Combined treatment with endothelin- and PAF-antagonists reduces posttransplant lung ischemia/reperfusion injury

Background: Pathophysiologic changes of posttransplant lung ischemia/reperf usion injury are mediated by redundant cellular and humoral mechanisms. We investigated the protective effect of combined administration of platelet a ctivating factor (PAF) and endothelin (ET) antagonists after prolonged isch emia in a small animal lung transplantation model. Methods: Orthotopic left Lung transplantation was performed after 20 hours cold ischemia in male Fischer (F344) rats weighing 200-250 g. Group I serve d as control. Ih Group II, donors received 1 mg/kg body weight of the endot helin antagonist TAK-044, and recipients 2 mg/kg. Group III was treated wit h the PAF antagonist TCV-309 (donor: 50 mu g/kg; recipient: 100 mu g/kg) (T akeda Chemicals Ltd.). Group IV received a combined treatment with both sub stances at the same dosage. Twenty-four hours after reperfusion, the native contralateral lung was occluded to assess gas exchange of the graft only, and 5 minutes later the thoracic aorta was punctured for arterial blood gas analysis (n = 5). In other animals (n = 5), lung tissue was frozen 24 hour s after reperfusion and assessed for myeloperoxidase activity (MPO) and thi obarbituric acid reactive substances. Results: Combined inhibition of PAF and ET-1 at the receptor level resulted in significantly improved graft function as compared to controls (Group I) , and to groups treated with either TAK-044 or TCV-309. This was determined by a higher arterial oxygen content (112 +/- 9 mmHg, p = .00061 vs control , 48 +/- 5 mmHg), reduced MPO activity (0.35 +/- 0.02 Delta hOD/mg/min,p = .000002 vs control, 1.1 +/- 0.1 Delta OD/mg/min) and reduced lipid peroxida tion (59.5 +/- 2.5 pmol/g, p = .011 vs control, 78.5 +/- 4.1 pmol/g). The i mprovement of arterial oxygen (Group II 77 +/- 10 mmHg, p = .027 vs control ; Group III 84 +/- 8 mmHg, p = .0081 vs control) and reduction of MPO activ ity (Group II 0.85 +/- 0.061 Delta OD/mg/min,p = .017; Group III 0.92 +/- 0 .079 Delta OD/mg/min, p = .058) in groups treated with either a PAF antagon ist or an ET antagonist was significantly less than in Group IV. Conclusions: Combined donor and recipient treatment with an ET antagonist a nd a PAF antagonist results in superior posttransplant graft function 24 ho urs after reperfusion, suggesting a synergistic role of ET-1 and PAF in the mediation of reperfusion injury in this model. Single treatment with eithe r of the antagonists revealed only a slight improvement compared to untreat ed controls.