肝纤维化动物模型的研究进展

肝纤维化及其发生发展的研究已从细胞水平进入分子生物学水平。但肝纤维化动物模型的建立 ,仍是临床研究和实验研究的重点和难点。至今已建立的常见肝纤维化动物模型有 :1四氯化碳诱导肝纤维化动物模型 ;2异种动物血清诱导肝纤维化动物模型 ;3乙醇诱导肝纤维化动物模型 ;4二甲基亚硝胺诱导肝纤维化动物模型 ;5复合因素诱导肝纤维化模型。文章综述了每一种动物模型复制的方法与该模型的肝脏病理变化 ,并对几种常见的动物实验模型进行比较。因不同的动物模型具有不同的特点 ,建议根据实验的要求选择适当的模型。     

A/H1N1不同动物模型研究的比较

A/H1N1自2009年3月暴发以来,严重危害人类健康和生命。为探明其机制及研发防治措施,建立良好的动物模型是研究的重要基础。本文报道了A/H1N1流感动物模型研究进展,对流感动物模型的选择原则、疾病特征、造模方法、模型的临床特征、病理变化、病毒复制等方面进行归纳,比较了鸡模型、小鼠模型、猪模型和雪貂模型特点。A/H1N1流感动物模型有各自的优点和缺点,应根据不同的实验目的和实验条件选择合适的造模方法和和实验动物进行造模。     

心肌缺血再灌注损伤模型的实验动物种属选择和建模方法比较

心肌缺血再灌注损伤（MIRI）是冠心病治疗中的难点和热点。MIRI动物模型是研究人员开展MIRI机制和防治策略研究时的重要载体。MIRI模型包括离体模型和在体模型,涉及多个种属的动物和多种造模方法,并且心肌缺血时间的设定在不同的研究中也存在较大差异。选择合适的动物模型和造模条件对实验结果有种重要影响,本文将从模型建立的角度,比较多种常见的MIRI模型及造模方法,为MIRI研究中动物模型的选择提供依据。     

四氯化碳诱导家兔肝纤维化模型的建立

采用腹腔注射四氯化碳诱导家兔肝发生纤维化的方法 ,建立家兔肝纤维化动物模型。结果表明 ,以 3 0 ,60 ,90 d观察 ,家兔肝纤维化程度随造模时间的延长而增加。与空白对照组比较 ,3 0 d见汇管区纤维增多 ,少量炎症细胞浸润 ,肝细胞水样变性。 60 d肝小叶中央静脉周围肝细胞肿胀 ,汇管区范围增大 ,成纤维细胞增生 ,小叶周围肝细胞形态基本正常。 90 d超声显示肝脏回声增强、光点增粗 ,血流阻力相对增加(P <0 .0 5) ;组织学显示汇管区内成纤维细胞大量增生 ,中央静脉周围纤维化 ,可见胶原纤维束向小叶内延伸。提示长期给予四氯化碳可诱导家兔肝纤维化形成 ,其病理变化具有阶段性。90 d肝纤维化形成稳定 ,与人的肝纤维化接近     

大鼠肝纤维化过程的肝细胞生长因子表达

肝纤维化是多种慢性肝病共同的病理变化,是各种慢性肝病发展至肝硬化的必经之路.肝纤维化主要表现为细胞外基质(ECM)的大量沉积[1],有效地预防和逆转肝纤维化是防止肝硬化的关键所在.大量的研究表明,肝纤维化的形成是细胞-细胞因子-基质间相互作用、相互调节的结果.肝细胞生长因子(HGF)能刺激多种类型细胞分化、增殖、再生、运动、迁移及形态的发生,是很强的促肝细胞增殖因子,不仅能刺激肝细胞的再生,促进肝功能恢复,而且可改善肝纤维化,在损伤因子刺激时保护肝细胞[2].本试验旨在用组织病理学和免疫组化方法,研究HGF在试验性肝纤维化不同时期肝组织中的分布与含量的变化,为进一步阐明HGF在肝纤维化发生中的作用机制做出贡献.     

猪链球菌2型感染动物模型研究进展

猪链球菌2型(SS2)是以败血症、脑膜炎、关节炎为主要特征的人兽共患病。该病不但对养猪业造成严重经济损失，也会给公共卫生和食品安全带来威胁，但由于其毒力因子和感染机制还不十分清楚，尚不能有效控制。不同动物模型的建立为研究病原的体内动态分布、感染机制、毒力因子及免疫应答等提供了依据。作者就国内外对SS2的造模方法及结果进行了介绍，并将不同动物模型的优缺点进行了比较，旨在掌握SS2动物模型研究的动态，为建立更有效的动物模型奠定基础。     

肝脏疾病动物模型的研究进展

肝脏是物质和能量代谢的重要枢纽,通常在酒精、药物、有毒化合物等有害物质作用下,将造成急性或慢性肝损伤,如果得不到有效缓解,可进一步恶化为肝纤维化、肝硬化或肝癌。实验性肝病动物模型对研究肝病发病机理、筛选治疗药物有重要意义。本文阐述急性肝损伤、脂肪肝、肝纤维化、肝硬化、肝癌等肝病的动物模型建立方法,为肝脏疾病的研究提供参考资料。     

实验性家兔肝纤维化模型的超声表现

实验动物肝纤维化的诊断目前仍为有创的肝穿刺活检和动物处死后的组织病理诊断,我们拟通过实验动物兔肝纤维时兔肝的二维超声表现和血流变化,实现实验动物肝纤维化的活体状态下无创性诊断,以方便建立肝纤维化动物模型。1材料与方法1.1动物模型的建立采用四氯化碳中毒性肝纤维化动物模型。具体方法:新西兰白兔40只,随机分为2组,每组20只,第1组为正常对照组,第2组为模型制作组。模型制作组按0.10m L/kg的剂量腹腔注射四氯化碳,5d注射一次。正常对照组按0.10m L/kg的剂量,腹腔注射生理盐水,5d注射一次。两组均持续60d。1.2超声检测内容采用A …     

四种肥胖动物造模方法的比较

肥胖症是遗传因素与环境因素共同作用所导致的营养代谢障碍性疾病,是慢性疾病发生的主要诱因.随着世界上许多国家工业化和城市化程度的不断加深,肥胖症的发病率和死亡率也不断升高,预防和治疗肥胖症已经成为21世纪的重要健康问题.为了确定引起肥胖的各种关键基因,并对其分子生物学机制进行深入的研究,肥胖动物模型是必不可少的研究对象.文章结合国内外研究进展综述了高脂肪饲料、下丘脑腹内侧核损伤、双侧卵巢切除法以及大量维生素D诱导等四种肥胖动物模型的造模特点、构建方法及造模成功判定的标准,为科研工作者今后在开展肥胖症相关实验研究和前期使用和选择肥胖动物模型提供参考.     

硬皮病动物模型及其应用研究进展

硬皮病是一种以组织纤维化、闭塞性血管炎和产生大量自身抗体为特征的结缔组织病,病因及发病机制至今尚未完全明了,尚无理想的治疗药物和方法。该文对建立硬皮病模型动物的选择进行了比较,介绍了应用博来霉素诱导Balb/c小鼠产生硬皮病样病变以及应用V型胶原重塑新西兰兔硬皮病样改变等建立硬皮病模型的方法,对应用这两种动物模型研究硬皮病发病机制和中药临床治疗研究概况进行了综述。     

Focal nodular hyperplasia in the livers of cynomolgus macaques (macaca fascicularis)

Two cases of spontaneous focal hepatic hyperplasia were observed in young female cynomolgus macaques (Macaca fascicularis). Grossly, a single raised nodule was observed in the left hepatic lobe. Histopathologically, the nodule compressed surrounding normal tissue; however, the hepatic cords within the nodule continued to those in the nor mal area except in part. Extensive fibrosis and absence of a normal hepatic triad were observed in the nodule. Thin fibrous septa radiating from the dense central stellate scarring and distended vessels were apparent in one animal. Hepatocytes in the nodule lacked cellular atypia, showed frequent PAS-positive eosinophilic inclusions in the cytoplasm and showed higher positive ratios for PCNA. The present cases resembled focal nodular hyperplasia reported in humans and a chimpanzee.     

Dimethylnitrosamine-induced liver fibrosis and recovery in NOD/SCID mice

There is a need for a new liver fibrosis model of immunodeficient mice to study the effects of cell therapy on liver disease because there are not many animal models available to study the effects of cell therapy. In this study, we induced liver fibrosis using dimethylnitrosamine (DMN) in NOD/SCID mice to create an animal model for liver disease. DMN (5 mg/kg, i.p.) was injected intraperitoneally for three consecutive days per week for 6 or 8 weeks, and the mice were sacrificed at weeks 0, 4 and 8 after the last DMN injection. The 6-week DMN-treated group gradually recovered from serum biochemical changes, histopathological toxic effects and lesions in the liver at weeks 4 and 8 after the last DMN injection. However, the progression of liver fibrosis and toxic levels were maintained in the 8-week DMN-treated group at week 4 after the last DMN injection. The increases in iron and extracellular matrix (collagen) in the DMN-treated group were confirmed by Prussian blue (PB) and Masson's trichrome (MT) staining, respectively. Additionally, activation of hepatic stellate cells was observed by alpha smooth muscle actin (α-SMA) immunostaining and western blot. In conclusion, treatment of NOD/SCID mice with 5 mg/kg of DMN for 8 weeks can be used to induce an appropriate animal model of disease for liver fibrosis. This model may be useful for evaluation of the efficacy and safety of cell therapies such as human mesenchymal stem cell therapy.     

Hepatic Fibrosis in Dogs

Hepatic fibrosis is commonly diagnosed in dogs, often as a sequela to chronic hepatitis (CH). The development of fibrosis is a crucial event in the progression of hepatic disease that is of prognostic value. The pathophysiology of hepatic fibrosis in human patients and rodent models has been studied extensively. Although less is known about this process in dogs, evidence suggests that fibrogenic mechanisms are similar between species and that activation of hepatic stellate cells is a key step. Diagnosis and staging of hepatic fibrosis in dogs requires histopathological examination of a liver biopsy specimen. However, performing a liver biopsy is invasive and assessment of fibrotic stage is complicated by the absence of a universally accepted staging scheme in veterinary medicine. Serum biomarkers that can discriminate among different fibrosis stages are used in human patients, but such markers must be more completely evaluated in dogs before clinical use. When successful treatment of its underlying cause is feasible, reversal of hepatic fibrosis has been shown to be possible in rodent models and human patients. Reversal of fibrosis has not been well documented in dogs, but successful treatment of CH is possible. In human medicine, better understanding of the pathomechanisms of hepatic fibrosis is leading to the development of novel treatment strategies. In time, these may be applied to dogs. This article comparatively reviews the pathogenesis of hepatic fibrosis, its diagnosis, and its treatment in dogs.     

Plasma concentration of transforming growth factor-β1 and hepatic fibrosis in dogs

Liver fibrosis is a morphologic alteration that accompanies chronic liver diseases. Apart from analysis of liver biopsy specimens, there has been no means of diagnosing and evaluating the course of liver fibrosis in the dog. Several plasma markers, including transforming growth factor beta-1 (TGF-β1), are used to indicate liver fibrosis in humans, but none has been validated for use in dogs. There is a significant correlation between the presence and severity of hepatic fibrosis and the plasma concentration of TGF-β1 in humans with hepatic fibrosis and cirrhosis. The feasibility of using TGF-β1 as a marker for hepatic fibrosis in dogs was evaluated by comparing plasma concentrations in 29 healthy dogs and 18 dogs with liver disease. The plasma concentrations of TGF-β1, were 193 to 598 pg/mL in the healthy dogs, 143 to 475 pg/mL in the 7 dogs with mild hepatic fibrosis or none at all, and 427 to 1289 pg/mL in 11 dogs with moderate to severe hepatic fibrosis. The plasma concentrations of TGF-β1 in the dogs with moderate to severe fibrosis differed significantly (P < 0.001) from those in the other 2 groups, whereas the concentrations in the dogs with mild or no fibrosis did not differ significantly from those in the healthy dogs (P > 0.05). It was concluded that TGF-β1 is a potential plasma marker for hepatic fibrosis in dogs.     

Sclerosing cholangitis in baboons (Papio spp) resembling primary sclerosing cholangitis of humans

Primary sclerosing cholangitis is a chronic and progressive cholestatic liver disease that has been extensively documented in the human literature. Although it shares many features in common with chronic lymphocytic cholangitis in cats, primary sclerosing cholangitis has never been reported in a nonhuman primate. Primary sclerosing cholangitis is characterized by the presence of intrahepatic and/or extrahepatic inflammation and concentric fibrosis of bile ducts, eventually leading to cirrhosis and hepatic failure. The pathogenesis and cause remain unknown, but the disease likely involves a multifactorial mechanism with genetic- and immune-mediated components. The authors report 2 cases that histologically resemble the condition in humans; they consist of 2 adult male baboons with a clinical history of chronic elevated liver enzymes. In both cases, the liver was histologically characterized by thick bands of fibrosis and mild lymphoplasmacytic periportal cholangiohepatitis with concentric periductal fibrosis, resulting in atrophy and loss of bile ducts. Immunohistochemical analysis revealed positivity of hepatocytes to cytokeratin 7. Masson stain demonstrated marked biliary fibrosis. This is the first report that resembles sclerosing cholangitis in a nonhuman primate, and it suggests that the baboon may provide a useful animal model for this condition in humans.     

Congenital hepatic fibrosis and cystic bile duct formation in Swiss Freiberger horses

Congenital hepatic fibrosis with autosomal recessive or dominant inheritance has been described in humans, cats, piglets, and dogs. In horses, only two cases of congenital hepatic fibrosis have been previously reported. This retrospective study of records from the Institute for Animal Pathology, University of Berne, identified 30 foals with liver lesions compatible with congenital hepatic fibrosis. Anamnestic data revealed clinical signs of severe liver injury in most affected animals. Pathologic examination showed severely enlarged, firm livers with thin-walled cysts. Histologically, the livers showed diffuse porto-portal bridging fibrosis with many small, irregularly formed and sometimes cystic bile ducts. All foals belonged to the Swiss Freiberger breed. Pedigree analysis revealed that the diseased animals could be traced back to one stallion. These results strongly suggest that congenital hepatic fibrosis in Swiss Freiberger horses is a recessively inherited autosomal genetic defect.     

Copper-induced hepatitis: the COMMD1 deficient dog as a translational animal model for human chronic hepatitis

Chronic inflammatory liver disease regardless of aetiology leads to failing regeneration and fibrosis, ending in cirrhosis. Both in man and in animals this worldwide health problem has no definitive cure. Chronic liver injury causes hepatic stellate cells to proliferate and differentiate into matrix-producing cells. New therapeutic options will be developed upon detailed understanding of the molecular mechanisms driving liver fibrosis. This may lead to new anti-fibrotic therapies which need to be tested in suitable models before application in the veterinary and human clinic. On the other side, to restore the failing regenerative capacity of the diseased liver cells, adult progenitor cells are of interest, as an alternative to whole organ transplantation. In order to find the most suitable large animal model it is important to recognise that the typical histopathological reaction pattern of the liver can differ between mammalian species. It is therefore imperative that specialists in veterinary internal medicine and pathology, being familiar with the diseases and pathologies of the liver in different animal species, are teaming-up in finding the best models for veterinary and human liver diseases. Several large animal models have been mentioned, like pigs, sheep, and dogs. Based on the observations that man and dog share the same hepatopathies and have identical clinical, pathological and pathogenetic reaction patterns during the development of liver disease, the dog seems to be a properly suited species to test new therapeutic strategies for pets and their best friends.     

Clinical jaundice in a dolphin

Clinical icterus related to hepatic fibrosis and atrophy, pancreatic fibrosis, and fibrosis of the extrahepatic biliary system was observed in a mature male bottle-nosed dolphin. The underlying cause of the hepatic disease was undetermined.     

Chronic copper toxicity in a dairy cow

A three year old Holstein dairy cow fed a ration containing a copper supplement died of chronic copper poisoning. The concentration of copper in the liver was 331 ppm (wet weight). The typical lesions of chronic copper toxicity including icterus, hepatic fibrosis and hemoglobinemic nephrosis were found at necropsy. The chronic copper toxicity was not considered to be a herd problem since the liver copper concentration in a slaughtered cull animal and blood samples taken from five animals in the same herd were within normal limits.     

Iron storage disease in captive Egyptian fruit bats (Rousettus aegyptiacus): relationship of blood iron parameters to hepatic iron concentrations and hepatic histopathology.

This study evaluated the relationship between blood iron parameters and hepatic iron concentrations, and correlation of histologic findings with hepatic iron concentrations in a captive population of Egyptian fruit bats (Rousettus aegyptiacus) and island flying foxes (Pteropus hypomelanus). Blood samples were collected for complete blood counts, plasma biochemical profiles, serum iron concentrations, total iron-binding capacity, whole-blood lead concentrations, and plasma ferritin assays. Liver samples obtained by laparotomy were divided, with one half processed for histologic examination and the other half frozen and submitted for tissue mineral analysis. The histologic sections were scored by two blinded observers for iron deposition, necrosis, and fibrosis. The Egyptian fruit bats had significantly higher liver iron (mean = 3,669 +/- 1,823 ppm) and lead (mean = 8.9 +/- 5.8 ppm) concentrations than the island flying foxes (mean [Fe] = 174 +/- 173 ppm, mean [Pb] = 1.9 +/- 0.5 ppm). Hepatic iron concentrations significantly correlated with tissue lead concentrations, histologic grading for iron and necrosis, serum iron, transferrin saturation, and plasma ferritin (P < 0.001). Blood lead concentrations negatively correlated with tissue lead concentrations (P < 0.001). When the product of transferrin saturation and serum iron was greater than 51, an individual animal had a high probability of having iron overload. When the product of these two variables was greater than 90, there was a high probability that the animal had hemochromatosis. On the basis of this study, it appears that evaluation of serum iron, transferrin saturation, and plasma ferritin are useful and noninvasive methods for diagnosis of hemochromatosis in Egyptian fruit bats.