Blockade of TGFβ Signaling: Prevention of Fibrosis/Dysfunction and Enhancement of Hepatocyte Regeneration in Injured Liver

Abstract

To clarify the role of transforming growth factor-β (TGFβ) in liver fibrosis, we specifically blocked TGFβ action by adenovirus-mediated local expression of a truncated TGFβ type II receptor (AdTβ-TR), which serves as a dominant-negative receptor. Rats were intravenously injected with AdTβ-TR, AdLacZ (a control adenovirus expressing β-galactosidase), or saline and then were treated with dimethyl-nitrosamine (DMN) for 3 weeks. Liver fibrosis, as assessed by histology and hydroxyproline content, was markedly attenuated in AdTβ-TR-treated rats. All AdTβ-TR-treated rats remained alive, and their serum levels of hyaluronic acid and transam-inases remained at low levels, whereas all the AdTβ-TR-untreated rats died of liver dysfunction. Some rats were first treated with DMN for 3 weeks; then AdTβ-TR, AdLacZ, or saline was applied followed by an additional 3-week DMN treatment. The truncated receptor was expressed mainly in the fibrotic area. Liver fibrosis progressed during the additional 3-week DMN treatment. However, in AdTβ-TR-treated rats, fibrosis remained at the level seen in rats given DMN for only 3 weeks. Electron microscopy of the AdTβ-TR-treated livers showed (1) less accumulation of extracellular matrix proteins in Disse’s spaces; (2) regenerated hepatocytes; and (3) fat droplet-rich “quiescent” hepatic stellate cells. The results demonstrate for the first time that TGFβ plays a critical role in liver fibrogenesis and its progression, and that anti-TGFβ intervention could be therapeutic, not only by suppressing fibrosis but by facilitating hepatocyte regeneration.