The anti-fibrotic effect of liver growth factor is associated with decreased intrahepatic levels of matrix metalloproteinases 2 and 9 and transforming growth factor beta 1 in bile duct-ligated rats.
Liver growth factor (LGF), a mitogen for liver cells, behaves as an anti-fibrotic agent even in extrahepatic sites, but its mechanistic basis is unknown. We aimed to determine the intrahepatic expression pattern of key modulators of liver fibrosis in bile duct-ligated rats (BDL) after injection of LGF. BDL rats received either LGF (4.5 microg/ratXdose, two doses/week, at time 0 or 2 or 5w after operation, depending on the group (BDL+LGF groups, n=20) or saline (BDL+S groups, n=20). Groups were compared in terms of fibrosis (histomorphometry), liver function (aminopyrine breath test), matrix metalloproteinases MMP-2 and MMP-9, transforming growth factor beta 1 (TGF-beta1) and liver endoglin content (Western blotting), and serum tissue inhibitor of metalloproteinases 1 (TIMP-1) levels (ELISA). In BDL+LGF rats, the fibrotic index was significantly lower at 5w, p=0.006, and at 8w, p=0.04, than in BDL+S rats. Liver function values in BDL+LGF rats were higher than those obtained in BDL+S rats (80% at 5w and 79% at 8w, versus 38% and 29%, p<0.01, taking healthy controls as 100%). Notably, in BDL+LGF rats the intrahepatic expression levels of both MMPs were lower at 2w (MMP-2, p=0.03; MMP-9, p=0.05) and 5w (MMP-2, p=0.05, MMP-9, p=0.04). In addition, the hepatic TGF-beta1 level in BDL+LGF rats was lower at 2w (36%, p=0.008), 5w (50%) and 8wk (37%), whereas intrahepatic endoglin expression remained constant in all BDL rats studied. LGF ameliorates liver fibrosis and improves liver function in BDL rats. The LGF-induced anti-fibrotic effect is associated with a decreased hepatic level of MMP-2, MMP-9 and TGF-beta1 in fibrotic rats.
Díaz-Gil
Juan J
JJ
Department of Experimental Biochemistry, Hospital Puerta de Hierro, Madrid, Spain. jdiaz.hpth@salud.madrid.org
García-Monzón
Carmelo
C
Rúa
Carmen
C
Martín-Sanz
Paloma
P
Cereceda
Rosa M
RM
Miquilena-Colina
María E
ME
Machín
Celia
C
Fernández-Martínez
Amalia
A
García-Cañero
Rarael
R
D000818:Animals; D017734:Bile Ducts, Extrahepatic / Q000601:surgery; D001663:Bilirubin / Q000494:pharmacology*; D015153:Blotting, Western; D001944:Breath Tests; D004195:Disease Models, Animal; D006133:Growth Substances; D008026:Ligation; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008106:Liver Cirrhosis, Experimental / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D008111:Liver Function Tests; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D009929:Organ Size / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D012709:Serum Albumin / Q000494:pharmacology*; D000075462:Serum Albumin, Human; D016212:Transforming Growth Factor beta / Q000378:metabolism*
D006133:Growth Substances; D012709:Serum Albumin; D016212:Transforming Growth Factor beta; C053498:albumin-bilirubin complex; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D001663:Bilirubin; D000075462:Serum Albumin, Human