Protective Effect of MDL28170 against Thioacetamide-Induced Acute Liver Failure in Mice

Abstract

Liver injury is known to often progress even after the hepatotoxicant is dissipated. The hydrolytic enzyme calpain, which is released from dying hepatocytes, destroys the surrounding cells and results in progression of injury. Therefore, control of calpain activation may be a suitable therapeutic intervention in cases of fulminant hepatic failure. This study evaluated the effects of a potent cell-permeable calpain inhibitor, MDL28170, and its mechanisms of action on thioacetamide (TAA)-induced hepatotoxicity in mice. We found that MDL28170 significantly decreased mortality and change in serum transaminase after TAA administration. The necroinflammatory response in the liver was also suppressed. Furthermore, a significant suppression of hepatocyte apoptosis could be found by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling assay. The upregulation of inducible nitric oxide synthase (iNOS) and tumor necrosis factor-α (TNF-α), both of which are known to mediate the propagation of inflammation, was abolished. MDL2810 also effectively blocked hepatic stellate cell activation, which is assumed to be the early step in liver fibrosis. These results demonstrated that MDL28170 attenuated TAA-induced acute liver failure by inhibiting hepatocyte apoptosis, abrogating iNOS and TNF-α mRNA upregulation and blocking hepatic stellate cell activation.

Electroporative interleukin-10 gene transfer ameliorates carbon tetrachloride-induced murine liver fibrosis by MMP and TIMP modulation1

“…IL-10 gene therapy significantly diminished this COX-2 expression ( Figure 3C). IL-10 gene therapy suppressed hepatic stellate cell activation after CCl 4 α-SMA [activated hepatic stellate cell (HSC) markers] are known to be activated after acute liver injury [27,28] . In the present study, the expression of α-SMA increased after chronic CCl 4 administration as measured using immunoblotting (Figure 4).…”