endothelin-1 and Cholangitis--Sclerosing

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.

Topics: Actins; Adrenergic beta-Antagonists; Animals; ATP Binding Cassette Transporter, Subfamily B; ATP-Binding Cassette Sub-Family B Member 4; Bile Ducts; Blood Pressure; Cholangitis, Sclerosing; Collagen Type I; Collagen Type I, alpha 1 Chain; Connective Tissue Growth Factor; Endothelin-1; Histological Techniques; Immunohistochemistry; Lasers; Leukocyte Common Antigens; Liver Cirrhosis; Mice; Mice, Knockout; Microdissection; Propranolol; Reverse Transcriptase Polymerase Chain Reaction; S100 Calcium-Binding Protein A4; S100 Proteins; Sympathetic Nervous System; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha