Mechanisms of ischemic injury are different in the steatotic and normal rat liver.
Hepatic steatosis is associated with significant morbidity and mortality after liver resection and transplantation. Although apoptosis is a key mechanism of reperfusion injury in the normal liver, the pathway leading to cell death in steatotic hepatocytes is unknown. A model of hepatic ischemia and reperfusion injury in fatty and lean Zucker rats was used. Fatty animals had increased aspartate aminotransferase (AST) release and decreased survival after 60 minutes of ischemia compared with lean animals. Apoptosis was the predominant form of cell death in the lean rats (82%), whereas necrosis was minimal. In contrast, fatty animals developed only moderate amounts of apoptosis but showed massive necrosis (73%) after 24 hours of reperfusion. Intracellular mediators of apoptosis, such as caspase 8, caspase 3, and cytochrome c, were significantly lower in the steatotic than in the lean liver indicating dysfunction in activation of the apoptotic pathway. The high percentage of necrosis in the steatotic rats was associated with renal acute tubular necrosis after 24 hours of reperfusion in the fatty, but not in lean rats. Caspase inhibition significantly decreased reperfusion injury in lean animals, but was ineffective in fatty animals. The results indicate that the increased susceptibility of fatty livers to reperfusion injury is associated with a change from an apoptotic form of cell death to necrosis. We conclude that new therapeutic strategies are necessary in the fatty liver.
Selzner
M
M
Department of Surgery, Duke University Medical Center, Durham, NC, USA.
Rüdiger
H A
HA
Sindram
D
D
Madden
J
J
Clavien
P A
PA
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001794:Blood Pressure; D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005234:Fatty Liver / Q000150:complications / Q000473:pathology* / Q000503:physiopathology; D007211:Indoles / Q000494:pharmacology; D007511:Ischemia / Q000150:complications / Q000473:pathology*; D007674:Kidney Diseases / Q000209:etiology; D008099:Liver / Q000473:pathology*; D008102:Liver Circulation; D008171:Lung Diseases / Q000209:etiology; D008297:Male; D009336:Necrosis; D009842:Oligopeptides / Q000494:pharmacology; D011169:Portal Vein / Q000503:physiopathology; D051381:Rats; D011924:Rats, Zucker; D015427:Reperfusion Injury / Q000150:complications / Q000473:pathology; D013851:Thinness
D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors; D007211:Indoles; C118798:N-((1,3-dimethylindole-2-carbonyl)-valinyl)-3-amino-4-oxo-5-fluoropentanoic acid; D009842:Oligopeptides