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Hepatoprotective effects of cathepsin B inhibitor on acute hepatic failure induced by lipopolysaccharide/D-galactosamine in mice |
Bing-Zhu Yan, Li-Yan Chen, Lan Kang, Xiao-Ren Wang, Man-Ru Bi, Wei Wang and Bao-Shan Yang |
Harbin, China
Author Affiliations: Department of Infectious Diseases, Second Clinical Hospital, Harbin Medical University, Harbin 150086, China (Yan BZ, Chen LY, Kang L, Wang XR, Bi MR, Wang W and Yang BS)
Corresponding Author: Bao-Shan Yang, Professor, Department of Infectious Diseases, Second Clinical Hospital, Harbin Medical University, Harbin 150086, China (Tel: 86-451-86297420; Fax: 86-451-86605330; Email: baoshanyang@126.com) |
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Abstract BACKGROUND: Increasing evidence suggests that the inactiva-tion of cathepsin B attenuates hepatocyte apoptosis and liver damage. This study aimed to investigate the protective effects of a cathepsin B inhibitor (CA-074me) on lipopolysaccharide (LPS)/D-galactosamine (D-GalN)-induced acute hepatic failure (AHF) in mice.
METHODS: Mice were intraperitoneally injected with a combination of LPS/D-GalN to induce AHF with or without CA-074me pretreatment. The cumulative survival rates were calculated 48 hours after the induction of AHF. As well as changes in biochemical indicators and liver histology, hepatocyte apoptosis was assessed using a TUNEL method. Serum tumor necrosis factor-α (TNF-α) production, caspase-3, caspase-8, and caspase-9 activity was evaluated. Cytosolic cytochrome c and Bcl-2 expression were measured by Western blotting.
RESULTS: The marked elevation in serum aminotransferase activity and prothrombin time found in LPS/D-GalN-treated mice was significantly improved by pretreatment with CA-074me. The efficacy of CA-074me was also confirmed by histological analysis and TUNEL assay. The survival rate significantly improved in LPS/D-GalN-induced mice given CA-074me compared with untreated mice. LPS/D-GalN-induced caspase-3 and caspase-9 activation was remarkably suppressed by CA-074me. However, the increased levels of serum TNF-α and elevated caspase-8 activity in AHF mice were not significantly reduced by CA-074me. Moreover, CA-074me sharply reduced the increased expression of cytosolic cytochrome c and markedly augmented Bcl-2 expression.
CONCLUSION: These results suggest that CA-074me has a protective effect in acute hepatic failure induced by LPS/D-GalN.
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