We investigated whether anti-
transforming growth factor beta (
TGF-beta) molecular intervention can halt the progression of
liver fibrosis in rats. To block
TGF-beta action in a specific manner, we prepared an adenovirus expressing a truncated
type II TGF-beta receptor (AdTbeta-TR), which specifically inhibits
TGF-beta signaling as a dominant-negative receptor. We also used an adenovirus expressing bacterial
beta-galactosidase (AdLacZ) as a control adenovirus. Rats were treated with
dimethylnitrosamine (DMN) for 3 weeks; then, AdTbeta-TR, AdLacZ, or saline was intravenously applied once, followed by an additional 3-week DMN treatment. The ratio between the truncated receptor and the wild-type receptor at the
mRNA level was 15 at 1 week and 10 at 3 weeks after gene transfer. Immunohistostaining analysis showed that the truncated receptor was expressed mainly in septal cells including hepatic stellate cells.
Liver fibrosis, as assessed by histology,
hydroxyproline content, and the serum level of
hyaluronic acid, progressed during the additional 3-week DMN treatment. However, in rats infected with AdTbeta-TR, the
fibrosis remained at the level seen in rats given DMN for only 3 weeks. All AdTbeta-TR-treated rats remained alive, whereas DMN-treated rats infused with either AdLacZ or saline died of
liver dysfunction. In the livers of AdTbeta-TR-treated rats, electron microscopy showed: 1) less accumulation of
extracellular matrix proteins in the Disse's spaces; 2) regenerated hepatocytes; and 3) fat droplet-rich "quiescent" hepatic stellate cells. Our results demonstrate that
TGF-beta plays a critical role in the progression of
liver fibrosis, and suggest that anti-
TGF-beta intervention should be therapeutic in already-established fibrotic livers, not only by suppressing
fibrosis, but by facilitating hepatocyte regeneration.