Atorvastatin attenuates hepatic fibrosis in rats after bile duct ligation via decreased turnover of hepatic stellate cells.
OBJECTIVE
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 alphaSMA 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.
Trebicka
Jonel
J
Department of Internal Medicine I, University of Bonn, Germany. jonel.trebicka@ukb.uni-bonn.de
Hennenberg
Martin
M
Odenthal
Margarete
M
Shir
Khanwali
K
Klein
Sabine
S
Granzow
Michaela
M
Vogt
Annabelle
A
Dienes
Hans-Peter
HP
Lammert
Frank
F
Reichen
Jürg
J
Heller
Jörg
J
Sauerbruch
Tilman
T
D000818:Animals; D000069059:Atorvastatin; D001652:Bile Ducts; D049109:Cell Proliferation / Q000187:drug effects; D055166:Hepatic Stellate Cells / Q000187:drug effects*; D006538:Heptanoic Acids / Q000494:pharmacology*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D008026:Ligation; D008103:Liver Cirrhosis / Q000517:prevention & control*; D008297:Male; D011758:Pyrroles / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011758:Pyrroles; D000069059:Atorvastatin