Background: Substitution of the nitric oxide (NO) pathway reduces ischemia/reperfusion injury after lung transplantation. 8-Br-cGMP is a membrane-permeable analogue of cGMP, the second messenger of NO. In this study, we evaluated the effect of administration of 8-Br-cGMP in the flush solution on early graft function.
Methods: Unilateral left lung transplantation was performed in 10 weight-matched pairs of outbred pigs (24 to 31 kg). Donor lungs were flushed with 1.5 L cold (1 degree C) low potassium dextrane (LPD) solution and preserved for 20 hours. In group I (n = 5), 8-Br-cGMP (1 mg/kg) was added to the flush solution. In group II (n = 5), 8 microg/kg prostaglandin E1 (PGE1) was injected into the pulmonary artery (PA) before flush. One hour after reperfusion, the recipients' contralateral right PA and bronchus were ligated to assess graft function only. cGMP levels in the PA and pulmonary vein were measured. Extravascular lung water index (EVLWI), pulmonary vascular resistance, mean PA pressure, and gas exchange (PaO2) were assessed during a 5-hour observation period. Lipid peroxidation (thiobarbituric acid-reactive substance) and neutrophil migration to the allograft (myeloperoxidase activity) were measured at the end of the assessment.
Results: In group I, a significant reduction of EVLWI (group I, 6.7 +/- 1.0 mL/kg vs group II, 10.1 +/- 0.6 ml/kg after 2 hours of reperfusion; p = 0.022), TBARS (group I, 65.6 +/- 10.0 pmol/g vs group II, 120.8 +/- 7.2 pmol/g, p = 0.0039), and MPO activity (group I, 0.8 +/- 0.1 change in optical density, (deltaOD)/mg/min vs group II, 1.7 +/- 0.3 deltaOD/mg/min, p = 0.036) was noted in comparison with group II. PaO2 levels tended to be higher in cGMP-treated animals, but the changes were not significant. Hemodynamic parameters did not differ between groups.
Conclusions: In this large animal model of lung allograft ischemia/reperfusion injury, 8-Br-cGMP as additive to the flush solution improves posttransplant lung edema, lipid peroxidation, and neutrophil migration to the allograft. This effect is not attributable to improved flush by vasodilation, as we compared 8-Br-cGMP with PGE1 given before flush in control animals.