title: Optimal end point of FR167653 administration and expression of interleukin-8 messenger RNA on extended liver resection with ischemia in dogs.
abstract: 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.
authors.affiliation: Second Department of Surgery, Gunma University School of Medicine, Maebashi, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Aiba
authors.forename: I
authors.initials: I
authors.lastname: Takeyoshi
authors.forename: S
authors.initials: S
authors.lastname: Ohwada
authors.forename: J
authors.initials: J
authors.lastname: Kobayashi
authors.forename: K
authors.initials: K
authors.lastname: Iwanami
authors.forename: Y
authors.initials: Y
authors.lastname: Sunose
authors.forename: Y
authors.initials: Y
authors.lastname: Kawashima
authors.forename: K
authors.initials: K
authors.lastname: Mastumoto
authors.forename: M
authors.initials: M
authors.lastname: Muramoto
authors.forename: Y
authors.initials: Y
authors.lastname: Morishita
mesh_terms: 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*
chemical_list: C104334:FR 167653; D006131:Growth Inhibitors; D016209:Interleukin-8; D011720:Pyrazoles; D011725:Pyridines; D012333:RNA, Messenger; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase