Attenuation of CCl(4)-induced hepatic fibrosis by GdCl(3) treatment or dietary glycine.
The role of Kupffer cells in CCl(4)-induced fibrosis was investigated in vivo. Male Wistar rats were treated with phenobarbital and CCl(4) for 9 wk, and a group of rats were injected with the Kupffer cell toxicant gadolinium chloride (GdCl(3)) or were fed glycine, which inactivates Kupffer cells. After CCl(4) alone, the fibrosis score was 3.0 +/- 0.1 and collagen protein and mRNA expression were elevated, but GdCl(3) or glycine blunted these parameters. Glycine did not alter cytochrome P-450 2E1, making it unlikely that glycine affects CCl(4) metabolism. Treatment with GdCl(3) or glycine prevented CCl(4)-induced increases in transforming growth factor (TGF)-beta 1 protein levels and expression. CCl(4) treatment increased alpha-smooth muscle actin staining (score 3.0 +/- 0.2), whereas treatment with GdCl(3) and glycine during CCl(4) 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 GdCl(3) prevents stellate cell activation and the development of fibrosis.
Rivera
C A
CA
Laboratory of Hepatobiology and Toxicology, Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.
Bradford
B U
BU
Hunt
K J
KJ
Adachi
Y
Y
Schrum
L W
LW
Koop
D R
DR
Burchardt
E R
ER
Rippe
R A
RA
Thurman
R G
RG
D000199:Actins / Q000032:analysis; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D002251:Carbon Tetrachloride / Q000493:pharmacokinetics*; D003094:Collagen / Q000235:genetics; D004731:Endotoxins / Q000097:blood; D005682:Gadolinium / Q000494:pharmacology*; D015870:Gene Expression / Q000502:physiology; D005998:Glycine / Q000494:pharmacology*; D007728:Kupffer Cells / Q000187:drug effects / Q000473:pathology; D008099:Liver / Q000737:chemistry / Q000473:pathology; D008103:Liver Cirrhosis / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D009596:Nitrophenols / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017208:Rats, Wistar; D016212:Transforming Growth Factor beta / Q000032:analysis
D000199:Actins; D000893:Anti-Inflammatory Agents; D004731:Endotoxins; D009596:Nitrophenols; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D003094:Collagen; D005682:Gadolinium; D002251:Carbon Tetrachloride; C038958:gadolinium chloride; D005998:Glycine; C024836:4-nitrophenol