Liver growth factor antifibrotic activity in vivo is associated with a decrease in activation of hepatic stellate cells.

The antifibrotic activity of Liver Growth Factor (LGF), a liver mitogen, was previously demonstrated in several models of rat liver fibrosis and even in extrahepatic sites, such as carotid artery in hypertensive rats and rat CdCl2-induced lung fibrosis. In the present study, we have attempted to examine in depth its mechanism of antifibrotic action in bile duct-ligated (BDL) rats, with special emphasis on its activity in fibrogenic liver cells. BDL rats received either LGF 9 microg/week for 2 or 3 weeks (BDL+LGF, n=20/group) or saline (BDL+S, n=20/group), at times 0, week 2, or week 5 after operation. Groups were compared in terms of liver alpha-smooth muscle actin (SMA) content (western blotting and immunohistochemistry), hepatic apoptosis, liver desmin content (western blotting), and serum endothelin-1 (ELISA). LGF produced a marked decrease in liver alpha-SMA content compared with saline-injected rats, especially evident at longer times (5w and 8w; p<0.05). Moreover, LGF did not seem to influence HSC proliferation, as shown by measuring liver desmin content. The antifibrotic activity exerted by LGF seems to be closely related to a modulation of the activation state of fibrogenic liver cells (activated HSC and myofibroblasts) in BDL rats.

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.

Effects of maternal adrenalectomy on the developing dopaminergic system.

The present study show that maternal adrenalectomy affect the developmental model of the dopaminergic system in the hypothalamus and hippocampus, with sexual dimorphism observed in both areas. No changes were observed in the developmental dopamine (DA) model of the cortex and striatum through dopamine levels were increased in striatum.

The mitogenic activity of the liver growth factor is mediated by tumor necrosis factor alpha in rat liver.

BACKGROUND/AIMS: Liver growth factor (LGF) is a hepatic mitogen, however, the hepatic stimulation pathway remains to be characterized. The aim of this study was to determine whether tumor necrosis factor alpha (TNF-alpha) stimulation constitutes a step in the mitogenic pathway of LGF. METHODS: Rats were injected with 4.5 microg LGF/rat, and LGF activity was measured both by liver DNA synthesis stimulation and "proliferating cell nuclear antigen (PCNA)-positive" hepatocytes in rats injected with LGF or +anti-TNF-alpha. TNF-alpha expression was evaluated by reverse-transcription polymerase chain reaction. TNF-alpha-producing cells were immunodetected. Human endothelial cells (HUVEC) were stimulated by LGF. TNF-alpha was detected in the supernatant, and the expression of intercellular adhesion molecule-1 (ICAM-1) and vascular endothelial adhesion molecule-1 (VCAM-1) by flow cytometry analysis. RESULTS: LGF-injected rats showed higher intrahepatic TNF-alpha expression. DNA synthesis and PCNA-positive hepatocytes induced by LGF were inhibited by anti-TNF-alpha, PCNA-positive hepatocytes being especially abundant around the central vein when LGF was injected alone, but TNF-alpha exhibited increased signal intensity in endothelial cells of the portal vein. LGF stimulated TNF-alpha secretion in HUVEC, but did not stimulate ICAM-1 or VCAM-1 up-regulation. CONCLUSIONS: The mitogenic cascade initiated by LGF in rat liver in vivo depends, at least in part, on TNF-alpha stimulation. Portal vein endothelial cells seem to be a source of TNF-alpha.