In individuals with a genetic or acquired predisposition to impaired formation of a stable biliary HCO umbrella, up-regulation of Akt inhibitor purinergic signaling, ATP-dependent HCO secretion, and alkaline phosphatase expression can be expected as cholangiocytes (and hepatocytes) attempt to induce a stable biliary surface microclimate pH regulatory system. Consequently, extracellular ATP as a strong chemotactic molecule could then attract immune cells, thus leading to (auto-) immune attack against cholangiocytes as a consequence of an unstable biliary HCO umbrella. Our hypothesis needs confirmation by experimental studies both in vitro and in vivo.

Fundamental questions are: (1) Does a pH gradient exist at the apical cholangiocyte membrane, and if so, which elements contribute to it? (2) Are glycine-conjugated bile salt uptake and bile salt–induced cholangiocyte damage pH-dependent? (3) Is biliary pH lower in chronic fibrosing/sclerosing cholangiopathies such as PBC or PSC than in subjects without chronic cholangiopathies? (4) If so, does medical treatment (such as UDCA in PBC) normalize biliary pH? Confirmation of the concept of a biliary

HCO umbrella would have clinical impact both in Wnt assay further unraveling the pathogenesis of chronic fibrosing cholangiopathies and in developing therapeutic strategies that would focus on strengthening the biliary HCO umbrella in fibrosing cholangiopathies beyond the effects observed with UDCA so far. We gratefully acknowledge the stimulating discussions and critical reading of the manuscript by Alan F. Hofmann, Gustav Paumgartner, and Bruno Stieger. “
“Department of Infectious Diseases, Hamamatsu University School of Medicine, Hamamatsu, Japan Hepatitis C virus (HCV) employs various strategies to establish persistent infection

that can cause chronic liver disease. Our previous study showed that both the original patient serum Glycogen branching enzyme from which the HCV JFH-1 strain was isolated and the cell culture–generated JFH-1 virus (JFH-1cc) established infection in chimpanzees, and that infected JFH-1 strains accumulated mutations after passage through chimpanzees. The aim of this study was to compare the in vitro characteristics of JFH-1 strains emerged in each chimpanzee at early and late stages of infection, as it could provide an insight into the phenomenon of viral persistence. We generated full-genome JFH-1 constructs with the mutations detected in patient serum-infected (JFH-1/S1 and S2) and JFH-1cc–infected (JFH-1/C) chimpanzees, and assessed their effect on replication, infectious virus production, and regulation of apoptosis in cell culture. The extracellular HCV core antigen secreted from JFH-1/S1-, S2-, and C-transfected HuH-7 cells was 2.5, 8.9, and 2.1 times higher than that from JFH-1 wild-type (JFH-1/wt) transfected cells, respectively.