Improved anti-fibrotic effects by combined treatments of simvastatin and NS-398 in experimental liver fibrosis modelsopen access
- Kang, Seong Hee; Yim, Hyung Joon; Hwang, Ji-won; Kim, Mi-jung; Lee, Young-Sun; Jung, Young Kul; Yim, Hyungshin; Kim, Baek-Hui; Park, Hae-Chul; Seo, Yeon Seok; Kim, Ji Hoon; Yeon, Jong Eun; Um, Soon Ho; Byun, Kwan Soo
- Issue Date
- Liver cirrhosis; Hydroxymethylglutaryl-CoA reductase inhibitors; Cyclooxygenase 2 inhibitors; Hepatic stellate cells
- The Korean Journal of Internal Medicine, v.37, no.4, pp.745 - 756
- Journal Title
- The Korean Journal of Internal Medicine
- Start Page
- End Page
Efficient anti-fibrotic therapies are required for the treatment of liver cirrhosis. Hydroxymethylglutaryl-coenzyme A reductase inhibitors (statins) and cyclooxygenase-2 (COX-2) inhibitors have been reported to have anti-fibrotic effects. Here, we investigated whether combined treatment with a statin and a COX-2 inhibitor has synergistic anti-fibrotic effects.
The effects of treatment strategies incorporating both simvastatin and a COX-2 inhibitor, NS-398, were investigated using an immortalized human hepatic stellate cell line (LX-2) and a hepatic fibrosis mouse model developed using thioacetamide (TAA) in drinking water. Cellular proliferation was investigated via 5-bromo-2-deoxyuridine uptake. Pro- and anti-apoptotic factors were investigated through Western blotting and real-time polymerase chain reaction analysis.
The evaluation of the anti-proliferative effects on LX-2 cells showed that the observed effects were more pronounced with combination therapy than with single-drug therapy. Moreover, hepatic fibrosis and collagen deposition decreased significantly in TAA-treated mice in response to the combined treatment strategy. The mechanisms underlying the anti-fibrotic effects of the combination therapy were investigated. The effects of the combination therapy were correlated with increased expression levels of extracellular signal-regulated kinase 1/2 signaling molecules, upregulation of the Bax/Bcl-2 signaling pathway, inhibition of the transforming growth factor-β signaling pathway, and inhibition of tissue inhibitor of matrix metalloproteinases 1 and 2.
The combination of simvastatin and NS-398 resulted in a synergistic anti-fibrotic effect through multiple pathways. These findings offer a theoretical insight into the possible clinical application of this strategy for the treatment of advanced liver diseases with hepatic fibrosis.
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- 3. Graduate School > Biomedical Research Center > 1. Journal Articles
- 2. Clinical Science > Department of Pathology > 1. Journal Articles
- 2. Clinical Science > Department of Gastroenterology and Hepatology > 1. Journal Articles
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