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

Abstract

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. 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. 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). 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.