Abstract
The accelerated course of hepatic fibrosis that occurs in some patients after liver transplantation is an important clinical problem. Activation of hepatic stellate cell (HSCs) is the dominant event in hepatic fibrosis. Previous studies have shown that treatment with mammalian target of rapamycin (mTOR) inhibitors was more effective in reducing the progression of fibrosis than treatment with calcineurin inhibitors, suggesting that mTOR could be a crucial target for inhibition of fibrosis. In addition, N-acetylcysteine (NAC) has been shown to effectively suppress HSC activation-dependent expression of alpha-smooth muscle actin in HSCs, suggesting that NAC could be a candidate for the clinical treatment of hepatic fibrosis. Here, we have evaluated the effects of immunosuppressive drugs and NAC in a mice model of hepatic fibrosis and on HSC activation in vitro. We demonstrated that an mTOR inhibitor significantly inhibited fibrogenic genes in cultured HSCs until day 14. In addition, co-administration of NAC with everolimus further reduced the expression of fibrogenic genes and improved the characteristic of HSCs via blockage of HSC activation and up-regulation of fibrolytic gene. Moreover, in vivo studies showed that everolimus inhibited collagen deposition and inflammation in a mouse model of fibrogenesis, as determined by histological analysis, and everolimus treatment, in combination with NAC, significantly decreased extracellular matrix deposition and improved liver histology. These findings indicated that everolimus, combined with NAC, synergistically inhibited hepatic fibrosis and thus may become a valuable option in immunosuppressant therapy.
Original language | English |
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Pages (from-to) | 2627-2639 |
Number of pages | 13 |
Journal | American Journal of Translational Research |
Volume | 12 |
Issue number | 6 |
Publication status | Published - 2020 Jun 15 |
Keywords
- Animal model
- Fibrosis
- Hepatic stellate cells
- Immunosuppressive drugs
- MTOR inhibitor
- N-acetylcysteine
ASJC Scopus subject areas
- Molecular Medicine
- Clinical Biochemistry
- Cancer Research