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Differential regulation of protein S expression in hepatocytes and sinusoidal endothelial cells in rats with cirrhosis.

Fujii K, Kishiwada M, Hayashi T, Nishioka J, Gabazza EC, Okamoto T, Uemoto S, Suzuki K

Department of Molecular Pathobiology, Mie University Graduate School of Medicine, Tsu-city, Japan.

BACKGROUND: Liver dysfunction caused by intrasinusoidal microthrombi is frequently observed in patients with cirrhosis after hepatectomy, but the mechanistic pathway remains unknown. OBJECTIVE: In the present study, we evaluated the expression of protein S (PS) in hepatocytes and sinusoidal endothelial cells (SECs) from rats with dimethylnitrosoamine-induced cirrhosis before and after hepatectomy. RESULTS: The plasma level of PS antigen was significantly decreased in cirrhotic rats as compared to control rats treated with vehicle. PS expression was significantly decreased in hepatocytes isolated from cirrhotic rats as compared to controls. In contrast, PS expression was significantly increased in SECs isolated from rats with cirrhosis as compared to controls. Interleukin-6 (IL-6) upregulated the expression of PS in hepatocytes, and tumor necrosis factor-alpha (TNF-alpha) decreased its expression in SECs from both cirrhotic and normal rats. The production of IL-6 and TNF-alpha by Kupffer cells and SECs was decreased in rats with cirrhosis as compared to controls. After hepatectomy, microthrombus formation was markedly enhanced in sinusoids from rats with cirrhosis, and the plasma levels of IL-6 and TNF-alpha were significantly increased in rats with cirrhosis as compared to controls. Furthermore, PS production in SECs was decreased, whereas that in hepatocytes was significantly increased in cirrhotic rats as compared to controls. CONCLUSIONS: These findings suggest that PS expression is differently regulated in hepatocytes and SECs of rats with cirrhosis before and after hepatectomy, that the expression of PS is regulated by locally released inflammatory cytokines, and that decreased expression of PS in SECs may cause liver microthrombus formation, which is frequently observed in patients with cirrhosis after hepatectomy.

Published 14 November 2006 in J Thromb Haemost, 4(12): 2607-15.
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