“Cholangiopathies share common features
including bile duct proliferation, periportal Syk inhibitor fibrosis, and intrahepatic cholestasis. Damages of biliary epithelium by autoimunne disorder, virus infection, toxic compounds, and developmental abnormalities cause severe progressive hepatic disorders responsible for high mortality. However, the etiologies of these cholestatic diseases still remain unclear since useful models to study the pathogenic mechanisms are not available. In the present study, we have found that ezrin knockdown (Vil2kd/kd) mice develop severe intrahepatic cholestasis characterized by extensive bile duct proliferation, periductular fibrosis, and intrahepatic bile acid accumulation without developmental defects of bile duct morphology and infiltration of inflammatory cells. Ezrin is a membrane
cytoskeletal crosslinker protein, which is known to interact with transporters, scaffold proteins, and actin cytoskeleton at the plasma membrane. We found that the normal apical membrane localizations of several transport proteins including CFTR, AE-2, AQP1, and NHERF1 were disturbed in the bile ducts of Vil2kd/kd mice. Stable expression of a dominant negative form of ezrin in immortalized mouse cholangiocytes also led to the reduction of the surface expression this website of CFTR, AE-2, and AQP1. Reduced surface expression of these transport proteins was accompanied by reduced functional expression, as evidenced 上海皓元医药股份有限公司 by the fact these cells exhibited decreased CFTR-mediated Cl- efflux activity. Furthermore, bile flow and biliary HCO3- concentration were also significantly reduced in Vil2kd/kd mice. Conclusion: These data suggest that dysfunction of ezrin mimics important aspects of the pathological mechanisms responsible for cholangiopathies, and further that the Vil2kd/kd mouse may be a useful model to exploit in the development and testing of potential therapies for cholangiopathies. (Hepatology 2014;) “
“Within the last 20
years, the transjugular intrahepatic portal stent (TIPS) has gained its place in the therapeutic armamentarium for the complications of portal hypertension. Randomized controlled trials have shown that TIPS is more effective than other available treatments to reduce recurrence of refractory ascites, to control acute variceal hemorrhage, and to prevent variceal rebleeding. However, in all these clinical settings, TIPS increases the risk of hepatic encephalopathy and does not improve survival. Initially, the main drawback of the technique was shunt dysfunction, which was observed in up to 80% of patients within 2 years. This rate was tremendously reduced when PTFE-covered stents were used instead of bare ones.