TACROLIMUS (FK506) DOWN-REGULATES FREE-RADICAL TISSUE-LEVELS, SERUM CYTOKINES, AND NEUTROPHIL INFILTRATION AFTER SEVERE LIVER ISCHEMIA

Background. Liver ischemia and reperfusion injury is associated with a ctivation of multiple inflammatory pathways, including free radicals, cytokines, and neutrophil-mediated tissue damage among others. Tacroli mus (FK506) has shown important regulatory effects on some inflammator y pathways, such as cytokines, neutrophils, and adhesion molecules, In this study, we explored a new potential protective mechanism for tacr olimus in the liver inflammatory response after ischemia and reperfusi on, specifically its effect on liver tissue free radicals. Methods. To tal hepatic ischemia was produced in the rat for 90 min with an extrac orporeal portosystemic shunt. Animals (n=96) were divided into four gr oups: group 1 comprised normal rats for reference values; group 2 comp rised sham operated rats; in group 3, ischemic control rats received o nly the vehicle; and the experimental treatment group, group 4, receiv ed tacrolimus at a dose of 0.3 mg/kg, 4 hr before ischemia. Animal sur vival was followed up to 7 days. Liver function tests were performed a nd liver tissue free radicals and myeloperoxidase, serum cytokines (in terleukin 1, tumor necrosis factor-alpha), and liver histology were me asured 4 hr after reperfusion. Results. Seven-day survival was signifi cantly improved from only 20% in the control group to 55% in the tacro limus group (P<0.01). Liver function tests, histology, and myeloperoxi dase tissue values were significantly improved (P<0.05) with tacrolimu s pretreatment, Furthermore, a significant (P<0.05) downregulation of serum cytokines and liver tissue free radicals was observed. Conclusio ns. These data indicate a new and different protective mechanism for F K506 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, specific ally interleukin 1 and tumor necrosis, decreased neutrophil tissue mig ration as well.