Effects of anti-inflammatory cytokine agent (FR167653) and serine protease inhibitor on warm ischemia-reperfusion injury of the liver graft

BACKGROUND: The shortage of donors has become a serious problem. Some institutes have tried to use grafts retrieved from non-heart-beating donors (NHBDs), but the results have not been satisfactory. This study clarifies the effects of nafamostat mesilate (NM), a strong serine protease inhibitor, and FR167653, a suppressant of both tumor necrosis factor-alpha and interleukin-1beta release, on warm ischemia-reperfusion injury and establishes the procurement of the grafts for a successful liver transplant using uncontrolled NHBDs. METHODS: Male Wistar rats were divided into five groups as follows (n = 5): (1) heart-beating (HB) group, in which livers were retrieved from heart-beating donors; (2) non-heart-beating (NHB) group, in which livers were retrieved from NHBDs; (3) NM group, in which livers were retrieved from NHBDs pretreated with NM (0.2 mg/kg/hr, for 30 min); (4) FR group, in which livers were retrieved from NHBDs pretreated with FR167653 (2 mg/kg); and (5) FR+NM group, in which livers were retrieved from NHBDs pretreated with FR167653 and NM. The livers were perfused for 60 min with Krebs-Henseleit bicarbonate buffer after cold preservation 6 hr. RESULTS: In the NHB group, the values of interleukin-1beta, tumor necrosis factor-alpha, thromboxane B2, and leukotriene B4, and the expressions of nuclear factor-kappaB, activating protein 1, and cyclooxygenase-2 were significantly higher than those in the HB group. In the FR+NM group, those values were low, the structure of the sinusoids was preserved, and the sinusoidal lumen was maintained (the same as observed in the HB group). CONCLUSIONS: FR167653 and NM inhibited the induction of inflammatory cytokines and arachidonic acid cascade mediators. This combined therapy was effective in preserving sinusoidal microcirculation in the liver grafts from NHBDs.