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

Abstract

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 b-adrenoceptors, we used the Mdr2 À/À mouse model, which develops periportal fibrosis similar to human PSC. Liver tissues of Mdr2 À/À mice untreated or treated with the b-adrenoceptor antagonist propranolol were analyzed for inflammation and fibrosis progression at different time points by histological scoring and immunostaining for a-smooth muscle actin (a-SMA), CD45 and S100A4. Transaminases and hydroxyproline contents were determined. Expression of angiotensinogen, endothelin-1, TGF-b, TNF-a, 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 À/À mice, but immunostaining revealed no sinusoidal and only minor periportal contribution of myofibroblasts with prominent fibroblasts. Propranolol treatment of Mdr2 À/À mice improved liver architecture. Additionally, inflammation and fibrosis were significantly reduced. After 3 months of treatment, the antifibrotic effect of the b-blockade was most obvious. The transcript levels of procollagen 1A1, TNF-a, TGF-b, 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 b-adrenoceptors is a promising option to support future therapeutic strategies in the treatment of human PSC.

Effect of propranolol on capsular reaction around silicone implants in guinea pigs

“…The effect of propranolol in reducing capsular inflammation and thickness, and in modulating collagen deposition on textured implants observed in this experiment is consistent with findings from previous studies of others fibrosis conditions 19 , which showed that the application of nonselective beta-adrenoceptors antagonists inhibits maturation of collagen, reduces the number of vessels, collagen density, number of mast cells, eosinophils and myofibroblasts compared with control 22,23,25 .…”

Lysophosphatidic Acid Aberrancies and Hepatocellular Carcinoma: Studies in the MDR2 Gene Knockout Mouse

“…The literature shows that MDR2 −/− is related to liver regeneration and hepatocarcinogenesis due to a reduction of hepatocyte apoptosis, inflammation, and fibrosis (23)(24)(25)(26). Accordingly, the MDR2 −/− murine model of HCC has important similarities to patients and provides an opportunity to investigate and target the oncogenic processes associated with HCC.…”

Animal models of chronic liver diseases

“…The same group further demonstrated the potential therapeutic mechanism of norUDCA, a side chainmodified UDCA derivative, with Mdr2 Ϫ/Ϫ mice (45,56). More recently, blocking ␤-adrenoceptors by propranolol treatment was found to improve liver architecture, to delay progression of sclerosing cholangitis and to reduce fibrosis in Mdr2 Ϫ/Ϫ mice (176). These findings are now discussed as a potential new therapeutic option to treat human PSC.…”