- 作者: Lee-Won Chong; Yi-Chao Hsu; Yung-Tsung Chiu; Kuo-Ching Yang; Yi-Tsau Huang
- 作者服務機構: 1 Graduate Institute of Clinical Medicine, School of Medicine, National Yang Ming University, Tcdpei, Taiwan; ; 2 Division of Hepatology and Gastroenterology, Department of Internal Medicine, Shin Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan; ; 3 Institute of Traditional Medicine, School of Medicine, National Yang-Ming University, No. 155, Li-Nong Street, Sec. 2, Taipei, 112, Taiwan; ; 4 Department of Medical Research and Education, Taichung Veterans General Hospital. Taichung, Taiwan
- 中文摘要: --
- 英文摘要: Tumor necrosis factor-alpha (TNF-α) plays a central role in cellular necrosis, apoptosis, organ failure, tissue damage, inflammation and fibrosis. These processes, occurring in liver injury, may lead to cirrhosis. Thalidomide, α-N-phthalidoglutarimide, (C13H10N2)4, has been shown to have immunomodulatory and anti-inflammatory properties, possibly mediated through its anti-TNF-α effect. In this study, we investigated the in vitro and in vivo effects of thalidomide on hepatic fibrosis. A cell line of rat hepatic stellate cells (HSC-T6) was stimulated with transforming growth factor-β1 (TGF-β1) or TNF-α. The inhibitory effects of thalidomide on the NFκB signaling cascade and fibrosis markers including α-smooth muscle actin (α-SMA) and collagen, were assessed. An in vivo therapeutic study was conducted in dimethylnitrosamine (DMN)-treated rats, which were randomly assigned to 1 of 4 groups: vehicle (0.7% carboxyl methyl cellulose, CMC), thalidomide (40 mg/kg), thalidomide (200 mg/kg), or silymarin (50 mg/kg), each given by gavage twice daily for 3 weeks starting after 1 week of DMN administration. Thalidomide (100-800 nM) concentration-dependently inhibited NFkB transcriptional activity induced by TNF-α, including IKKα expression and ΙκΒα phosphorylation in HSC-T6 cells. In addition, thalidomide also suppressed TGF-βl-induced α-SMA expression and collagen deposition in HSC-T6 cells. Fibrosis scores of livers from DMN-treated rats receiving high dose of thalidomide (0.89 ±0.20) were significantly reduced in comparison with those of DMN-treated rats receiving vehicle (1.56±0.18). Hepatic collagen contents of DMN rats were also significantly reduced by either thalidomide or silymarin treatment. Immunohistochemical double staining results showed that α-SMA- and NFKB-positive cells were decreased in the livers from DMN rats receiving either thalidomide or silymarin treatment. In addition, real-time PCR analysis indicated that hepatic mRNA expressions of TGF-β1, α-SMA, collagen 1α2, TNF-α and iNOS genes were attenuated by thalidomide treatment. In conclusion, our results showed that thalidomide inhibited activation of HSC-T6 cells by TNF-α and ameliorated liver fibrosis in DMN-intoxicated rats.
- 中文關鍵字: --
- 英文關鍵字: collagen, hepatic fibrosis, NFκB, α-smooth muscle actin, thalidomide, transforming growth factor-β1, tumor necrosis factor-α