1 (GRO/CINC-1) levels were measured and livers were examined for microscopic changes. Dose-dependent protection against TAA liver injury was based on transaminase levels and inflammatory cytokine production, and was measured 9 h after TAA when the peak release of cytokines occurred. RESULT: Rolipram suppressed liver injury based on serum aspartate transaminase (AST), alanine transaminase (ALT) and histology and reduced TNF-alpha, IL-1beta and GRO/CINC-1 levels. Rolipram, at doses of 0.5-5 mg/kg, suppressed serum transaminase and TNF-alpha production in a dose-dependent manner, and these effects were significant at doses of 2.5 and 5 mg/kg. CONCLUSION: In our rodent model of acute liver injury, rolipram clearly reduced liver damage and inhibited pro-inflammatory cytokine production. These results suggest that specific type IV phosphodiesterase inhibitors, such as rolipram, have potent hepatoprotective effects that are associated with suppressing inflammatory cytokine production.     

Specific type IV phosphodiesterase inhibitor ameliorates thioacetamide-induced liver injury in rats

Background and Aims:  Rolipram is a specific type IV phosphodiesterase inhibitor that suppresses the activity of immune cells and the production of pro-inflammatory cytokines. In this study, we assessed the effect of rolipram on acute liver injury using thioacetamide (TAA)-induced liver injury in rats as a model.
Methods:  Rats were treated with rolipram (0.5–5 mg/kg, intraperitoneally) or vehicle and injected 30 min later with TAA (100 mg/kg, subcutaneously). Serum transaminase concentrations and tumor necrosis factor-α (TNF-α), interleukin 1β (IL-1β) and growth related oncogene/cytokine-induced neutrophil chemoattractant-1 (GRO/CINC-1) levels were measured and livers were examined for microscopic changes. Dose-dependent protection against TAA liver injury was based on transaminase levels and inflammatory cytokine production, and was measured 9 h after TAA when the peak release of cytokines occurred.
Result:  Rolipram suppressed liver injury based on serum aspartate transaminase (AST), alanine transaminase (ALT) and histology and reduced TNF-α, IL-1β and GRO/CINC-1 levels. Rolipram, at doses of 0.5–5 mg/kg, suppressed serum transaminase and TNF-α production in a dose-dependent manner, and these effects were significant at doses of 2.5 and 5 mg/kg.
Conclusion:  In our rodent model of acute liver injury, rolipram clearly reduced liver damage and inhibited pro-inflammatory cytokine production. These results suggest that specific type IV phosphodiesterase inhibitors, such as rolipram, have potent hepatoprotective effects that are associated with suppressing inflammatory cytokine production.