Yamaguchi Y, Akizuki E, Ichiguchi O, Matsumura F, Goto M, Miyanari N, Mori K, Yamada S, Ogawa M
Department of Surgery II, Kumamoto University Medical School, Japan.
Gastroenterology. 1997 Feb;112(2):551-60. doi: 10.1053/gast.1997.v112.pm9024309.
BACKGROUND & AIMS: Neutrophils are important in the development of tissue injury induced by ischemia-reperfusion. The ability of an inhibitor of neutrophil elastase (ONO-5046) to protect against ischemia-reperfusion injury in rat liver was investigated by measuring serum concentrations of cytokine-induced neutrophil chemoattractant.
Liver ischemia was induced in rats by occluding the portal vein for 30 minutes, and ONO-5046 or anticoagulants were injected intravenously 5 minutes before vascular clamping.
Serum concentration of cytokine-induced neutrophil chemoattractant increased after reperfusion, reached a maximum at 6 hours, and then gradually decreased. However, pretreatment of animals with heparin (50 U/kg), antithrombin III (250 U/kg), or ONO-5046 (10 mg/kg) resulted in significantly smaller increases in the serum concentration of cytokine-induced neutrophil chemoattractant after reperfusion. Pretreatment with both ONO-5046 and heparin, or both ONO-5046 and antithrombin III, produced additive effects. Pretreatment of rats with both ONO-5046 and heparin or both ONO-5046 and antithrombin III also inhibited the increase in cytokine-induced neutrophil chemoattractant mRNA in liver. These combined treatments significantly reduced the increases in both the number of neutrophils accumulated in the liver and the hepatic activity of myeloperoxidase.
Cytokine-induced neutrophil chemoattractant production after ischemia-reperfusion in the liver is mediated by neutrophil elastase and activation of coagulation within the hepatic microcirculation.
中性粒细胞在缺血再灌注诱导的组织损伤发展过程中起重要作用。通过测量细胞因子诱导的中性粒细胞趋化因子的血清浓度，研究了中性粒细胞弹性蛋白酶抑制剂（ONO-5046）对大鼠肝脏缺血再灌注损伤的保护作用。
通过阻断门静脉30分钟诱导大鼠肝脏缺血，并在血管夹闭前5分钟静脉注射ONO-5046或抗凝剂。
再灌注后细胞因子诱导的中性粒细胞趋化因子血清浓度升高，在6小时达到峰值，然后逐渐下降。然而，用肝素（50 U/kg）、抗凝血酶III（250 U/kg）或ONO-5046（10 mg/kg）预处理动物，导致再灌注后细胞因子诱导的中性粒细胞趋化因子血清浓度升高明显较小。ONO-5046与肝素或ONO-5046与抗凝血酶III联合预处理产生相加效应。用ONO-5046与肝素或ONO-5046与抗凝血酶III联合预处理大鼠也抑制了肝脏中细胞因子诱导的中性粒细胞趋化因子mRNA的增加。这些联合治疗显著降低了肝脏中积累的中性粒细胞数量和髓过氧化物酶的肝脏活性的增加。
肝脏缺血再灌注后细胞因子诱导的中性粒细胞趋化因子产生是由中性粒细胞弹性蛋白酶和肝微循环内凝血激活介导的。
