The three major immune disorders of the liver are autoimmune hepatitis(AIH),primary biliary cirrhosis(PBC) and primary sclerosing cholangitis(PSC).Variant forms of these diseases are generally called overlap syndromes...The three major immune disorders of the liver are autoimmune hepatitis(AIH),primary biliary cirrhosis(PBC) and primary sclerosing cholangitis(PSC).Variant forms of these diseases are generally called overlap syndromes,although there has been no standardised definition.Patients with overlap syndromes present with both hepatitic and cholestatic serum liver tests and have histological features of AIH and PBC or PSC.The AIH-PBC overlap syndrome is the most common form,affecting almost 10% of adults with AIH or PBC.Single cases of AIH and autoimmune cholangitis(AMA-negative PBC) overlap syndrome have also been reported.The AIH-PSC overlap syndrome is predominantly found in children,adolescents and young adults with AIH or PSC.Interestingly,transitions from one autoimmune to another have also been reported in a minority of patients,especially transitions from PBC to AIH-PBC overlap syndrome.Overlap syndromes show a progressive course towards liver cirrhosis and liver failure without treatment.Therapy for overlap syndromes is empiric,since controlled trials are not available in these rare disorders.Anticholestatic therapy with ursodeoxycholic acid is usually combined with immunosuppressive therapy with corticosteroids and/or azathioprine in both AIH-PBC and AIH-PSC overlap syndromes.In end-stage disease,liver transplantation is the treatment of choice.展开更多
AIM：Stress-activated signaling pathways responsible for hepatic ischemia reperfusion injury and their modulation by protective interventions are widely unknown.Preconditioning of rat livers with Atrial Natriuretic Pe...AIM：Stress-activated signaling pathways responsible for hepatic ischemia reperfusion injury and their modulation by protective interventions are widely unknown.Preconditioning of rat livers with Atrial Natriuretic Peptide(ANP)attenuates ischemia reperfusion injury(Gerbes et al.Hepatology1998,18:1309-1317),SinANP has recently been shown to be a regulator of the p38MAPKpathway in endothelial cells(Kiemer et al.CircRes2002,90:874-881).aim of this thudy was to investigate activities of MAPK during ischemia and reperfusion and effects of ANP on MAPK.METHODS:Rat livers were perfused with KH-buffer in the presence or absence of ANP for 20min,kept in cold UWsloution for 24h,and reperfused forupto120min,Activities of p38MAPKand JNKwas determined by in vitro phosphorylation assays using MBP and c-jun as substrates.After SDS/PAGE electrophoresis,gels were quantified by phosphorimaging.RESULTS:Activity of p38MAPKin control organs decreased in the course of ischemia and reperfusion by85%,whereas ANPincreased p38 activity by up to 30-fold.JNKactivation of control livers increased in the course of ischemia and reperfusion by up to three-fold.This increase in JNK activrity was slightly elevated in ANP preconditioned organs.CONCLUSION:This work represents a systematic investigation of MAPK activation during liver ischemia and reperfusion.Employing ANP,for the first time a pharmacological approach to modulate these central signal transduction molecules is presented.展开更多
文摘The three major immune disorders of the liver are autoimmune hepatitis(AIH),primary biliary cirrhosis(PBC) and primary sclerosing cholangitis(PSC).Variant forms of these diseases are generally called overlap syndromes,although there has been no standardised definition.Patients with overlap syndromes present with both hepatitic and cholestatic serum liver tests and have histological features of AIH and PBC or PSC.The AIH-PBC overlap syndrome is the most common form,affecting almost 10% of adults with AIH or PBC.Single cases of AIH and autoimmune cholangitis(AMA-negative PBC) overlap syndrome have also been reported.The AIH-PSC overlap syndrome is predominantly found in children,adolescents and young adults with AIH or PSC.Interestingly,transitions from one autoimmune to another have also been reported in a minority of patients,especially transitions from PBC to AIH-PBC overlap syndrome.Overlap syndromes show a progressive course towards liver cirrhosis and liver failure without treatment.Therapy for overlap syndromes is empiric,since controlled trials are not available in these rare disorders.Anticholestatic therapy with ursodeoxycholic acid is usually combined with immunosuppressive therapy with corticosteroids and/or azathioprine in both AIH-PBC and AIH-PSC overlap syndromes.In end-stage disease,liver transplantation is the treatment of choice.
基金the Deutsche Forschungsgemeinschaft(DFG:Ge 576/14-2 and FOR 440/1-2:KI 702/2)A.K.K.is a recipient of the"Bayerischer Habilitationsfrderpreis".
文摘AIM：Stress-activated signaling pathways responsible for hepatic ischemia reperfusion injury and their modulation by protective interventions are widely unknown.Preconditioning of rat livers with Atrial Natriuretic Peptide(ANP)attenuates ischemia reperfusion injury(Gerbes et al.Hepatology1998,18:1309-1317),SinANP has recently been shown to be a regulator of the p38MAPKpathway in endothelial cells(Kiemer et al.CircRes2002,90:874-881).aim of this thudy was to investigate activities of MAPK during ischemia and reperfusion and effects of ANP on MAPK.METHODS:Rat livers were perfused with KH-buffer in the presence or absence of ANP for 20min,kept in cold UWsloution for 24h,and reperfused forupto120min,Activities of p38MAPKand JNKwas determined by in vitro phosphorylation assays using MBP and c-jun as substrates.After SDS/PAGE electrophoresis,gels were quantified by phosphorimaging.RESULTS:Activity of p38MAPKin control organs decreased in the course of ischemia and reperfusion by85%,whereas ANPincreased p38 activity by up to 30-fold.JNKactivation of control livers increased in the course of ischemia and reperfusion by up to three-fold.This increase in JNK activrity was slightly elevated in ANP preconditioned organs.CONCLUSION:This work represents a systematic investigation of MAPK activation during liver ischemia and reperfusion.Employing ANP,for the first time a pharmacological approach to modulate these central signal transduction molecules is presented.
