Adenovirus-mediated gene expression in the septal cells of cirrhotic rat livers

Liver cirrhosis is characterized by the formation of fibrous septa following hepatic necrosis and fibrosis, and finally progression to severe hepatic failure and/or hepatocellular carcinoma. To establish effective therapy for cirrhosis using a designed gene, we examined whether recombinant adenovirus vectors could transfer foreign genes into the septal cells of cirrhotic livers.

Rats with cirrhosis induced by 4-8 weeks treatment with carbon tetrachloride were intravenously infected with a recombinant adenovirus Adex1CALacZ bearing a bacterial lacZ gene. Expression of the transferred gene was determined by X-gal staining. The infectivity of the vectors in vitro was examined using slice cultures from the cirrhotic rat livers.

In normal rat livers, almost all hepatocytes expressed beta-galactosidase from the recombinant adenovirus vectors. In rat liver fibrosis, the adenovirus-mediated gene transfer to hepatocytes is markedly reduced compared with normal rat liver. In cirrhosis, there is an even stronger reduction in the number of transduced hepatocytes. On the other hand, in vitro infection to the slice culture demonstrated that the cirrhotic hepatocytes still maintained adenovirus infectivity. Moreover, in the kidney, which is the second target organ of adenovirus, there was no difference in infectivity between normal and cirrhotic rats.

The recombinant adenovirus intravenously transmitted the foreign gene to septal cells in extranodular fibrous septa, rather than to hepatocytes within small nodules. Therefore, septal cells in the cirrhotic liver should be targeted with the adenovirus vector for a successful in vivo therapeutic strategy.