The therapeutic effect of CORM-3 on acute liver failure induced by lipopolysaccharide/D-galactosamine in mice.

BACKGROUND: Acute liver failure (ALF) is a severe and life-threatening clinical syndrome resulting in a high mortality and extremely poor prognosis. Recently, a water-soluble CO-releasing molecule (CORM-3) has been shown to have anti-inflammatory effect. The present study was to investigate the effect of CORM-3 on ALF and elucidate its underlying mechanism. METHODS: ALF was induced by a combination of LPS/D-GalN in mice which were treated with CORM-3 or inactive CORM-3 (iCORM-3). The efficacy of CORM-3 was evaluated based on survival, liver histopathology, serum aminotransferase activities (ALT and AST) and total bilirubin (TBiL). Serum levels of inflammatory cytokines (TNF-alpha, IL-6, IL-1beta and IL-10) and liver immunohistochemistry of NF-kappaB-p65 were determined; the expression of inflammatory mediators such as iNOS, COX-2 and TLR4 was measured using Western blotting. RESULTS: The pretreatment with CORM-3 significantly improved the liver histology and the survival rate of mice compared with the controls; CORM-3 also decreased the levels of ALT, AST and TBiL. Furthermore, CORM-3 significantly inhibited the increased concentration of pro-inflammatory cytokines (TNF-alpha, IL-6 and IL-1beta) and increased the anti-inflammatory cytokine (IL-10) productions in ALF mice. Moreover, CORM-3 significantly reduced the increased expression of iNOS and TLR4 in liver tissues and inhibited the nuclear expression of NF-kappaB-p65. CORM-3 had no effect on the increased expression of COX-2 in the ALF mice. An iCORM-3 failed to prevent acute liver damage induced by LPS/D-GalN. CONCLUSION: These findings provided evidence that CORM-3 may offer a novel alternative approach for the management of ALF through anti-inflammatory functions.

Hepatoprotective effects of cathepsin B inhibitor on acute hepatic failure induced by lipopolysaccharide/D-galactosamine in mice.

BACKGROUND: Increasing evidence suggests that the inactivation 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-alpha (TNF-alpha) 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-alpha 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.