Aiba M, Takeyoshi I, Ohwada S, Kobayashi J, Iwanami K, Sunose Y, Kawashima Y, Mastumoto K, Muramoto M, Morishita Y
Second Department of Surgery, Gunma University School of Medicine, Maebashi, Japan.
J Am Coll Surg. 2000 Sep;191(3):251-8. doi: 10.1016/s1072-7515(00)00336-7.
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.
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.
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.
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.
FR167653是白细胞介素-1和肿瘤坏死因子生成的强效抑制剂。我们之前报道过，FR167653可抑制缺血再灌注后白细胞介素-1信使核糖核酸（mRNA）的表达，并对扩大肝切除术后的缺血再灌注损伤起到保护作用。在本研究中，我们在犬模型的扩大肝切除伴缺血过程中，研究了FR167653给药的最佳终点以及FR167653给药对白细胞介素-8（IL-8）mRNA表达的抑制作用。
右门静脉蒂夹闭60分钟，但左门静脉保持通畅以避免门静脉淤血。再灌注后切除75%的肝脏。实验I：成年杂种犬分为三组：对照组（n = 9）；FR-2组（n = 6），在缺血开始前30分钟至再灌注后2小时通过门静脉给予FR167653；FR-6组（n = 6），在缺血前30分钟至再灌注后6小时给予FR167653。采集肝静脉血以检测肝酶。再灌注6小时后采集肝脏标本进行组织学研究，并对多形核中性粒细胞进行计数。实验II：通过逆转录聚合酶链反应测量IL-8的表达。
FR-2组和FR-6组再灌注后的天冬氨酸转氨酶和丙氨酸转氨酶水平以及再灌注6小时后的透明质酸水平均显著（p < 0.05）低于对照组。再灌注后FR-2组和FR-6组之间无显著差异。组织学上，FR-2组和FR-6组的肝组织损伤较轻，且FR-2组和FR-6组的多形核中性粒细胞浸润显著低于对照组。FR-2组和FR-6组的3天生存率在统计学上（p < 0.05）优于对照组。FR处理组中IL-8 mRNA表达受到抑制。
FR167653应在再灌注后不久给药，而再灌注后无需给药数小时。FR167653可抑制IL-8 mRNA生成并抑制多形核中性粒细胞浸润。
