Protection against CCl4-induced injury in liver by adenovirally introduced thioredoxin gene.

Antioxidation therapy is a promising strategy for treating or preventing oxidative stress-related liver diseases. The human thioredoxin (TRX) gene was inserted into an adenovirus vector (Adv-TRX), which was administered to mice. The mice were treated with 1 ml/kg CCl4 48 h after the infection. Blood samples were taken and the liver was excised 24 h after the CCl4 treatment. Serum ammonia, aspartate aminotransferase (AST), and alanine aminotransferase (ALT) levels were determined, and liver sections were stained with hematoxylin and eosin. RT-PCR analysis showed that the introduced TRX gene was expressed only in the liver. Adv-TRX decreased the serum ammonia, AST, and ALT levels. Hematoxylin-eosin staining indicated that the CCl4-induced injury was significantly prevented by the Adv-TRX infection. The gene delivery of TRX, which plays a central role in intracellular redox control, was shown to be effective in protecting the liver against oxidative stress-induced injury.

Stimulation of hepatocyte survival and suppression of CCl4-induced liver injury by the adenovirally introduced C/EBPbeta gene.

Gene therapy has attracted attention as a potentially effective alternative to liver transplantation for the treatment of hepatic failure. We chose the C/EBPbeta gene, which plays vital roles in liver regeneration, as a candidate for gene therapy, and examined its effect on hepatocyte survival and the suppression of liver inflammation. C/EBPbeta gene overexpression significantly maintained hepatocyte viability during 12 days of the culture. Urea synthesis ability, which is a liver-specific function, in Adv-C/EBPbeta-infected hepatocytes was stably maintained during the culture, but the activity per cell was significantly lower than that in non-infected cells. On the contrary, DNA synthesis activity in Adv-C/EBPbeta-infected hepatocytes was significantly higher than that in non-infected cells. COX-2 was induced in Adv-C/EBPbeta-infected hepatocytes, and the addition of NS398, a specific inhibitor of COX-2, suppressed the viability-maintenance effect. COX-2 was thus shown to be involved in the survival effect of C/EBPbeta gene. The introduction of the C/EBPbeta gene into liver-damaged mice significantly suppressed the serum AST and ALT activities. These results indicate that C/EBPbeta appears to be a survival factor under stressful conditions, and the introduction of the gene has therapeutic function against liver injury.