NEUTROPHIL ENDOPEPTIDASE INHIBITOR IMPROVES PULMONARY-FUNCTION DURINGREPERFUSION AFTER 18-HOUR PRESERVATION

Background: Reperfusion injury remains a significant problem after lun g transplantation and is thought to be in part mediated by neutrophils . Ulinastatin inhibits release of elastase and cathepsin G from neutro phil granules, We hypothesized that inhibition of these neutrophil end opeptidases (proteases) would attenuate pulmonary reperfusion injury, Methods: With an isolated, whole blood-perfused, ventilated rabbit lun g model, we Studied the effects of ulinastatin. All lungs were flushed with cold Euro-Collins solution, harvested en bloc, stored inflated a t 4 degrees C for 18 hours, and reperfused with whole blood, The 18-ho ur control lungs (n = 8) were stored and reperfused, Low-dose (n = 8) and high-dose (n = 7) groups were treated with total doses of ulinasta tin of 25,000 and 50,000 units, respectively, during flush and reperfu sion. An additional control group of lungs (n = 8) was harvested, flus hed, and immediately reperfused, Results: The pulmonary artery pressur e was significantly lower in the high-dose group than in the 18-hour c ontrol group (36.7 +/- 1.8 vs 44.8 +/- 2.9 mm Hg, p = 0.034), The perc entage 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 ulinasta tin treatments did not result in a significant improvement in oxygenat ion 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 reperfusi on injury after 18 hours of hypothermic pulmonary ischemia, with resul tant improvements in pulmonary artery pressure and airway compliance, Improvement in pulmonary function after preservation and reperfusion w ith a neutrophil endopeptidase inhibitor confirms the role of endopept idases in reperfusion injury and suggests an intervention to reduce th eir detrimental effects on early graft function.