A novel tumor necrosis factor-alpha suppressant, ONO-SM362, prevents liver failure and promotes liver regeneration after extensive hepatectomy.

Abstract

BACKGROUND:

Tumor necrosis factor (TNF)-alpha is a cytokine that initiates liver regeneration after hepatectomy (HTx), although extensive HTx can cause liver failure with significant rise in serum TNF-alpha levels. To test our hypothesis that modulation of endogenous TNF-alpha attenuates liver failure even after extensive HTx, we used ONO-SM362, a novel TNF-alpha inhibitor, in mice subjected to 85% HTx.

METHODS:

ICR mice were divided into 5 groups: 70% HTx, 85% HTx, 85% HTx plus ONO-SM362, 85% HTx plus monoclonal TNF-alpha antibody (mAb), and 85% HTx plus FR167653, a TNF-alpha inhibitor. We analyzed the survival rate, blood ammonia (NH(3)), serum TNF-alpha levels, TNF-alpha 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.

RESULTS:

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-alpha level. ONO-SM362 and mAb improved animal survival and enhanced PCNA LI. In addition, ONO-SM362 inhibited TNF-alpha mRNA expression in the remnant liver and suppressed PMNs infiltration.

CONCLUSIONS:

Suppression of excessive TNF-alpha production using ONO-SM362 ameliorated liver failure after 85% HTx.

• Authors: Toshiro Ogata, Kenichiro Yamashita, Hiroyuki Horiuchi, Koji Okuda, Satoru Todo
• Journal: Surgery (Surgery) Vol. 143 Issue 4 Pg. 545-55 (Apr 2008) ISSN: 1532-7361 [Electronic] United States
• PMID: 18374053 (Publication Type: Evaluation Study, Journal Article)

Chemical References

• (1S,2R)-2-hexyloxy carbonylamino-1 methyl-2-(3-methoxyphenyl) ethyl disodium phosphate
• Anti-Inflammatory Agents
• Organophosphorus Compounds
• Tumor Necrosis Factor-alpha

Topics

• Animals
• Anti-Inflammatory Agents (pharmacology)
• Disease Models, Animal
• Hepatectomy (adverse effects)
• Liver Failure (etiology, mortality, prevention & control)
• Liver Regeneration (drug effects)
• Male
• Mice
• Mice, Inbred ICR
• Organophosphorus Compounds (pharmacology, therapeutic use)
• Survival Analysis
• Tumor Necrosis Factor-alpha (antagonists & inhibitors)