Neutrophil endopeptidase inhibitor improves pulmonary function during reperfusion after eighteen-hour preservation

Background: Reperfusion injury remains a significant problem after lung transplantation and is thought to be in part mediated by neutrophils. Ulinastatin inhibits release of elastase and cathepsin G from neutrophil granules, We hypothesized that inhibition of these neutrophil endopeptidases (proteases) would attenuate pulmonary reperfusion injury, Methods: With an isolated, whole blood-perfused, ventilated rabbit lung model, we Studied the effects of ulinastatin. All lungs were flushed with cold Euro-Collins solution, harvested en bloc, stored inflated at 4 degrees C for 18 hours, and reperfused with whole blood, The 18-hour control lungs (n = 8) were stored and reperfused, Low-dose (n = 8) and high-dose (n = 7) groups were treated with total doses of ulinastatin of 25,000 and 50,000 units, respectively, during flush and reperfusion. An additional control group of lungs (n = 8) was harvested, flushed, and immediately reperfused, Results: The pulmonary artery pressure was significantly lower in the high-dose group than in the 18-hour control group (36.7 +/- 1.8 vs 44.8 +/- 2.9 mm Hg, p = 0.034), The percentage decrease in dynamic airway compliance was significantly less in the high-dose group than in the 18-hour control group (-13.8% +/- 4.4% vs -25.1% +/- 3.7%, p = 0.032), Both low-dose and high-dose ulinastatin treatments did not result in a significant improvement in oxygenation with respect to the 18-hour control group (72.2 +/- 25.8 vs 32.5 +/- 4.9 mm Hg, p = 0.21), Conclusions: Ulinastatin diminishes reperfusion injury after 18 hours of hypothermic pulmonary ischemia, with resultant improvements in pulmonary artery pressure and airway compliance, Improvement in pulmonary function after preservation and reperfusion with a neutrophil endopeptidase inhibitor confirms the role of endopeptidases in reperfusion injury and suggests an intervention to reduce their detrimental effects on early graft function.