Optimal end point of FR167653 administration and expression of interleukin-8 messenger RNA on extended liver resection with ischemia in dogs.
BACKGROUND
FR167653 is a potent suppressant of interleukin-1 and tumor necrosis factor production. We previously reported that FR167653 inhibited the expression of interleukin-1 messenger RNA (mRNA) after ischemia-reperfusion and provided a protective effect against ischemia-reperfusion injury after extended liver resection. In this study we investigated the optimal end point of FR167653 administration and the inhibition of interleukin-8 (IL-8) mRNA expression caused by the administration of FR167653 during extended liver resection with ischemia in a dog model.


METHODS
The right portal pedicle was clamped for 60 minutes but the left portal vein was left patent to avoid portal congestion. After reperfusion 75% of the liver was resected. EXPERIMENT I: Adult mongrel dogs were divided into three groups: the control group (n = 9); the FR-2 group (n = 6), which received FR167653 through the portal vein starting 30 minutes before the onset of ischemia until 2 hours after reperfusion; and the FR-6 group (n = 6), which received FR167653 starting 30 minutes before ischemia until 6 hours after reperfusion. Hepatic venous blood was collected to measure liver enzymes. Liver specimens were harvested for histologic study 6 hours after reperfusion and polymorphonuclear neutrophils were counted. EXPERIMENT II: The expression of IL-8 was measured by reverse-transcriptase polymerase chain reaction.


RESULTS
Aspartate aminotransferase and alanine aminotransferase levels after reperfusion and hyaluronic acid levels 6 hours after reperfusion were significantly (p < 0.05) lower in the FR-2 and FR-6 groups than in the control group. There were no significant differences between the FR-2 and FR-6 groups after reperfusion. Histologically liver tissue damage was mild in the FR-2 and FR-6 groups, and polymorphonuclear neutrophil infiltration was significantly lower in the FR-2 and FR-6 groups than in the control group. The 3-day survival rate was statistically (p < 0.05) better in the FR-2 and FR-6 groups than in the control group. IL-8 mRNA expression was inhibited in the FR-treated group.


CONCLUSIONS
FR167653 should be administered until shortly after reperfusion and need not be administered for many hours after reperfusion. FR167653 inhibits IL-8 mRNA production and inhibits polymorphonuclear neutrophil infiltration.
Aiba
M
M
Second Department of Surgery, Gunma University School of Medicine, Maebashi, Japan.
Takeyoshi
I
I
Ohwada
S
S
Kobayashi
J
J
Iwanami
K
K
Sunose
Y
Y
Kawashima
Y
Y
Mastumoto
K
K
Muramoto
M
M
Morishita
Y
Y
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D004285:Dogs; D006131:Growth Inhibitors / Q000008:administration & dosage*; D016209:Interleukin-8 / Q000378:metabolism*; D011720:Pyrazoles / Q000008:administration & dosage*; D011725:Pyridines / Q000008:administration & dosage*; D012333:RNA, Messenger / Q000378:metabolism*; D015427:Reperfusion Injury / Q000378:metabolism*
C104334:FR 167653; D006131:Growth Inhibitors; D016209:Interleukin-8; D011720:Pyrazoles; D011725:Pyridines; D012333:RNA, Messenger; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase