Abstract

Objective: U-74006F (Freedox, Upjohn Inc.) is the only Lazaroid which is currently in clinical use. A number of experimental studies demonstrate that Lazaroids reduce ischemia/reperfusion injury in various organ systems. We evaluated the effect of U-74006F on reperfusion injury in a large animal model of lung allotransplantation.

Methods: Two different treatment modalities were evaluated (donor-/donor + recipient treatment) and compared with corresponding control groups. Unilateral left lung transplantation was performed in 21 weight matched pigs (24--31 kg). Donor lungs were flushed with 1.5 l cold (1°C) LPD solution and preserved for 20 h. In group I (n = 5) donor animals were pretreated with U-74006F (10 mg/kg iv) 20 min before harvest. In addition U-74006F was added to the flush solution (10 mg/l). In group III (n = 6) the Lazaroid was given to the donor before flush and to the recipient before reperfusion (3 mg/kg iv). Group II and IV (n = 5) served as control. One hour after reperfusion the recipient contralateral right pulmonary artery and bronchus were ligated to assess graft function only. Extravascular lung water index (EVLWI), mean pulmonary artery pressure, cardiac output and gas exchange were assessed during a five hour observation period. Lipid peroxidation (MDA) and neutrophil migration (MPO) to the allograft were measured at the end of the assessment.

Results: A significant change of MDA concentration was shown in group III (group III 7.87 pmol/g ± 0.46 vs. group IV 12.08 ± 0.72 pmol/g (p = 0.0065) normal lung tissue 4.13 ± 0.42 pmol/g). MPO activity was reduced in group III 3.74 ± 0.25 ΔOD/mg/min vs. group IV 4.97 ± 0.26 ΔOD/mg/min, (p = 0.027), normal lung tissue 1.04 ± 0.27 ΔOD/mg/min). Two animals in group III, however, died before the end of the assessment (right heart failure, ventricular fibrillation). In both treated groups pulmonary hemodynamics and gas exchange after reperfusion. In group II and IV, a tendency towards a reduced EVLWI was noted.

Conclusion: We conclude that combined treatment of donor and recipient with U-47006F reduces free radical mediated injury and neutrophil migration to the allograft, however, this did not result in a significant reduction of posttransplant lung edma and improvement in pulmonary hemodynamics. Donor pretreatment alone did not improve lung allograft reperfusion injury.