Alcohol-induced sinusoidal endothelial cell dysfunction in the mouse is associated with exacerbated liver apoptosis and can be reversed by caspase inhibition

The purpose of this study was to determine if a correlation exists between alcohol-induced liver sinusoidal endothelial cell (SEC) dysfunction and alc ohol-induced augmented liver apoptosis in the mouse. Mice were fed an alcoh ol-containing liquid diet for 7 weeks. On the last day of feeding, the anim als were treated with the pan-caspase inhibitor IDN1529 (N-[(indole-2-)-ala ninyl]-3-amino-4-oxo-fluorepentanoic acid), killed, and plasma amino transf erase 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) pl asma hyaluronan levels, frequency of apoptotic nuclei (20-fold), and caspas e-3 activity (1.7-fold), but did not affect plasma amino transferase activi ty. Transmission electron microscopy revealed that SEC was among the cell t ypes undergoing apoptosis. Livers of alcohol-fed mice displayed marked fat accumulation without necrosis or fibrosis. Treatment of mice with IDN1529 r eversed the alcohol effects on plasma hyaluronan levels, liver caspase-3 ac tivity, and frequency of apoptotic nuclei. However, the inhibitor did not p revent fat accumulation in the liver. These data suggest that alcohol-induc ed exacerbation of apoptosis in the liver, which extends to the SEC, causes functional impairment of the sinusoidal lining and can be reversed by casp ase inhibition. (C) 2001 Elsevier Science Ireland Ltd. All rights reserved.