Development for Anti-Cytokine Therapy on Hepatic Graft Reperfusion Injury.

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Inflammatory cytokines, interleukin (IL)-l and tumor necrosis factor (TNF), may play an important role in hepatic ischemia-reperfusion (I/R) injury. To study the role of IL-l in hepatic I/R injury, we investigated the effect of pretreatment with IL-l receptor antagonist (IL-1ra) on the production of IL-l and TNF,histological findings in the liver, and the survival rate for 7 days. The animals were subjected to 90 min of warm liver ischemia by clamping the portal vein and hepatic artery of the left and middle lobes. In the IL-lra-treated group, IL-lra was given 5 min before inducing liver ischemia. IL-la (ELISA) and TNF (L929) were determined in blood and liver at 0,30,90, and 180 min post-reperfusion. In addition, at 180 min post-reperfusion the damaged (left lateral and median lobes) and non-damaged (right lateral and caudate lobes) livers were removed respectively for IL-la and TNF determination. In another experiment to determine the effect of IL-lra pretreatment on survival rate fo … More r 7 days, after 90 min of liver ischemia, the vessels were released and the right lateral and caudate lobes were excised, leaving only the ischemic left lateral and median lobes. In both groups, IL-la was undetectable in blood, but was increased in liver tissue. TNF increased in both blood and liver tissue as reperfusion time increased. The histological findings were minimal in the IL-lra-treated group even at 180 min post-reperfusion. Furthermore, in the IL-lra-treated group, the production of TNF was decreased in both blood and liver tissue as compared with that in the non-treated group. At 180 min post-reperfusion, damaged liver produced significantly more IL-la and TNF than the non-damaged liver. Survival rates in the IL-lra-treated group and in the non-treated group were 80% (8/10) and 30% (6/20), respectively. The data demonstrated that the production of IL-l and TNF increases in hepatic I/R injury and that pretreatment with IL-lra protects the liver from ischemic insult, indicating the important role of IL-l in I/R injury. Less