Garcia-Criado F J, Palma-Vargas J M, Valdunciel-Garcia J J, Toledo A H, Misawa K, Gomez-Alonso A, Toledo-Pereyra L H
Department of Surgery, Experimental Surgery, University of Salamanca, Spain.
Transplantation. 1997 Aug 27;64(4):594-8. doi: 10.1097/00007890-199708270-00008.
Liver ischemia and reperfusion injury is associated with activation of multiple inflammatory pathways, including free radicals, cytokines, and neutrophil-mediated tissue damage among others. Tacrolimus (FK506) has shown important regulatory effects on some inflammatory pathways, such as cytokines, neutrophils, and adhesion molecules. In this study, we explored a new potential protective mechanism for tacrolimus in the liver inflammatory response after ischemia and reperfusion, specifically its effect on liver tissue free radicals.
Total hepatic ischemia was produced in the rat for 90 min with an extracorporeal portosystemic shunt. Animals (n=96) were divided into four groups: group 1 comprised normal rats for reference values; group 2 comprised sham operated rats; in group 3, ischemic control rats received only the vehicle; and the experimental treatment group, group 4, received tacrolimus at a dose of 0.3 mg/kg, 4 hr before ischemia. Animal survival was followed up to 7 days. Liver function tests were performed and liver tissue free radicals and myeloperoxidase, serum cytokines (interleukin 1, tumor necrosis factor-alpha), and liver histology were measured 4 hr after reperfusion.
Seven-day survival was significantly improved from only 20% in the control group to 55% in the tacrolimus group (P<0.01). Liver function tests, histology, and myeloperoxidase tissue values were significantly improved (P<0.05) with tacrolimus pretreatment. Furthermore, a significant (P<0.05) down-regulation of serum cytokines and liver tissue free radicals was observed.
These data indicate a new and different protective mechanism for FK506 in regard to its ability to down-regulate free radical levels in livers subjected to severe ischemia and reperfusion. Tacrolimus, also confirmed to be a potent suppressor of the cytokine response, specifically interleukin 1 and tumor necrosis, decreased neutrophil tissue migration as well.
肝缺血再灌注损伤与多种炎症途径的激活有关，包括自由基、细胞因子以及中性粒细胞介导的组织损伤等。他克莫司（FK506）已显示出对某些炎症途径具有重要的调节作用，如细胞因子、中性粒细胞和黏附分子。在本研究中，我们探索了他克莫司在肝缺血再灌注后炎症反应中的一种新的潜在保护机制，特别是其对肝组织自由基的影响。
通过体外门体分流使大鼠全肝缺血90分钟。将动物（n = 96）分为四组：第1组为正常大鼠作为参考值；第2组为假手术大鼠；第3组为缺血对照大鼠，仅接受赋形剂；实验治疗组第4组在缺血前4小时接受0.3mg/kg剂量的他克莫司。对动物存活情况进行长达7天的随访。在再灌注后4小时进行肝功能测试，并检测肝组织自由基、髓过氧化物酶、血清细胞因子（白细胞介素1、肿瘤坏死因子-α）以及肝组织学。
7天存活率从对照组的仅20%显著提高到他克莫司组的55%（P<0.01）。他克莫司预处理后，肝功能测试、组织学和髓过氧化物酶组织值均显著改善（P<0.05）。此外，观察到血清细胞因子和肝组织自由基显著下调（P<0.05）。
这些数据表明FK506在下调严重缺血再灌注肝脏中自由基水平的能力方面具有一种新的且不同的保护机制。他克莫司也被证实是细胞因子反应的有效抑制剂，特别是白细胞介素1和肿瘤坏死因子，同时也减少了中性粒细胞向组织的迁移。
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