Tumor necrosis factor (TNF)-α is a cytokine that initiates liver regeneration after hepatectomy (HTx), although extensive HTx can cause liver failure with significant rise in serum TNF-α levels. To test our hypothesis that modulation of endogenous TNF-α attenuates liver failure even after extensive HTx, we used ONO-SM362, a novel TNF-α inhibitor, in mice subjected to 85% HTx.
ICR mice were divided into 5 groups: 70% HTx, 85% HTx, 85% HTx plus ONO-SM362, 85% HTx plus monoclonal TNF-α antibody (mAb), and 85% HTx plus FR167653, a TNF-α inhibitor. We analyzed the survival rate, blood ammonia (NH3), serum TNF-α levels, TNF-α mRNA expression in the liver and spleen by real-time polymerase chain reaction, histologic changes, polymorphonuclear neutrophils (PMNs) infiltration, and proliferating cell nuclear antigen labeling index (PCNA LI) in the 5 groups.
The survival rate at 7 days after surgery was 100%, 0%, 100%, 50%, and 0%, for the 70% HTx, 85% HTx, 85% HTx + ONO-SM362, 85% HTx + mAb, and 85% HTx + FR167653, respectively. Mice that underwent 85% HTx died from liver failure associated with a significant rise in serum TNF-α level. ONO-SM362 and mAb improved animal survival and enhanced PCNA LI. In addition, ONO-SM362 inhibited TNF-α mRNA expression in the remnant liver and suppressed PMNs infiltration.
Suppression of excessive TNF-α production using ONO-SM362 ameliorated liver failure after 85% HTx.
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Published online: February 13, 2008
Accepted: November 2, 2007
© 2008 Mosby, Inc. Published by Elsevier Inc. All rights reserved.