Catecholamines participate in the pathogenesis of portal hypertension and liver fibrosis through ... more Catecholamines participate in the pathogenesis of portal hypertension and liver fibrosis through alpha1-adrenoceptors. However, the underlying cellular and molecular mechanisms are largely unknown. Here, we investigated the effects of norepinephrine (NE) on human hepatic stellate cells (HSC), which exert vasoactive, inflammatory, and fibrogenic actions in the injured liver. Adrenoceptor expression was assessed in human HSC by RT-PCR and immunocytochemistry. Intracellular Ca2+ concentration ([Ca2+]i) was studied in fura-2-loaded cells. Cell contraction was studied by assessing wrinkle formation and myosin light chain II (MLC II) phosphorylation. Cell proliferation and collagen-alpha1(I) expression were assessed by [3H]thymidine incorporation and quantitative PCR, respectively. NF-kappaB activation was assessed by luciferase reporter gene and p65 nuclear translocation. Chemokine secretion was assessed by ELISA. Normal human livers expressed alpha(1A)-adrenoceptors, which were markedly...
Excessive alcohol consumption causes a wide spectrum of liver disease, ranging from simple steato... more Excessive alcohol consumption causes a wide spectrum of liver disease, ranging from simple steatosis to severe forms of liver injury such as steatohepatitis, liver fibrosis, cirrhosis, and liver cancer. Moreover, alcohol consumption also accelerates liver fibrosis in patients with other types of liver diseases such as viral hepatitis and nonalcoholic fatty liver disease. Virtually all clinical complications of alcoholic liver disease occur in patients with established fibrosis and cirrhosis, thus making fibrosis a key parameter for treatment and prognosis of patients. Here, the authors review diagnosis, management, and antifibrotic therapy of alcoholic liver fibrosis. They discuss both the unique features of alcoholic liver fibrosis and the similarities to liver fibrosis from other etiologies, and review molecular pathogenesis and animal models. Finally, future directions for basic and clinical research on alcoholic liver fibrosis are proposed.
Alcoholic hepatitis (AH) is often associated with advanced fibrosis, which negatively impacts sur... more Alcoholic hepatitis (AH) is often associated with advanced fibrosis, which negatively impacts survival. We aimed at identifying kinases deregulated in livers from patients with AH and advanced fibrosis in order to discover novel molecular targets. Extensive phosphoprotein analysis by reverse phase protein microarrays was performed in AH (n=12) and normal human livers (n=7). Ribosomal S6 kinase (p90RSK) hepatic expression was assessed by qPCR, Western blot and immunohistochemistry. Kaempferol was used as a selective pharmacological inhibitor of the p90RSK pathway to assess the regulation of experimentally-induced liver fibrosis and injury, using in vivo and in vitro approaches. Proteomic analysis identified p90RSK as one of the most deregulated kinases in AH. Hepatic p90RSK gene and protein expression was also upregulated in livers with chronic liver disease. Immunohistochemistry studies showed increased p90RSK staining in areas of active fibrogenesis in cirrhotic livers. Therapeutic administration of kaempferol to carbon tetrachloride-treated mice resulted in decreased hepatic collagen deposition, and expression of profibrogenic and proinflammatory genes, compared to vehicle administration. In addition, kaempferol reduced the extent of hepatocellular injury and degree of apoptosis. In primary hepatic stellate cells, kaempferol and small interfering RNA decreased activation of p90RSK, which in turn regulated key profibrogenic actions. In primary hepatocytes, kaempferol attenuated proapoptotic signalling. p90RSK is upregulated in patients with chronic liver disease and mediates liver fibrogenesis in vivo and in vitro. These results suggest that the p90RSK pathway could be a new therapeutic approach for liver diseases characterised by advanced fibrosis.
Page 1. La inflamación crónica del hígado se asocia al depósito de colágeno y otras proteínas de ... more Page 1. La inflamación crónica del hígado se asocia al depósito de colágeno y otras proteínas de la matriz extracelular en el pa-rénquima hepático, un proceso denominado fibrosis hepáti-ca1. Si el agente causante del daño ...
Alcoholic cirrhosis is one of the most common indications for liver transplantation (LT) in weste... more Alcoholic cirrhosis is one of the most common indications for liver transplantation (LT) in western countries. A major concern about transplant patients due to alcoholic liver disease (ALD) is alcoholic recidivism. Data concerning psycho-social characteristics of patients with 6 months of abstinence at initial evaluation for LT is scarce. Objectives. The aims of this study were 1) To evaluate the psycho-social profile of a cohort of patients with alcoholic cirrhosis being evaluated for LT. 2) Determine factors associated with abstinence from alcohol at initial psycho-social evaluation for LT and 3) To evaluate the potential impact of alcohol-free beer consumption on 6-month abstinence. Ninety patients referred to the Alcohol Unit of the Hospital Clínic of Barcelona (January 1995-December 1996) were included. Univariate and multivariate logistic regression analyses were used to identify the factors associated with cessation in alcohol consumption and with 6-month abstinence. Factors ...
Catecholamines participate in the pathogenesis of portal hypertension and liver fibrosis through ... more Catecholamines participate in the pathogenesis of portal hypertension and liver fibrosis through alpha1-adrenoceptors. However, the underlying cellular and molecular mechanisms are largely unknown. Here, we investigated the effects of norepinephrine (NE) on human hepatic stellate cells (HSC), which exert vasoactive, inflammatory, and fibrogenic actions in the injured liver. Adrenoceptor expression was assessed in human HSC by RT-PCR and immunocytochemistry. Intracellular Ca2+ concentration ([Ca2+]i) was studied in fura-2-loaded cells. Cell contraction was studied by assessing wrinkle formation and myosin light chain II (MLC II) phosphorylation. Cell proliferation and collagen-alpha1(I) expression were assessed by [3H]thymidine incorporation and quantitative PCR, respectively. NF-kappaB activation was assessed by luciferase reporter gene and p65 nuclear translocation. Chemokine secretion was assessed by ELISA. Normal human livers expressed alpha(1A)-adrenoceptors, which were markedly...
Excessive alcohol consumption causes a wide spectrum of liver disease, ranging from simple steato... more Excessive alcohol consumption causes a wide spectrum of liver disease, ranging from simple steatosis to severe forms of liver injury such as steatohepatitis, liver fibrosis, cirrhosis, and liver cancer. Moreover, alcohol consumption also accelerates liver fibrosis in patients with other types of liver diseases such as viral hepatitis and nonalcoholic fatty liver disease. Virtually all clinical complications of alcoholic liver disease occur in patients with established fibrosis and cirrhosis, thus making fibrosis a key parameter for treatment and prognosis of patients. Here, the authors review diagnosis, management, and antifibrotic therapy of alcoholic liver fibrosis. They discuss both the unique features of alcoholic liver fibrosis and the similarities to liver fibrosis from other etiologies, and review molecular pathogenesis and animal models. Finally, future directions for basic and clinical research on alcoholic liver fibrosis are proposed.
Alcoholic hepatitis (AH) is often associated with advanced fibrosis, which negatively impacts sur... more Alcoholic hepatitis (AH) is often associated with advanced fibrosis, which negatively impacts survival. We aimed at identifying kinases deregulated in livers from patients with AH and advanced fibrosis in order to discover novel molecular targets. Extensive phosphoprotein analysis by reverse phase protein microarrays was performed in AH (n=12) and normal human livers (n=7). Ribosomal S6 kinase (p90RSK) hepatic expression was assessed by qPCR, Western blot and immunohistochemistry. Kaempferol was used as a selective pharmacological inhibitor of the p90RSK pathway to assess the regulation of experimentally-induced liver fibrosis and injury, using in vivo and in vitro approaches. Proteomic analysis identified p90RSK as one of the most deregulated kinases in AH. Hepatic p90RSK gene and protein expression was also upregulated in livers with chronic liver disease. Immunohistochemistry studies showed increased p90RSK staining in areas of active fibrogenesis in cirrhotic livers. Therapeutic administration of kaempferol to carbon tetrachloride-treated mice resulted in decreased hepatic collagen deposition, and expression of profibrogenic and proinflammatory genes, compared to vehicle administration. In addition, kaempferol reduced the extent of hepatocellular injury and degree of apoptosis. In primary hepatic stellate cells, kaempferol and small interfering RNA decreased activation of p90RSK, which in turn regulated key profibrogenic actions. In primary hepatocytes, kaempferol attenuated proapoptotic signalling. p90RSK is upregulated in patients with chronic liver disease and mediates liver fibrogenesis in vivo and in vitro. These results suggest that the p90RSK pathway could be a new therapeutic approach for liver diseases characterised by advanced fibrosis.
Page 1. La inflamación crónica del hígado se asocia al depósito de colágeno y otras proteínas de ... more Page 1. La inflamación crónica del hígado se asocia al depósito de colágeno y otras proteínas de la matriz extracelular en el pa-rénquima hepático, un proceso denominado fibrosis hepáti-ca1. Si el agente causante del daño ...
Alcoholic cirrhosis is one of the most common indications for liver transplantation (LT) in weste... more Alcoholic cirrhosis is one of the most common indications for liver transplantation (LT) in western countries. A major concern about transplant patients due to alcoholic liver disease (ALD) is alcoholic recidivism. Data concerning psycho-social characteristics of patients with 6 months of abstinence at initial evaluation for LT is scarce. Objectives. The aims of this study were 1) To evaluate the psycho-social profile of a cohort of patients with alcoholic cirrhosis being evaluated for LT. 2) Determine factors associated with abstinence from alcohol at initial psycho-social evaluation for LT and 3) To evaluate the potential impact of alcohol-free beer consumption on 6-month abstinence. Ninety patients referred to the Alcohol Unit of the Hospital Clínic of Barcelona (January 1995-December 1996) were included. Univariate and multivariate logistic regression analyses were used to identify the factors associated with cessation in alcohol consumption and with 6-month abstinence. Factors ...
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