Liver damage using suicide genes - A model for oval cell activation

Liver regeneration from the facultative hepatic stem cells, the oval cells, takes place in situations in which liver regeneration from pre-existing he patocytes is prevented. Different models have been used to stimulate oval c ell response. Many of them involve the use of carcinogenic agents with or w ithout partial hepatectomy, In this study we show that adenovirus-mediated gene transfer of the suicide gene thymidine kinase followed by ganciclovir administration caused hepatotoxicity of variable intensity. Rats with moder ate elevation in serum transaminases recovered normal liver architecture fe w weeks after adenovirus injection. In contrast, rats with severe liver dam age exhibited a marked and persisting activation of oval cells accompanied by ductular hyperplasia, In some rats, such lesion eventually evolved to ch olangiofibrosis and in one rat to cholangiocarcinoma, Deposition of fibrone ctin and increased number of hepatic stellate cells were found in associati on with oval cells and cholangiofibrotic lesions. Hepatocyte growth factor was hyperexpressed in the livers with intense oval cell response or ductula r proliferation, suggesting a participation of this factor in those lesions . In summary, our data demonstrate activation of oval cell response after g ene transfer of thymidine kinase followed by ganciclovir administration. Th ese findings indicate that high doses of this therapy causes liver damage t ogether with an impairment in hepatocellular regeneration.