Journal
HEPATOLOGY RESEARCH
Volume 19, Issue 1, Pages 85-97Publisher
ELSEVIER SCI IRELAND LTD
DOI: 10.1016/S1386-6346(00)00087-5
Keywords
caspase-3; caspase inhibitor; plasma hyaluronan; TUNEL; electron microscopy
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The purpose of this study was to determine if a correlation exists between alcohol-induced liver sinusoidal endothelial cell (SEC) dysfunction and alcohol-induced augmented liver apoptosis in the mouse. Mice were fed an alcohol-containing liquid diet for 7 weeks. On the last day of feeding, the animals were treated with the pan-caspase inhibitor IDN1529 (N-[(indole-2-)-alaninyl]-3-amino-4-oxo-fluorepentanoic acid), killed, and plasma amino transferase activity, plasma hyaluronan, liver caspase-3 activity, the frequency of apoptotic nuclei in the liver, liver histology and electron microscopic appearance evaluated. Alcohol feeding significantly increased (2.5-fold) plasma hyaluronan levels, frequency of apoptotic nuclei (20-fold), and caspase-3 activity (1.7-fold), but did not affect plasma amino transferase activity. Transmission electron microscopy revealed that SEC was among the cell types undergoing apoptosis. Livers of alcohol-fed mice displayed marked fat accumulation without necrosis or fibrosis. Treatment of mice with IDN1529 reversed the alcohol effects on plasma hyaluronan levels, liver caspase-3 activity, and frequency of apoptotic nuclei. However, the inhibitor did not prevent fat accumulation in the liver. These data suggest that alcohol-induced exacerbation of apoptosis in the liver, which extends to the SEC, causes functional impairment of the sinusoidal lining and can be reversed by caspase inhibition. (C) 2001 Elsevier Science Ireland Ltd. All rights reserved.
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