A novel tumor necrosis factor-alpha suppressant, ONO-SM362, prevents liver failure and promotes liver regeneration after extensive hepatectomy.
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.
Ogata
Toshiro
T
Department of Surgery, Faculty of Medicine Kurume University, Fukuoka, Japan. ogacchi@med.kurume-u.ac.jp
Yamashita
Kenichiro
K
Horiuchi
Hiroyuki
H
Okuda
Koji
K
Todo
Satoru
S
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D004195:Disease Models, Animal; D006498:Hepatectomy / Q000009:adverse effects*; D017093:Liver Failure / Q000209:etiology / Q000401:mortality / Q000517:prevention & control*; D008115:Liver Regeneration / Q000187:drug effects*; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009943:Organophosphorus Compounds / Q000494:pharmacology / Q000627:therapeutic use; D016019:Survival Analysis; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors*
C528329:(1S,2R)-2-hexyloxy carbonylamino-1 methyl-2-(3-methoxyphenyl) ethyl disodium phosphate; D000893:Anti-Inflammatory Agents; D009943:Organophosphorus Compounds; D014409:Tumor Necrosis Factor-alpha