Microvascular Permeability of the Non–Heart-Beating Rabbit Lung After Warm Ischemia and Reperfusion: Role of Neutrophil Elastase

Abstract Background . The duration of warm ischemia and reperfusion injury is a major limiting factor in the setting of lung transplantation with non–heart-beating donors (NHBD). We hypothesized that reperfusion with neutrophil elastase inhibitor or leukocyte-depleted blood has an inhibitory effect on the ischemia-reperfusion injury of NHBD rabbit lungs. Methods . To assess the lung injury, we used a perfused rabbit lung model and measured the hemodynamic parameters and filtration coefficient. The rabbit lungs after hypoxic cardiac arrest for 30, 50, and 60 minutes were harvested at room temperature, and ventilated lungs were reperfused for 1 hour at a constant flow (120 mL/min). The group with 60 minutes of warm ischemia and hypoxia was further divided into three groups to determine the effects of leukocyte-depleted reperfusion or neutrophil elastase inhibitor, (1) no other special treatment, (2) reperfusion with leukocyte-depleted blood, and (3) administration of 10 mg of specific neutrophil elastase inhibitor. The lungs reperfused immediately after harvest from the heart-beating donor were regarded as the control. Results . Sixty minutes of warm ischemia and hypoxia resulted in an increase in filtration coefficient (0.68 ± 0.20 g · min −1 · cm H 2 O −1 per 100 g) compared with the control values of 0.13 ± 0.03 g · min −1 · cm H 2 O −1 per 100 g. The increase in filtration coefficient after 60 minutes of warm ischemia and hypoxia in NHBD was remarkably suppressed by leukocyte depletion (0.23 ± 0.07) and by neutrophil elastase inhibitor (0.21 ± 0.08). The shunt fraction and histology results were also near normal. Conclusions . These results suggested that leukocyte depletion or treatment with neutrophil elastase inhibitor during reperfusion reduces alveolar–capillary damage caused by lung ischemia–reperfusion injury in the NHBD lung transplantation setting. This effect might be mediated by inhibition of neutrophil elastase activity or sequestration, and thus may lead to the increased availability of NHBD lungs.