Attenuation of CCl4-induced hepatic fibrosis by GdCl3 treatment or dietary glycine

The role of Kupffer cells in CCl4-induced fibrosis was investigated in vivo. Male Wistar rats were treated with phenobarbital and CCl4 for 9 wk, and a group of rats were injected with the Kupffer cell toxicant gadolinium chloride (GdCl3) or were fed glycine, which inactivates Kupffer cells. After CCl4 alone, the fibrosis score was 3.0 +/- 0.1 and collagen protein and mRNA expression were elevated, but GdCl3 or glycine blunted these parameters. Glycine did not alter cytochrome P-450 2E1, making it unlikely that glycine affects CCl4 metabolism. Treatment with GdCl3 or glycine prevented CCl4-induced increases in transforming growth factor (TGF)-beta1 protein levels and expression. CCl4 treatment increased alpha -smooth muscle actin staining (score 3.0 +/- 0.2), whereas treatment with GdCl3 and glycine during CCl4 exposure blocked this effect (1.2 +/- 0.5); there was no staining with glycine treatment. These results support previous in vitro data and demonstrate that treatment of rats with the selective Kupffer cell toxicant GdCl3 prevents stellate cell activation and the development of fibrosis.