title: Telmisartan plus propranolol improves liver fibrosis and bile duct proliferation in the PSC-like Abcb4-/- mouse model.
abstract: 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.
  
  
  OBJECTIVE
  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.
authors.affiliation: Department of Gastroenterology and Hepatology, University Hospital of Cologne, Kerpenerstrasse 62, 50924, Cologne, Germany. susanne.mende@uk-koeln.de
authors.forename: Susanne
authors.initials: S
authors.lastname: Mende
authors.forename: Sigrid
authors.initials: S
authors.lastname: Schulte
authors.forename: Ingo
authors.initials: I
authors.lastname: Strack
authors.forename: Heike
authors.initials: H
authors.lastname: Hunt
authors.forename: Margarete
authors.initials: M
authors.lastname: Odenthal
authors.forename: Galyna
authors.initials: G
authors.lastname: Pryymachuck
authors.forename: Maria
authors.initials: M
authors.lastname: Quasdorff
authors.forename: Münevver
authors.initials: M
authors.lastname: Demir
authors.forename: Dirk
authors.initials: D
authors.lastname: Nierhoff
authors.forename: Hans-Peter
authors.initials: HP
authors.lastname: Dienes
authors.forename: Tobias
authors.initials: T
authors.lastname: Goeser
authors.forename: Hans-Michael
authors.initials: HM
authors.lastname: Steffen
authors.forename: Ulrich
authors.initials: U
authors.lastname: Töx
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology / Q000627:therapeutic use*; D001565:Benzoates / Q000494:pharmacology / Q000627:therapeutic use*; D001652:Bile Ducts / Q000187:drug effects / Q000473:pathology; D015209:Cholangitis, Sclerosing / Q000188:drug therapy* / Q000378:metabolism; D024042:Collagen Type I / Q000378:metabolism; D000090602:Collagen Type I, alpha 1 Chain; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D004359:Drug Therapy, Combination; D008099:Liver / Q000187:drug effects / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D058628:Myofibroblasts / Q000378:metabolism; D011433:Propranolol / Q000494:pharmacology / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000378:metabolism; D044140:Receptor, Angiotensin, Type 1 / Q000627:therapeutic use*; D000077333:Telmisartan; D000097202:ATP-Binding Cassette Sub-Family B Member 4
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D000319:Adrenergic beta-Antagonists; D001562:Benzimidazoles; D001565:Benzoates; D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain; D016207:Cytokines; D011433:Propranolol; D012333:RNA, Messenger; D044140:Receptor, Angiotensin, Type 1; D000077333:Telmisartan; D000097202:ATP-Binding Cassette Sub-Family B Member 4