A dual inhibitor of TNF-alpha and IL-1 mitigates liver and kidney dysfunction and improves survival in rat endotoxemia.
OBJECTIVE
Endotoxin shock induces multiple organ dysfunction syndromes that are associated with a substantial increase in mortality. In this study, we evaluated the effect of FR167653, a potent suppressant of tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 (IL-1) production, on lipopolysaccharide (LPS)-induced liver and kidney injury and lethality in rats.


METHODS
Male Sprague-Dawley rats weighing from 200 to 270g received an injection of LPS. The FR group received an infusion of FR167653 at 0.2 mg/kg/hr, commencing 30 min prior to the LPS injection and continuing for 5.5 hr, while the control group received an infusion of a vehicle in the same fashion. Separate groups of animals were used for the survival study (n=5 each), and for blood sampling (n=5 each group, each time point).


RESULTS
The FR group showed a significantly better survival rate'than the control group. Serum levels of GOT, Cr, and BUN were significantly lower in the FR group than in the control group. The elevation of TNF-alpha and IL-1beta at 2 hr after LPS administration was significantly lower in the FR group than in the control group.


CONCLUSIONS
FR167653 administration is effective in decreasing serum TNF-alpha and IL-1beta levels and associated injury to liver and kidney caused by LPS-induced endotoxemia, as well as decreasing mortality.
Takeyoshi
Izumi
I
Second Department of Surgery, Gunma University School of Medicine, Maebashi, Japan. takeyosi@showa.gunma-u.ac.jp
Yoshinari
Daisuke
D
Kobayashi
Mitsunobu
M
Kurabayashi
Makoto
M
Morishita
Yasuo
Y
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D019446:Endotoxemia / Q000188:drug therapy* / Q000503:physiopathology*; D007375:Interleukin-1 / Q000097:blood; D008070:Lipopolysaccharides; D008107:Liver Diseases / Q000188:drug therapy* / Q000503:physiopathology; D008111:Liver Function Tests; D008171:Lung Diseases / Q000188:drug therapy* / Q000503:physiopathology; D008297:Male; D011720:Pyrazoles / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis / Q000037:antagonists & inhibitors*
D000894:Anti-Inflammatory Agents, Non-Steroidal; C104334:FR 167653; D007375:Interleukin-1; D008070:Lipopolysaccharides; D011720:Pyrazoles; D011725:Pyridines; D014409:Tumor Necrosis Factor-alpha