β -Adrenoceptor blockade in sclerosing cholangitis of Mdr2 knockout mice: antifibrotic effects in a model of nonsinusoidal fibrosis

Primary sclerosing cholangitis (PSC) is a cholestatic liver disease with high propensity to develop into 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 β -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 β -adrenoceptor antagonist propranolol were analyzed for inflammation and fibrosis progression at different time points by histological scoring and immunostaining for α -smooth muscle actin ( α -SMA), CD45 and S100A4. Transaminases and hydroxyproline contents were determined. Expression of angiotensinogen, endothelin-1, TGF- β , TNF- α , 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 β -blockade was most obvious. The transcript levels of procollagen 1A1, TNF- α , TGF- β , 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. Therefore, the blockade of β -adrenoceptors is a promising option to support future therapeutic strategies in the treatment of human PSC.