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

Abstract

Background: Pathophysiologic changes of posttransplant lung ischemia/reperfusion injury are mediated by redundant cellular and humoral mechanisms. We investigated the protective effect of combined administration of platelet activating factor (PAF) and endothelin (ET) antagonists after prolonged ischemia 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 served as control. In Group II, donors received 1 mg/kg body weight of the endothelin antagonist TAK-044, and recipients 2 mg/kg. Group III was treated with the PAF antagonist TCV-309 (donor: 50 μg/kg; recipient: 100 μg/kg) (Takeda Chemicals Ltd.). Group IV received a combined treatment with both substances 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 hours after reperfusion and assessed for myeloperoxidase activity (MPO) and thiobarbituric 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 ΔOD/mg/min, p = .000002 vs control, 1.1 ± 0.1 ΔOD/mg/min) and reduced lipid peroxidation (59.5 ± 2.5 pmol/g, p = .011 vs control, 78.5 ± 4.1 pmol/g). The improvement 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 activity (Group II 0.85 ± 0.061 ΔOD/mg/min, p = .017; Group III 0.92 ± 0.079 ΔOD/mg/min, p = .058) in groups treated with either a PAF antagonist or an ET antagonist was significantly less than in Group IV. Conclusions Combined donor and recipient treatment with an ET antagonist and a PAF antagonist results in superior posttransplant graft function 24 hours after reperfusion, suggesting a synergistic role of ET-1 and PAF in the mediation of reperfusion injury in this model. Single treatment with either of the antagonists revealed only a slight improvement compared to untreated controls.