Matsuda T, Yamaguchi Y, Matsumura F, Akizuki E, Okabe K, Liang J, Ohshiro H, Ichiguchi O, Yamada S, Mori K, Ogawa M
Department of Surgery II, Kumamoto University Medical School, Honjo, Japan.
J Trauma. 1998 Mar;44(3):475-84. doi: 10.1097/00005373-199803000-00009.
Neutrophils may play an important role in the development of liver ischemia/reperfusion injury. We investigated the effects of the immunosuppressants azathioprine (AZA), cyclosporine A (CsA), tacrolimus (FK506), and rapamycin (RPM) on the expression of cytokine-induced neutrophil chemoattractant (CINC) after ischemia/reperfusion of the liver.
Liver ischemia was induced in male Wistar rats by occluding the portal vein with a microvascular clip for 30 minutes. Rats received two intramuscular injections of AZA (4 mg/kg), CsA (5 mg/kg), FK506 (0.5 mg/kg), or RPM (0.5 mg/kg) 3 and 24 hours before ischemia/reperfusion of the liver.
Serum CINC concentrations in untreated animals increased, peaked 6 hours after reperfusion, and thereafter decreased gradually. Pretreatment with AZA, CsA, FK506, and RPM, however, inhibited the increase in serum CINC concentrations after reperfusion. CINC mRNA in liver tissue increased and peaked 3 hours after reperfusion, but was significantly lower in animals treated with AZA, CsA, FK506, and RPM. In vitro CINC production by Kupffer cells harvested from animals treated with AZA, CsA, FK506, or RPM 3 hours after reperfusion was also significantly lower than that observed in untreated animals. Both myeloperoxidase activity and the number of neutrophils accumulating in the liver 24 hours after reperfusion in animals treated with AZA, CsA, FK506, and RPM were significantly lower than in untreated animals. This correlated with lower serum aspartate transaminase, alanine transaminase, and lactate dehydrogenase levels in animals treated with AZA, CsA, FK506, and RPM 24 hours after reperfusion.
The immunosuppressants AZA, CsA, FK506, and RPM reduce neutrophil accumulation and attenuate ischemia/reperfusion injury of the liver.
中性粒细胞可能在肝缺血/再灌注损伤的发展中起重要作用。我们研究了免疫抑制剂硫唑嘌呤（AZA）、环孢素A（CsA）、他克莫司（FK506）和雷帕霉素（RPM）对肝脏缺血/再灌注后细胞因子诱导的中性粒细胞趋化因子（CINC）表达的影响。
通过用微血管夹夹闭门静脉30分钟，在雄性Wistar大鼠中诱导肝缺血。大鼠在肝脏缺血/再灌注前3小时和24小时接受两次肌肉注射AZA（4mg/kg）、CsA（5mg/kg）、FK506（0.5mg/kg）或RPM（0.5mg/kg）。
未治疗动物的血清CINC浓度升高，在再灌注后6小时达到峰值，此后逐渐下降。然而，用AZA、CsA、FK506和RPM预处理可抑制再灌注后血清CINC浓度的升高。肝组织中的CINC mRNA在再灌注后3小时增加并达到峰值，但在用AZA、CsA、FK506和RPM治疗的动物中显著降低。再灌注后3小时从用AZA、CsA、FK506或RPM治疗的动物中收获的库普弗细胞的体外CINC产生也显著低于未治疗动物中观察到的水平。用AZA、CsA、FK506和RPM治疗的动物在再灌注后24小时肝脏中积累的髓过氧化物酶活性和中性粒细胞数量均显著低于未治疗动物。这与用AZA、CsA、FK506和RPM治疗的动物在再灌注后24小时较低的血清天冬氨酸转氨酶、丙氨酸转氨酶和乳酸脱氢酶水平相关。
免疫抑制剂AZA、CsA、FK506和RPM减少中性粒细胞积聚并减轻肝脏的缺血/再灌注损伤。
