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Telmisartan Plus Propranolol Improves Liver Fibrosis and Bile Duct Proliferation in the PSC-Like Abcb4−/− Mouse Model
- Source :
- Digestive Diseases and Sciences. 58:1271-1281
- Publication Year :
- 2012
- Publisher :
- Springer Science and Business Media LLC, 2012.
-
Abstract
- 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.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.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.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, p0.0005), bile duct proliferation (TP 8 months and TP delayed 8 months, p = 0.006 and p0.0005, respectively), and procollagen α1(I), endothelin-1, TIMP-1 and MMP3 mRNA as well as α-SMA, CK-19, and TIMP-1 protein.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.
- Subjects :
- medicine.medical_specialty
Sympathetic nervous system
ATP Binding Cassette Transporter, Subfamily B
Cirrhosis
Physiology
medicine.drug_class
Adrenergic beta-Antagonists
Cholangitis, Sclerosing
Drug Evaluation, Preclinical
Benzoates
Gastroenterology
Collagen Type I
Receptor, Angiotensin, Type 1
Primary sclerosing cholangitis
Mice
Internal medicine
Renin–angiotensin system
medicine
Animals
RNA, Messenger
Telmisartan
Myofibroblasts
Beta blocker
Mice, Knockout
Mice, Inbred BALB C
business.industry
Hepatology
medicine.disease
Propranolol
Bile duct proliferation
Collagen Type I, alpha 1 Chain
Disease Models, Animal
medicine.anatomical_structure
Liver
Cytokines
Benzimidazoles
Drug Therapy, Combination
Bile Ducts
business
medicine.drug
Subjects
Details
- ISSN :
- 15732568 and 01632116
- Volume :
- 58
- Database :
- OpenAIRE
- Journal :
- Digestive Diseases and Sciences
- Accession number :
- edsair.doi.dedup.....152aa76122d0b0be46890ffcce4333da
- Full Text :
- https://doi.org/10.1007/s10620-012-2499-3