Universität zu Köln

Trebicka, Jonel ORCID: 0000-0002-7028-3881, Hennenberg, Martin, Odenthal, Margarete, Shir, Khanwali, Klein, Sabine ORCID: 0000-0001-6691-2895, Granzow, Michaela, Vogt, Annabelle, Dienes, Hans-Peter, Lammert, Frank, Reichen, Juerg, Heller, Joerg and Sauerbruch, Tilman (2010). Atorvastatin attenuates hepatic fibrosis in rats after bile duct ligation via decreased turnover of hepatic stellate cells. J. Hepatol., 53 (4). S. 702 - 713. AMSTERDAM: ELSEVIER. ISSN 1600-0641

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Abstract

Background & Aims: Activation of hepatic stellate cells (HSC) and transdifferentiation to myofibroblasts following liver injury is the main culprit for hepatic fibrosis. Myofibroblasts show increased proliferation, migration, contraction, and production of extracellular matrix (ECM). In vitro, HMG-CoA reductase inhibitors (statins) inhibit proliferation and induce apoptosis of myofibroblastic HSC. To investigate the antifibrotic effects of atorvastatin in vivo we used bile duct ligated rats (BDL). Methods: BDL rats were treated with atorvastatin (15 mg/kg/d) immediately after ligation (prophylactically) or in on-going fibrosis (therapeutically). Fibrosis was assessed by hydroxyproline content and Sirius-red staining. The activation of HSC was investigated by analysis of alpha SMA expression. mRNA levels of cytokines and procollagen were analyzed by RT-PCR, and MMP-2 activity by zymography. Proliferation was assessed by expression of cathepsins (B and D), proliferating cell nuclear antigen (PCNA), and Ki67-staining. Apoptosis was characterized by caspase-3 activity, cleavage of PARP-1, and TUNEL assay. Hepatic inflammation was investigated by serum parameters and liver histology. Results: Prophylactic and early therapy with atorvastatin significantly attenuated fibrosis and HSC activation. Later therapy lacked significant effects on fibrosis but reduced profibrotic cytokine expression and led to a more quiescent state of HSC with less proliferation and apoptosis, while hepatic inflammation did not change. Conclusions: This study shows that very early atorvastatin treatment inhibits HSC activation and fibrosis in the BDL model in vivo, while late treatment reduces HSC turnover and activity. Our findings underline that long-term studies in humans are warranted. (C) 2010 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Trebicka, Jonel UNSPECIFIED orcid.org/0000-0002-7028-3881 UNSPECIFIED Hennenberg, Martin UNSPECIFIED UNSPECIFIED UNSPECIFIED Odenthal, Margarete UNSPECIFIED UNSPECIFIED UNSPECIFIED Shir, Khanwali UNSPECIFIED UNSPECIFIED UNSPECIFIED Klein, Sabine UNSPECIFIED orcid.org/0000-0001-6691-2895 UNSPECIFIED Granzow, Michaela UNSPECIFIED UNSPECIFIED UNSPECIFIED Vogt, Annabelle UNSPECIFIED UNSPECIFIED UNSPECIFIED Dienes, Hans-Peter UNSPECIFIED UNSPECIFIED UNSPECIFIED Lammert, Frank UNSPECIFIED UNSPECIFIED UNSPECIFIED Reichen, Juerg UNSPECIFIED UNSPECIFIED UNSPECIFIED Heller, Joerg UNSPECIFIED UNSPECIFIED UNSPECIFIED Sauerbruch, Tilman UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-495762
DOI:	10.1016/j.jhep.2010.04.025
Journal or Publication Title:	J. Hepatol.
Volume:	53
Number:	4
Page Range:	S. 702 - 713
Date:	2010
Publisher:	ELSEVIER
Place of Publication:	AMSTERDAM
ISSN:	1600-0641
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language COA REDUCTASE INHIBITORS; ENDOTHELIAL DYSFUNCTION; LIVER FIBROSIS; PROLIFERATION; SIMVASTATIN; EXPRESSION; PROTEIN; HYPERTENSION; FIBROBLASTS; RECEPTOR Multiple languages Gastroenterology & Hepatology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/49576