In BDL rats and isolated HSCs, the treatment with sorafenib reduced hepatic alpha SMA and procollagen-1 alpha mRNA expression. As shown by immunohistochemical staining, perisinusoidal alpha SMA expression was reduced by sorafenib in BDL rats. This was associated

with reduced perisinusoidal deposition of extracellular matrix, as revealed by Sirius red staining. Although no change in PARP cleavage and only a minor increase in hepatic caspase-3 activity were detected in BDL rats in response to sorafenib, livers of sorafenib-treated BDL rats contained small DNA fragments, which were not observed in untreated BDL rats. In conclusion, sorafenib treatment reduces the number of activated HSCs BMS-754807 supplier in cirrhotic livers. This leads to the decrease in intrahepatic vascular resistance, but also to liver damage in the dosage we used. Therefore, any translation to portal hypertensive patients who may profit from sorafenib should be done with particular care. Laboratory Investigation (2011) 91, 241-251; doi:10.1038/labinvest.2010.148; published online 4 October 2010″
“Primary sclerosing cholangitis (PSC) is a cholestatic liver disease with high propensity to develop into LY294002 in vitro cholangiocarcinoma. The hepatobiliary disorder of PSC is due to progressive fibrosis surrounding the intra-and extrahepatic bile ducts. Until now, no effective medical therapy exists.

To study the progression of sclerosing cholangitis after inhibition of the sympathetic nervous system by blockade of the beta-adrenoceptors, we used the Mdr2(-/-) mouse model, which develops periportal fibrosis similar to human PSC. Liver tissues of Mdr2(-/-) mice untreated or treated with the beta-adrenoceptor antagonist propranolol were analyzed for inflammation and fibrosis progression at different time points by histological scoring and immunostaining for alpha-smooth muscle actin (alpha-SMA), CD45 and S100A4. Transaminases and hydroxyproline contents were buy WZB117 determined. Expression of angiotensinogen, endothelin-1, TGF-beta,

TNF-alpha, CTGF and procollagen 1A1 was studied by real-time PCR on laser-microdissected areas of acinar zones I and II-III. After 3 months, periportal fibrosis had developed in Mdr2(-/-) mice, but immunostaining revealed no sinusoidal and only minor periportal contribution of myofibroblasts with prominent fibroblasts. Propranolol treatment of Mdr2(-/-) mice improved liver architecture. Additionally, inflammation and fibrosis were significantly reduced. After 3 months of treatment, the antifibrotic effect of the beta-blockade was most obvious. The transcript levels of procollagen 1A1, TNF-alpha, TGF-beta, CTGF and endothelin-1 were markedly repressed in the portal areas of treated mice. Taken together, these data show that propranolol efficiently delays progression of sclerosing cholangitis.