title: Alcohol-induced sinusoidal endothelial cell dysfunction in the mouse is associated with exacerbated liver apoptosis and can be reversed by caspase inhibition.
abstract: 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-fluoropentanoic 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.
authors.affiliation: Divisions of Digestive Diseases and Nutrition, Department of Internal Medicine, University of Kentucky College of Medicine, 800 Rose Street, MN649A-0084, 40536, Lexington, KY, USA
authors.initials: IV
authors.lastname: Deaciuc
authors.initials: NB
authors.lastname: D'Souza
authors.initials: F
authors.lastname: Fortunato
authors.initials: DB
authors.lastname: Hill
authors.initials: TG
authors.lastname: Sarphie
authors.initials: CJ
authors.lastname: McClain