INTERLEUKIN-1 AND TUMOR-NECROSIS-FACTOR PRODUCTION AS THE INITIAL STIMULANTS OF LIVER ISCHEMIA AND REPERFUSION INJURY

The mechanisms by which polymorphonuclear neutrophils (PMNs) are recruited by the ischemic and reperfused liver are still unknown. The purpose of this study was to determine whether tumor necrosis factor-alpha (TNF) and/or interleukin-1 alpha (IL-1) acted as potential mediators for PMN infiltration after liver ischemia and reperfusion. The potential effect of FK 506, a powerful immunosuppressant, was also studied. Male Sprague-Dawley rats were subjected to 60 and 90 min of total hepatic ischemia, with an extracorporeal portosystemic shunt. FK 506 (0.3 mg/kg) was intravenously administered 4 hr before ischemia (FK 506 group), and control animals received normal saline solution (NS group). Plasma TNF, IL-1 levels, and PMN infiltration in liver tissue were serially examined at the end of ischemia, 5, 30, 60, and 360 min after reperfusion. The degree of liver necrosis was assessed at 360 min following reperfusion. In the NS group, IL-1 and TNF revealed a transient elevation at 30 and 60 min after reperfusion, following 60 min of ischemia. When the ischemia was increased to 90 min, the IL-1 activity had a rapid elevation (330.5 +/- 129 pg/ml) at 5 min, which remained at high levels (197.8 +/- 70.4 pg/ml) until 6 hr after reperfusion, whereas the TNF activity decreased to normal levels following a similar peak (355 +/- 181.9 pg/ml) at 5 min after reperfusion. The time course of IL-1 release in the NS group, with 90 min of ischemia, correlated directly with the PMN infiltration. Irrespective of the ischemic period, the FK 506 group inhibited the elevation of TNF and IL-1 levels, which resulted in amelioration of PMN infiltration and hepatic lesion. It appears then that IL-1, rather than TNF, acted as a continuous stimulant for PMN infiltration following severe liver ischemia and reperfusion. (C) 1993 Academic Press, Inc.