Non-alcoholic fatty liver disease(NAFLD)or metabolic(dysfunction)-associated fatty liver disease is the leading cause of chronic liver diseases defined as a disease spectrum comprising hepatic steatosis,non-alcoholic ...Non-alcoholic fatty liver disease(NAFLD)or metabolic(dysfunction)-associated fatty liver disease is the leading cause of chronic liver diseases defined as a disease spectrum comprising hepatic steatosis,non-alcoholic steatohepatitis(NASH),liver fibrosis,cirrhosis,and hepatic carcinoma.NASH,characterized by hepatocyte injury,steatosis,inflammation,and fibrosis,is associated with NAFLD prognosis.Ductular reaction(DR)is a common compensatory reaction associated with liver injury,which involves the hepatic progenitor cells(HPCs),hepatic stellate cells,myofibroblasts,inflammatory cells(such as macrophages),and their secreted substances.Recently,several studies have shown that the extent of DR parallels the stage of NASH and fibrosis.This review summarizes previous research on the correlation between DR and NASH,the potential interplay mechanism driving HPC differentiation,and NASH progression.展开更多
Basic and translational wound healing research in the biliary tree lag significantly behind similar studies on the skin and gastrointestinal tract. This is at least partly attributable to lack of easy access to the bi...Basic and translational wound healing research in the biliary tree lag significantly behind similar studies on the skin and gastrointestinal tract. This is at least partly attributable to lack of easy access to the biliary tract for study. But clinical relevance, more interest in biliary epithelial cell （BEC） pathophysiology, and widespread availability of BEC cultures are factors reversing this trend. In the extra-hepatic biliary tree, ineffectual wound healing, scarring and stricture development are pressing issues. In the smallest intra-hepatic bile ducts either impaired BEC proliferation or an exuberant response can contribute to liver disease. Chronic inflammation and persistent wound healing reactions in large and small bile ducts often lead to liver cancer. General concepts of wound healing as they apply to the biliary tract, importance of cellular processes dependent on IL-6/gp130/STAT3 signaling pathways, unanswered questions, and future directions are discussed.展开更多
AIM: To investigate if loss of epithelial cell adhesion molecule (EpCAM) is associated with microinvasion in hepatocellular carcinomas (HCCs) in the presence of chronic hepatitis B.
Non-alcoholic fatty liver disease(NAFLD)is a disease spectrum caused in part by insulin resistance and genetic predisposition.This disease is primarily characterized by excessive lipid accumulation in hepatocytes in t...Non-alcoholic fatty liver disease(NAFLD)is a disease spectrum caused in part by insulin resistance and genetic predisposition.This disease is primarily characterized by excessive lipid accumulation in hepatocytes in the absence of alcohol abuse and other causes of liver damage.Histologically,NAFLD is divided into several periods:simple steatosis,non-alcoholic steatohepatitis(NASH),hepatic fibrosis,cirrhosis,and hepatocellular carcinoma.With the increasing prevalence of obesity and hyperlipidemia,NAFLD has become the main cause of chronic liver disease worldwide.As a result,the pathogenesis of this disease is drawing increasing attention.Ductular reaction(DR)is a reactive bile duct hyperplasia caused by liver injury that involves hepatocytes,cholangiocytes,and hepatic progenitor cells.Recently,DR is shown to play a pivotal role in simple steatosis progression to NASH or liver fibrosis,providing new research and treatment options.This study reviews several DR signaling pathways,including Notch,Hippo/YAP-TAZ,Wnt/β-catenin,Hedgehog,HGF/c-Met,and TWEAK/Fn14,and their role in the occurrence and development of NASH.展开更多
AIM： To clarify the pathogenesis of ductular proliferation and its possible association with oval cell activation and hepatocyte regeneration. METHODS： Immunohistochemical staining and image analysis of the ductular...AIM： To clarify the pathogenesis of ductular proliferation and its possible association with oval cell activation and hepatocyte regeneration. METHODS： Immunohistochemical staining and image analysis of the ductular structures in the liver tissues from 11 patients with severe chronic hepatitis B and 2 healthy individuals were performed. The liver specimens were sectioned serially, and then cytokeratin 8 （CK8）, CK19, OV6, proliferating cell nuclear antigens （PCNA）, glutathione-S-transferase （GST）, α-fetal protein （AFP） and albumin were stained immunohistochemically. RESULTS： Typical and atypical types of ductular proliferation were observed in the portal tracts of the liver tissues in all 11 patients. The proliferating ductular cells were positive for CKS, CK19, OV6 and PCNA staining. Some atypical ductular cells displayed the morphological and immunohistochemical characteristics of hepatic oval cells. Some small hepatocyte-like cells were between hepatic oval cells and mature hepatocytes morphometrically and immunohistochemically. CONCLUSION： The proliferating ductules in the liver of patients with severe chronic liver disease may have different origins. Some atypical ductular cells are actually activated hepatic oval cells. Atypical ductular proliferation is related to hepatocyte regeneration and small hepatocyte-like cells may be intermediate transient cells between hepatic oval cells and mature hepatocytes.展开更多
Background:Biliary atresia is a rare congenital bile duct disease that is the leading cause of liver fibrosis in neonates.Granulocyte colony-stimulating factor(GCSF)is a potential therapy for hepatocellular diseases,b...Background:Biliary atresia is a rare congenital bile duct disease that is the leading cause of liver fibrosis in neonates.Granulocyte colony-stimulating factor(GCSF)is a potential therapy for hepatocellular diseases,but data on GCSF for cholestatic conditions remain limited.Materials and methods:The current study examines the role of GCSF in improving bile duct obstruction in mice.Two doses were administered:10.0 mg/kg/day and 61.5 mg/kg/day,which is the animal equivalent dose of 5.0 mg/kg in humans.Seven days(D7)after bile duct ligation(BDL),Swiss mice were treated with phosphate buffered saline or GCSF for 5 days.The intrahepatic adaptive response of BDL mice was evaluated on postsurgical days D12,D19,and D26.Results:Treatment with 61.5 mg/kg of GCSF resulted in a significant increase in circulating leukocytes and neutrophils on D12.Amelioration of liver injury,as shown by reduced aspartate aminotransferase levels,increased albumin levels and survival rate,as well as reduced intrahepatic inflammation and hepatic myeloperoxidase expression,downregulated ductular proliferation,periportal fibroblast activation,and fibrosis,enhanced expressions of hepatocyte growth factor,peroxisome proliferator-activated receptoralpha,and ki67,and suppressed expression of cleaved caspase-3 protein,was noted after treatment with 61.5 mg/kg of GCSF.Additionally,GCSF treatment was associated with an increased number of intrahepatic cd3-Sca1tc-Kitt bone marrow cells.展开更多
Primary biliary cholangitis(PBC)is a chronic cholestatic liver disease that is observed more frequently in middle-aged women.This disorder is considered an autoimmune disease,since liver injury is sustained by the pre...Primary biliary cholangitis(PBC)is a chronic cholestatic liver disease that is observed more frequently in middle-aged women.This disorder is considered an autoimmune disease,since liver injury is sustained by the presence of selfdirected antimitochondrial antibodies targeting the bile duct cells.The prognosis may vary depending on an early diagnosis and response to therapy.However,nearly a third of patients can progress to liver cirrhosis,thus requiring a liver transplant.Traditional immunosuppressive therapies,commonly employed for other autoimmune diseases,have limited effects on PBC.In fact,dramatic functional changes that occur in the biliary epithelium in the course of inflammation play a major role in perpetuating the injury.In this minireview,after a background on the disease and possible predisposing factors,the sequential cooperation of cellular/molecular events leading to end-stage PBC is discussed in detail.The rise and maintenance of the autoimmune process,as well as the response of the biliary epithelia during inflammatory injury,are key factors in the progression of the disease.The so-called“ductular reaction(DR)”,intended as a reactive expansion of cells with biliary phenotype,is a process frequently observed in PBC and partially understood.However,recent findings suggest a strict relationship between this pathological picture and the progression to liver fibrosis,cell senescence,and loss of biliary ducts.All these issues(onset of chronic inflammation,changes in secretive and proliferative biliary functions,DR,and its relationship with other pathological events)are discussed in this manuscript in an attempt to provide a snapshot,for clinicians and researchers,of the most relevant and sequential contributors to the progression of this human cholestatic disease.We believe that interpreting this disorder as a multistep process may help identify possible therapeutic targets to prevent evolution to severe disease.展开更多
AIM： To investigate the effects of troglitazone （TGZ）, an anti-diabetic drug which activates peroxisome proliferatoractivated receptor-y （PPAR-y）, for liver tissue repair, and the development of ductular reaction...AIM： To investigate the effects of troglitazone （TGZ）, an anti-diabetic drug which activates peroxisome proliferatoractivated receptor-y （PPAR-y）, for liver tissue repair, and the development of ductular reaction, following common bile duct ligation （BDL） in rats. METHODS： Rats were supplemented with TGZ （0.2% w/w in the pelleted food） for i wk before BDL or sham operation. Animals were killed at 1, 2, or 4 wk after surgery. RESULTS： The development of liver fibrosis was reduced in rats receiving TGZ, as indicated by significant decreases of procollagen type I gene expression and liver hydroxyproline levels. Accumulation of a-smooth-muscle actin （SMA）-expressing cells surrounding newly formed bile ducts following BDL, as well as total hepatic levels of SMA were partially inhibited by TGZ treatment, indicating the presence of a reduced number and/or activation of hepatic stellate cells （HSC） and myofibroblasts. Development of the ductular reaction was inhibited by TGZ, as indicated by histochemical evaluation and hepatic activity of γ-glutamyltransferase （GGT）. CONCLUSION： Treatment with thiazolidinedione reduces ductular proliferation and fibrosis in a model of chronic cholestasis, and suggests that limiting cholangiocyte proliferation may contribute to the lower development of scarring in this system.展开更多
AIM To elucidate the role of STAT3 in hepatocarcinogenesis and biliary ductular proliferation following chronic liver injury. METHODS We investigated thioacetamide(TAA)-induced liver injury, compensatory hepatocyte pr...AIM To elucidate the role of STAT3 in hepatocarcinogenesis and biliary ductular proliferation following chronic liver injury. METHODS We investigated thioacetamide(TAA)-induced liver injury, compensatory hepatocyte proliferation, and hepatocellular carcinoma(HCC) development in hepatic STAT3-deficient mice. In addition, we evaluated TAAinduced biliary ductular proliferation and analyzed the activation of sex determining region Y-box9(SOX9) and Yes-associated protein(YAP), which regulate the transdifferentiation of hepatocytes to cholangiocytes.RESULTS Both compensatory hepatocyte proliferation and HCC formation were significantly decreased in hepatic STAT3-deficient mice as compared with control mice. STAT3 deficiency resulted in augmentation of hepatic necrosis and fibrosis. On the other hand, biliary ductular proliferation increased in hepatic STAT3-deficient livers as compared with control livers. SOX9 and YAP were upregulated in hepatic STAT3-deficient hepatocytes.CONCLUSION STAT3 may regulate hepatocyte proliferation as well as transdifferentiation into cholangiocytes and serve as a therapeutic target for HCC inhibition and biliary regeneration.展开更多
AIM： Although increased insulin-like growth factor-I receptor （IGF-IR） gene expression has been reported in hepatocellular carcinoma, studies assessing IGF-IR in chronic hepatitis C （CHC） and cirrhosis are scarce...AIM： Although increased insulin-like growth factor-I receptor （IGF-IR） gene expression has been reported in hepatocellular carcinoma, studies assessing IGF-IR in chronic hepatitis C （CHC） and cirrhosis are scarce. We therefore aimed to evaluate IGF-IR and IGF-I rnRNA expression in liver from patient with CHC. METHODS： IGF-IR and IGF-I rnRNA content were determined by semi-quantitative RT-PCR and IGF-IR protein expression was determined by immunohistochemistry in hepatic tissue obtained from patients with CHC before （34 patients） and after （10 patients） therapy with interferon-α and ribavirin. RESULTS： An increase of IGF-IR rnRNA content was observed in hepatic tissue obtained from all CHC patients as well as from 6 cadaveric liver donors following orthopic transplantation （an attempt to evaluate normal livers） in comparison to normal liver, while no relevant modifications were detected in IGF-I mRNA content. The irnrnunohistochemical results showed that the raise in IGF-IR rnRNA content was related both to ductular reaction and to increased IGF-IR expression in hepatocytes. A decrease in IGF-IR rnRNA content was observed in patients who achieved sustained virological response after therapy, suggesting an improvement in hepatic damage. CONCLUSION： The up-regulation of IGF-IR expression in hepatocytes of patients with CHC could constitute an attempt to stimulate hepatocyte regeneration. Considering that liver is the organ with the highest levels of IGF-I, our finding of increased IGF-IR expression after both acute and chronic hepatic damage highlights the need for additional studies to elucidate the role of IGF-I in liver regeneration.展开更多
基金the National Natural Science Foundation of China,No.81970511&82270620.
文摘Non-alcoholic fatty liver disease(NAFLD)or metabolic(dysfunction)-associated fatty liver disease is the leading cause of chronic liver diseases defined as a disease spectrum comprising hepatic steatosis,non-alcoholic steatohepatitis(NASH),liver fibrosis,cirrhosis,and hepatic carcinoma.NASH,characterized by hepatocyte injury,steatosis,inflammation,and fibrosis,is associated with NAFLD prognosis.Ductular reaction(DR)is a common compensatory reaction associated with liver injury,which involves the hepatic progenitor cells(HPCs),hepatic stellate cells,myofibroblasts,inflammatory cells(such as macrophages),and their secreted substances.Recently,several studies have shown that the extent of DR parallels the stage of NASH and fibrosis.This review summarizes previous research on the correlation between DR and NASH,the potential interplay mechanism driving HPC differentiation,and NASH progression.
文摘Basic and translational wound healing research in the biliary tree lag significantly behind similar studies on the skin and gastrointestinal tract. This is at least partly attributable to lack of easy access to the biliary tract for study. But clinical relevance, more interest in biliary epithelial cell （BEC） pathophysiology, and widespread availability of BEC cultures are factors reversing this trend. In the extra-hepatic biliary tree, ineffectual wound healing, scarring and stricture development are pressing issues. In the smallest intra-hepatic bile ducts either impaired BEC proliferation or an exuberant response can contribute to liver disease. Chronic inflammation and persistent wound healing reactions in large and small bile ducts often lead to liver cancer. General concepts of wound healing as they apply to the biliary tract, importance of cellular processes dependent on IL-6/gp130/STAT3 signaling pathways, unanswered questions, and future directions are discussed.
基金Supported by Key Project of Tianjin Science and Technology Committee,No.05YFSZSF02500Foundation of Tianjin,No.08JCYBJC08300Key Research Project of Tianjin Healthy Bureau,No.11KG112
文摘AIM: To investigate if loss of epithelial cell adhesion molecule (EpCAM) is associated with microinvasion in hepatocellular carcinomas (HCCs) in the presence of chronic hepatitis B.
基金Supported by the National Natural Science Foundation of China,No. 81770582the Graduates’ Innovation FundHuazhong University of Science and Technology,No. 2021yjsCXCY106
文摘Non-alcoholic fatty liver disease(NAFLD)is a disease spectrum caused in part by insulin resistance and genetic predisposition.This disease is primarily characterized by excessive lipid accumulation in hepatocytes in the absence of alcohol abuse and other causes of liver damage.Histologically,NAFLD is divided into several periods:simple steatosis,non-alcoholic steatohepatitis(NASH),hepatic fibrosis,cirrhosis,and hepatocellular carcinoma.With the increasing prevalence of obesity and hyperlipidemia,NAFLD has become the main cause of chronic liver disease worldwide.As a result,the pathogenesis of this disease is drawing increasing attention.Ductular reaction(DR)is a reactive bile duct hyperplasia caused by liver injury that involves hepatocytes,cholangiocytes,and hepatic progenitor cells.Recently,DR is shown to play a pivotal role in simple steatosis progression to NASH or liver fibrosis,providing new research and treatment options.This study reviews several DR signaling pathways,including Notch,Hippo/YAP-TAZ,Wnt/β-catenin,Hedgehog,HGF/c-Met,and TWEAK/Fn14,and their role in the occurrence and development of NASH.
基金Supported by the National Natural Science Foundation of China, No. 30370391
文摘AIM： To clarify the pathogenesis of ductular proliferation and its possible association with oval cell activation and hepatocyte regeneration. METHODS： Immunohistochemical staining and image analysis of the ductular structures in the liver tissues from 11 patients with severe chronic hepatitis B and 2 healthy individuals were performed. The liver specimens were sectioned serially, and then cytokeratin 8 （CK8）, CK19, OV6, proliferating cell nuclear antigens （PCNA）, glutathione-S-transferase （GST）, α-fetal protein （AFP） and albumin were stained immunohistochemically. RESULTS： Typical and atypical types of ductular proliferation were observed in the portal tracts of the liver tissues in all 11 patients. The proliferating ductular cells were positive for CKS, CK19, OV6 and PCNA staining. Some atypical ductular cells displayed the morphological and immunohistochemical characteristics of hepatic oval cells. Some small hepatocyte-like cells were between hepatic oval cells and mature hepatocytes morphometrically and immunohistochemically. CONCLUSION： The proliferating ductules in the liver of patients with severe chronic liver disease may have different origins. Some atypical ductular cells are actually activated hepatic oval cells. Atypical ductular proliferation is related to hepatocyte regeneration and small hepatocyte-like cells may be intermediate transient cells between hepatic oval cells and mature hepatocytes.
基金funded by the Prometheus USA(www.prometheususa.org)and Vietnam National Foundation for Science&Technology Development(NAFOSTED)under grant number 108.05e2017.30.
文摘Background:Biliary atresia is a rare congenital bile duct disease that is the leading cause of liver fibrosis in neonates.Granulocyte colony-stimulating factor(GCSF)is a potential therapy for hepatocellular diseases,but data on GCSF for cholestatic conditions remain limited.Materials and methods:The current study examines the role of GCSF in improving bile duct obstruction in mice.Two doses were administered:10.0 mg/kg/day and 61.5 mg/kg/day,which is the animal equivalent dose of 5.0 mg/kg in humans.Seven days(D7)after bile duct ligation(BDL),Swiss mice were treated with phosphate buffered saline or GCSF for 5 days.The intrahepatic adaptive response of BDL mice was evaluated on postsurgical days D12,D19,and D26.Results:Treatment with 61.5 mg/kg of GCSF resulted in a significant increase in circulating leukocytes and neutrophils on D12.Amelioration of liver injury,as shown by reduced aspartate aminotransferase levels,increased albumin levels and survival rate,as well as reduced intrahepatic inflammation and hepatic myeloperoxidase expression,downregulated ductular proliferation,periportal fibroblast activation,and fibrosis,enhanced expressions of hepatocyte growth factor,peroxisome proliferator-activated receptoralpha,and ki67,and suppressed expression of cleaved caspase-3 protein,was noted after treatment with 61.5 mg/kg of GCSF.Additionally,GCSF treatment was associated with an increased number of intrahepatic cd3-Sca1tc-Kitt bone marrow cells.
文摘Primary biliary cholangitis(PBC)is a chronic cholestatic liver disease that is observed more frequently in middle-aged women.This disorder is considered an autoimmune disease,since liver injury is sustained by the presence of selfdirected antimitochondrial antibodies targeting the bile duct cells.The prognosis may vary depending on an early diagnosis and response to therapy.However,nearly a third of patients can progress to liver cirrhosis,thus requiring a liver transplant.Traditional immunosuppressive therapies,commonly employed for other autoimmune diseases,have limited effects on PBC.In fact,dramatic functional changes that occur in the biliary epithelium in the course of inflammation play a major role in perpetuating the injury.In this minireview,after a background on the disease and possible predisposing factors,the sequential cooperation of cellular/molecular events leading to end-stage PBC is discussed in detail.The rise and maintenance of the autoimmune process,as well as the response of the biliary epithelia during inflammatory injury,are key factors in the progression of the disease.The so-called“ductular reaction(DR)”,intended as a reactive expansion of cells with biliary phenotype,is a process frequently observed in PBC and partially understood.However,recent findings suggest a strict relationship between this pathological picture and the progression to liver fibrosis,cell senescence,and loss of biliary ducts.All these issues(onset of chronic inflammation,changes in secretive and proliferative biliary functions,DR,and its relationship with other pathological events)are discussed in this manuscript in an attempt to provide a snapshot,for clinicians and researchers,of the most relevant and sequential contributors to the progression of this human cholestatic disease.We believe that interpreting this disorder as a multistep process may help identify possible therapeutic targets to prevent evolution to severe disease.
基金Supported by the Italian MIUR Grant, No. MM_06315722,by the University of Florenceby the Italian Liver Foundation. Eva Efsen was Supported in Part by the Tode Travel Grant, the Direktφr Madsen's GrantFhv. Direktφr Nielsen's Grant (Denmark)
文摘AIM： To investigate the effects of troglitazone （TGZ）, an anti-diabetic drug which activates peroxisome proliferatoractivated receptor-y （PPAR-y）, for liver tissue repair, and the development of ductular reaction, following common bile duct ligation （BDL） in rats. METHODS： Rats were supplemented with TGZ （0.2% w/w in the pelleted food） for i wk before BDL or sham operation. Animals were killed at 1, 2, or 4 wk after surgery. RESULTS： The development of liver fibrosis was reduced in rats receiving TGZ, as indicated by significant decreases of procollagen type I gene expression and liver hydroxyproline levels. Accumulation of a-smooth-muscle actin （SMA）-expressing cells surrounding newly formed bile ducts following BDL, as well as total hepatic levels of SMA were partially inhibited by TGZ treatment, indicating the presence of a reduced number and/or activation of hepatic stellate cells （HSC） and myofibroblasts. Development of the ductular reaction was inhibited by TGZ, as indicated by histochemical evaluation and hepatic activity of γ-glutamyltransferase （GGT）. CONCLUSION： Treatment with thiazolidinedione reduces ductular proliferation and fibrosis in a model of chronic cholestasis, and suggests that limiting cholangiocyte proliferation may contribute to the lower development of scarring in this system.
基金Supported by JSp S Grant-in-Aid for Scientific Research(C)No.16K09385 to Torimura T
文摘AIM To elucidate the role of STAT3 in hepatocarcinogenesis and biliary ductular proliferation following chronic liver injury. METHODS We investigated thioacetamide(TAA)-induced liver injury, compensatory hepatocyte proliferation, and hepatocellular carcinoma(HCC) development in hepatic STAT3-deficient mice. In addition, we evaluated TAAinduced biliary ductular proliferation and analyzed the activation of sex determining region Y-box9(SOX9) and Yes-associated protein(YAP), which regulate the transdifferentiation of hepatocytes to cholangiocytes.RESULTS Both compensatory hepatocyte proliferation and HCC formation were significantly decreased in hepatic STAT3-deficient mice as compared with control mice. STAT3 deficiency resulted in augmentation of hepatic necrosis and fibrosis. On the other hand, biliary ductular proliferation increased in hepatic STAT3-deficient livers as compared with control livers. SOX9 and YAP were upregulated in hepatic STAT3-deficient hepatocytes.CONCLUSION STAT3 may regulate hepatocyte proliferation as well as transdifferentiation into cholangiocytes and serve as a therapeutic target for HCC inhibition and biliary regeneration.
文摘AIM： Although increased insulin-like growth factor-I receptor （IGF-IR） gene expression has been reported in hepatocellular carcinoma, studies assessing IGF-IR in chronic hepatitis C （CHC） and cirrhosis are scarce. We therefore aimed to evaluate IGF-IR and IGF-I rnRNA expression in liver from patient with CHC. METHODS： IGF-IR and IGF-I rnRNA content were determined by semi-quantitative RT-PCR and IGF-IR protein expression was determined by immunohistochemistry in hepatic tissue obtained from patients with CHC before （34 patients） and after （10 patients） therapy with interferon-α and ribavirin. RESULTS： An increase of IGF-IR rnRNA content was observed in hepatic tissue obtained from all CHC patients as well as from 6 cadaveric liver donors following orthopic transplantation （an attempt to evaluate normal livers） in comparison to normal liver, while no relevant modifications were detected in IGF-I mRNA content. The irnrnunohistochemical results showed that the raise in IGF-IR rnRNA content was related both to ductular reaction and to increased IGF-IR expression in hepatocytes. A decrease in IGF-IR rnRNA content was observed in patients who achieved sustained virological response after therapy, suggesting an improvement in hepatic damage. CONCLUSION： The up-regulation of IGF-IR expression in hepatocytes of patients with CHC could constitute an attempt to stimulate hepatocyte regeneration. Considering that liver is the organ with the highest levels of IGF-I, our finding of increased IGF-IR expression after both acute and chronic hepatic damage highlights the need for additional studies to elucidate the role of IGF-I in liver regeneration.
