LEUKOTRIENES IN RENAL-TRANSPLANT REJECTION IN RATS - DISTINCT ROLES FOR LEUKOTRIENE-B(4) AND PEPTIDOLEUKOTRIENES IN THE PATHOGENESIS OF ALLOGRAFT INJURY

To investigate the role of leukotrienes in renal allograft rejection, we studied the effects of specific leukotriene inhibitors in a rat kid ney transplant model. The enhanced renal production of leukotrienes ob served in allograft recipients was reduced in a dose-dependent manner by the specific 5-lipoxygenase inhibitor MK886. This suppression of le ukotriene production caused a substantial improvement in renal functio n. Inhibition of 5-lipoxygenase also reduced the severity of vascular inflammation and endothelial injury in allografts, and profoundly inhi bited expression of donor MHC class II Ag on kidney cells. Survival of renal allograft recipients was prolonged from 10 +/- 1 days in contro ls to 16 +/- 1 days in animals that received a 6-day course of MK886 ( p < 0.05). To investigate the relative roles of LTB4 compared to pepti doleukotrienes in these processes, we treated a separate group of anim als with the specific peptidoleukotriene receptor antagonist SKF106203 . This agent inhibits the interaction of peptidoleukotrienes with thei r receptor(s) but does not affect the biologic actions of LTB4. In the se studies, SKF106203 caused a modest improvement in renal allograft f unction that was of lesser magnitude than that seen with the 5-lipoxyg enase inhibitor. SKF106203 also reduced vascular inflammation in allog rafts, but had no effect on expression of MHC class II Ag. We conclude that leukotrienes play a key role in the pathogenesis of renal allogr aft rejection. Furthermore, the detrimental effects of leukotrienes in rejection are mediated by distinct actions of LTB4 and peptidoleukotr ienes.