- 作者：Jonel Trebicka ; Martin Hennenberg ; Margarete Odenthal ; Khanwali Shir ; Sabine Klein ; Michaela Granzow ; Annabelle Vogt ; Hans-Peter Dienes ; Frank Lammert ; Jü ; rg Reichen ; Jö ; rg Heller ; Tilman Saue
- 关键词：Fibrogenesis ; HMG-CoA reductase inhibitor ; Cytokines ; Hepatic stellate cells ; Proliferation ; Apoptosis
- 刊名：Journal of Hepatology
- 出版年：2010
- 出版时间：October 2010
- 年：2010
- 卷：53
- 期：4
- 页码：702-712
- 全文大小：3140 K
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 αSMA 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.