Portacaval shunt causes apoptosis and liver atrophy in rats despite increases in endogenous levels of major hepatic growth factors |
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Authors: | Gandhi Chandrashekhar R Murase Noriko Subbotin Vladimir M Uemura Tadahiro Nalesnik Michael Demetris Anthony J Fung John J Starzl Thomas E |
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Affiliation: | Thomas E. Starzl Transplantation Institute, University of Pittsburgh, E-1540 BST, 200 Lothrop Street, Pittsburgh, PA 15213, USA. gandhics@msx.upmc.edu |
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Abstract: | BACKGROUND/AIMS: The response to the liver damage caused by portacaval shunt (PCS) is characterized by low-grade hyperplasia and atrophy. To clarify mechanisms of this dissociation, we correlated the expression of 'hepatotrophic factors' and the antihepatotrophic and proapoptotic peptide, transforming growth factor (TGF)-beta, with the pathologic changes caused by PCS in rats. METHODS: PCS was created by side-to-side anastomosis between the portal vein and inferior vena cava, with ligation of the hilar portal vein. Hepatic growth mediators were measured to 2 months. RESULTS: The decrease in the liver/body weight ratio during the first 7 days which stabilized by day 15, corresponded to parenchymal cell apoptosis and increases in hepatic TGF-beta concentration that peaked at 1.4 x baseline at 15 days before returning to control levels by day 30. Variable increases in the concentrations of growth promoters (hepatocyte growth factor, TGF-alpha and augmenter of liver regeneration) also occurred during the period of hepatocellular apoptosis. CONCLUSIONS: The development of hepatic atrophy was associated with changes in TGF-beta concentration, and occurred despite increased expression of multiple putative growth promoters. The findings suggest that apoptosis set in motion by TGF-beta constrains the amount of hepatocyte proliferation independently from control of liver volume. |
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