Telmisartan Plus Propranolol Improves Liver Fibrosis and Bile Duct Proliferation in the PSC-Like Abcb4−/− Mouse Model

• Published in: Digestive diseases and sciences Vol. 58; no. 5; pp. 1271 - 1281
• Main Authors: Mende, Susanne, Schulte, Sigrid, Strack, Ingo, Hunt, Heike, Odenthal, Margarete, Pryymachuck, Galyna, Quasdorff, Maria, Demir, Münevver, Nierhoff, Dirk, Dienes, Hans-Peter, Goeser, Tobias, Steffen, Hans-Michael, Töx, Ulrich
• Format: Journal Article
• Language: English
• Published: Boston Springer US 01.05.2013
• Subjects: Adrenergic beta-Antagonists - pharmacology; Adrenergic beta-Antagonists - therapeutic use; Animals; ATP Binding Cassette Transporter, Subfamily B - genetics; ATP-Binding Cassette Sub-Family B Member 4; Benzimidazoles - pharmacology; Benzimidazoles - therapeutic use; Benzoates - pharmacology; Benzoates - therapeutic use; Bile Ducts - drug effects; Bile Ducts - pathology; Biochemistry; Cholangitis, Sclerosing - drug therapy; Cholangitis, Sclerosing - metabolism; Collagen Type I - metabolism; Collagen Type I, alpha 1 Chain; Cytokines - metabolism; Disease Models, Animal; Drug Evaluation, Preclinical; Drug Therapy, Combination; Gastroenterology; Hepatology; Liver - drug effects; Liver - pathology; Medicine; Medicine & Public Health; Mice; Mice, Inbred BALB C; Mice, Knockout; Myofibroblasts - metabolism; Oncology; Original Article; Propranolol - pharmacology; Propranolol - therapeutic use; Receptor, Angiotensin, Type 1 - therapeutic use; RNA, Messenger - metabolism; Telmisartan; Transplant Surgery; Beta blocker; AT1R-blocker; Sclerosing cholangitis; Abcb4 knockout; Fibrogenesis
• ISSN: 0163-2116; 1573-2568
• DOI: 10.1007/s10620-012-2499-3

Background Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease leading to cirrhosis and cholangiocellular carcinoma. Inhibitors of the renin–angiotensin system or the sympathetic nervous system delay liver fibrogenesis in animal models. Aims We investigated the antifibrotic potential of telmisartan, an angiotensin II type 1 receptor antagonist, and the β-adrenoceptor blocker propranolol in the PSC-like Abcb4 knockout mouse model. Methods Sixty-five Abcb4 −/− mice were treated with telmisartan for 3 or 5 months (T) and with telmisartan plus propranolol for 3, 5, or 8 months (TP), or for 2 or 5 months starting with a delay of 3 months (TP delayed). Liver hydroxyproline content, inflammation, fibrosis, and bile duct proliferation were assessed; fibrosis-related molecules were analyzed by real-time polymerase chain reaction and Western blotting. Results Compared to controls, telmisartan monotherapy had no significant influence on hydroxyproline; however, telmisartan plus propranolol reduced hydroxyproline (TP 3 months, p  = 0.008), fibrosis score (TP 3 months and TP 8 months, p  = 0.043 and p  = 0.008, respectively; TP delayed 8 months, p  < 0.0005), bile duct proliferation (TP 8 months and TP delayed 8 months, p  = 0.006 and p  < 0.0005, respectively), and procollagen α1(I), endothelin-1, TIMP-1 and MMP3 mRNA as well as α-SMA, CK-19, and TIMP-1 protein. Conclusions Telmisartan plus propranolol reduces liver fibrosis and bile duct proliferation in the PSC-like Abcb4 −/− mouse model, even when started at late stages of fibrosis, and may thus represent a novel therapeutic option for cholestatic liver diseases such as PSC.