Improved anti-fibrotic effects by combined treatments of simvastatin and NS-398 in experimental liver fibrosis models

Seong Hee Kang, Hyung Joon Yim, Ji Won Hwang, Mi Jung Kim, Young-Sun Lee, Young Kul Jung, Hyungshin Yim, Baek-Hui Kim, Hae Chul Park, Yeon Seok Seo, Ji Hoon Kim, Jong Eun Yeon, Soon Ho Um, Kwan Soo Byun

Research output: Contribution to journalArticlepeer-review

Abstract

Background/Aims: 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. Methods: 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. Results: 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. Conclusions: 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.

Original languageEnglish
Pages (from-to)745-756
Number of pages12
JournalKorean Journal of Internal Medicine
Volume37
Issue number4
DOIs
Publication statusPublished - 2022

Keywords

  • Cyclooxygenase 2 inhibitors
  • Hepatic stellate cells
  • Hydroxymethylglutaryl-CoA reductase inhibitors
  • Liver cirrhosis

ASJC Scopus subject areas

  • Internal Medicine

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