AIM:To establish an appropriate primate model of fulminant hepatic failure (FHF).METHODS:We have,for the first time,established a large animal model of FHF in Macaca mulatta by intraperitoneal infusion of amatoxin and...AIM:To establish an appropriate primate model of fulminant hepatic failure (FHF).METHODS:We have,for the first time,established a large animal model of FHF in Macaca mulatta by intraperitoneal infusion of amatoxin and endotoxin.Clinical features,biochemical indexes,histopathology and iconography were examined to dynamically investigate the progress and outcome of the animal model.RESULTS:Our results showed that the enzymes and serum bilirubin were markedly increased and the enzyme-bilirubin segregation emerged 36 h after toxin administration.Coagulation activity was significantly decreased.Gradually deteriorated parenchymal abnormality was detected by magnetic resonance imaging (MRI) and ultrasonography at 48 h.The liver biopsy showed marked hepatocyte steatosis and massive parenchymal necrosis at 36 h and 49 h,respectively.The autopsy showed typical yellow atrophy of the liver.Hepatic encephalopathy of the models was also confirmed by hepatic coma,MRI and pathological changes of cerebral edema.The lethal effects of the extrahepatic organ dysfunction were ruled out by their biochemical indices,imaging and histopathology.CONCLUSION:We have established an appropriate large primate model of FHF,which is closely similar to clinic cases,and can be used for investigation of the mechanism of FHF and for evaluation of potential medical therapies.展开更多
AIM： To investigate the impact of dietary copper given at different time points on the onset of fulminant hepatitis. METHODS： The Long-Evans cinnamon （LEC） rat mod- el of Wilson＇s disease （WD） was used to study...AIM： To investigate the impact of dietary copper given at different time points on the onset of fulminant hepatitis. METHODS： The Long-Evans cinnamon （LEC） rat mod- el of Wilson＇s disease （WD） was used to study the im- pact of high dietary copper （hCu） on the induction of fulminant hepatitis at early or late time points of life. High Cu diet was started in rat pups or in adults （month 5） for three months. Animals that received reduced di- etary copper （rCu） throughout their lifetime served as a control. Hepatitis-associated serum markers （alanine aminotransferase, aspartate transaminase, bilirubin） were analyzed in animal groups receiving hCu or rCu. Liver copper content and liver histology were revealed at sacrifice. A set of 5 marker genes previously found to be affected in injured liver and which are related to angiogenesis （Vegfa）, fat metabolism （Srebf1）, ex- tracellular matrix （Timp1）, oxidative stress （Hmox1）, and the cell cycle （Cdknla） were analyzed by real-time polymerase chain reaction. RESULTS： Regardless of the time point when hCu was started, LEC rats （35/36） developed fulminant hepati- tis and died. Animals receiving rCu （36/36） remained healthy, did not develop hepatitis, and survived long term without symptoms of overt disease, although liver copper accumulated in adult animals （477 ± 75 μg/g）. With regard to start of hCu, onset of fulminant hepatitis was significantly （P 〈 0.001） earlier in adults （35±9 d） that showed pre-accumulation of liver copper as com- pared to the pup group （77±15 d）. Hepatitis-associ- ated serum markers, liver copper and liver histology, as well as gene expression, were affected in LEC rats re- ceiving hCu. However, except for early and rapid onset of hepatitis, biochemical and molecular markers were similar at the early and late time points of disease. CONCLUSION： Rapid onset of fulminant hepatitis in asymptomatic LEC rats with elevated liver copper sug- gests that there is a critical threshold of liver copper which is important to trigger the course of WD.展开更多
The role of chemokines in murine hepatitis virus strain 3 (MHV-3) induced fulminant hepatic failure (FHF) is not well defined. In this study, we investigated the role of the CXC chemokine receptor 3 (CXCR3)- associate...The role of chemokines in murine hepatitis virus strain 3 (MHV-3) induced fulminant hepatic failure (FHF) is not well defined. In this study, we investigated the role of the CXC chemokine receptor 3 (CXCR3)- associated chemokine [monokine induced by IFN-gamma (Mig/CXCL9) and interferon-gamma-inducible protein 10 (IP-10/CXCL10)] in the recruitment of intrahepatic lymphocytes and subsequent fulminant hepatic failure induced by MHV-3. Balb/cJ mice (6-8 weeks, female) were intraperitioneally injected with 100 PFU MHV-3.The proportions and numbers of T cells and NK cells as well as the expression of CXCR3 on T cells and NK cells in the liver, spleen and blood were analyzed by flow cytometry. The hepatic mRNA level of the CXCR3-associated chemokines (CXCL9 and CXCL10) was detected by realtime PCR. A transwell migration assay was used to assess the chemotactic effect of MHV-3-infected hepatocytes on the splenic lymphocytes. Following MHV-3 infection, the number of hepatic NK cells and T cells and the frequencies of hepatic NK cells and T cells expressing CXCR3 increased markedly; however, in the spleen and peripheral blood, they both decreased significantly. Moreover, the hepatic mRNAs levels of CXCL9 and CXCL10 were significantly elevated post infection. The transwell migration assay demonstrated that MHV-3-infected hepatocytes have the capacity to attract and recruit the splenic NK cells and T cells, and CXCL10 plays a key role in lymphocyte mobilization from the spleen. These results suggest that the CXCR3- associated chemokines (CXCL9 and CXCL10) may play animportant role in the recruitment of intrahepatic lymphocytes and subsequent necroinflammation and hepatic failure in MHV-3 infection.展开更多
The pathogenesis of autoimmune hepatitis (AIH) is complex. However,it is believed that a susceptible individual,owing to his genetic background,sex and age,can develop the disease following exposure to an environmenta...The pathogenesis of autoimmune hepatitis (AIH) is complex. However,it is believed that a susceptible individual,owing to his genetic background,sex and age,can develop the disease following exposure to an environmental trigger. Autoimmune hepatitis does not follow a Mendelian pattern of inheritance; hence no single causative genetic locus has been identified. However,several genes,inside and outside the HLA locus,have been linked to an increased susceptibility to AIH. Epidemiological evidence also suggests that the sex and age of the patient plays a role in AIH pathogenesis as the disease onset occurs mainly in the two first decades of life and a higher disease incidence is observed in females. No environmental trigger has been identified,but several have been proposed,mainly viruses and xenobiotics. This article aims at reviewing the current knowledge on susceptibility factors leading to AIH and putative triggers,emphasizing fundamental mechanisms responsible for the break of liver immunological tolerance.展开更多
基金Supported by National Basic Research Program of China,No.2009CB522401grand from Natural Science Foundation ofChina,No. 30870983 and 30971118
文摘AIM:To establish an appropriate primate model of fulminant hepatic failure (FHF).METHODS:We have,for the first time,established a large animal model of FHF in Macaca mulatta by intraperitoneal infusion of amatoxin and endotoxin.Clinical features,biochemical indexes,histopathology and iconography were examined to dynamically investigate the progress and outcome of the animal model.RESULTS:Our results showed that the enzymes and serum bilirubin were markedly increased and the enzyme-bilirubin segregation emerged 36 h after toxin administration.Coagulation activity was significantly decreased.Gradually deteriorated parenchymal abnormality was detected by magnetic resonance imaging (MRI) and ultrasonography at 48 h.The liver biopsy showed marked hepatocyte steatosis and massive parenchymal necrosis at 36 h and 49 h,respectively.The autopsy showed typical yellow atrophy of the liver.Hepatic encephalopathy of the models was also confirmed by hepatic coma,MRI and pathological changes of cerebral edema.The lethal effects of the extrahepatic organ dysfunction were ruled out by their biochemical indices,imaging and histopathology.CONCLUSION:We have established an appropriate large primate model of FHF,which is closely similar to clinic cases,and can be used for investigation of the mechanism of FHF and for evaluation of potential medical therapies.
基金Supported by Deutsche Forschungsgemeinschaft, SCHM 964/10-1Innovative Medizinische Forschung, Münster
文摘AIM： To investigate the impact of dietary copper given at different time points on the onset of fulminant hepatitis. METHODS： The Long-Evans cinnamon （LEC） rat mod- el of Wilson＇s disease （WD） was used to study the im- pact of high dietary copper （hCu） on the induction of fulminant hepatitis at early or late time points of life. High Cu diet was started in rat pups or in adults （month 5） for three months. Animals that received reduced di- etary copper （rCu） throughout their lifetime served as a control. Hepatitis-associated serum markers （alanine aminotransferase, aspartate transaminase, bilirubin） were analyzed in animal groups receiving hCu or rCu. Liver copper content and liver histology were revealed at sacrifice. A set of 5 marker genes previously found to be affected in injured liver and which are related to angiogenesis （Vegfa）, fat metabolism （Srebf1）, ex- tracellular matrix （Timp1）, oxidative stress （Hmox1）, and the cell cycle （Cdknla） were analyzed by real-time polymerase chain reaction. RESULTS： Regardless of the time point when hCu was started, LEC rats （35/36） developed fulminant hepati- tis and died. Animals receiving rCu （36/36） remained healthy, did not develop hepatitis, and survived long term without symptoms of overt disease, although liver copper accumulated in adult animals （477 ± 75 μg/g）. With regard to start of hCu, onset of fulminant hepatitis was significantly （P 〈 0.001） earlier in adults （35±9 d） that showed pre-accumulation of liver copper as com- pared to the pup group （77±15 d）. Hepatitis-associ- ated serum markers, liver copper and liver histology, as well as gene expression, were affected in LEC rats re- ceiving hCu. However, except for early and rapid onset of hepatitis, biochemical and molecular markers were similar at the early and late time points of disease. CONCLUSION： Rapid onset of fulminant hepatitis in asymptomatic LEC rats with elevated liver copper sug- gests that there is a critical threshold of liver copper which is important to trigger the course of WD.
基金the National Key Basic Research Program of China (2007CB512900, 2005CB522901, 2005CB 522507)the National Science Fund of China (NSFC 30672380, 30571643)
文摘The role of chemokines in murine hepatitis virus strain 3 (MHV-3) induced fulminant hepatic failure (FHF) is not well defined. In this study, we investigated the role of the CXC chemokine receptor 3 (CXCR3)- associated chemokine [monokine induced by IFN-gamma (Mig/CXCL9) and interferon-gamma-inducible protein 10 (IP-10/CXCL10)] in the recruitment of intrahepatic lymphocytes and subsequent fulminant hepatic failure induced by MHV-3. Balb/cJ mice (6-8 weeks, female) were intraperitioneally injected with 100 PFU MHV-3.The proportions and numbers of T cells and NK cells as well as the expression of CXCR3 on T cells and NK cells in the liver, spleen and blood were analyzed by flow cytometry. The hepatic mRNA level of the CXCR3-associated chemokines (CXCL9 and CXCL10) was detected by realtime PCR. A transwell migration assay was used to assess the chemotactic effect of MHV-3-infected hepatocytes on the splenic lymphocytes. Following MHV-3 infection, the number of hepatic NK cells and T cells and the frequencies of hepatic NK cells and T cells expressing CXCR3 increased markedly; however, in the spleen and peripheral blood, they both decreased significantly. Moreover, the hepatic mRNAs levels of CXCL9 and CXCL10 were significantly elevated post infection. The transwell migration assay demonstrated that MHV-3-infected hepatocytes have the capacity to attract and recruit the splenic NK cells and T cells, and CXCL10 plays a key role in lymphocyte mobilization from the spleen. These results suggest that the CXCR3- associated chemokines (CXCL9 and CXCL10) may play animportant role in the recruitment of intrahepatic lymphocytes and subsequent necroinflammation and hepatic failure in MHV-3 infection.
文摘The pathogenesis of autoimmune hepatitis (AIH) is complex. However,it is believed that a susceptible individual,owing to his genetic background,sex and age,can develop the disease following exposure to an environmental trigger. Autoimmune hepatitis does not follow a Mendelian pattern of inheritance; hence no single causative genetic locus has been identified. However,several genes,inside and outside the HLA locus,have been linked to an increased susceptibility to AIH. Epidemiological evidence also suggests that the sex and age of the patient plays a role in AIH pathogenesis as the disease onset occurs mainly in the two first decades of life and a higher disease incidence is observed in females. No environmental trigger has been identified,but several have been proposed,mainly viruses and xenobiotics. This article aims at reviewing the current knowledge on susceptibility factors leading to AIH and putative triggers,emphasizing fundamental mechanisms responsible for the break of liver immunological tolerance.
