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J Thorac Cardiovasc Surg 1996;112:607-613
© 1996 Mosby, Inc.

CARDIAC AND PULMONARY REPLACEMENT

NEUTROPHIL ENDOPEPTIDASE INHIBITOR IMPROVES PULMONARY FUNCTION DURING REPERFUSION AFTER EIGHTEEN-HOUR PRESERVATION

Supported by the National Institutes of Health under RO1 grant HL 48242 and NRSA fellowship F32HL09115-01A1. Additional support from CNPq—Conselho Nacional de Desenvolvimento Cientifico e Tecnologico, Brazil.

Presented in part at the Surgical Forum, American College of Surgeons, Oct. 25, 1995.

Received for publication Nov. 1, 1995 Revisions requested Jan. 4, 1996; revisions received Jan. 24, 1996 Accepted for publication Jan. 4, 1996. Address for reprints: Irving L. Kron, MD, Division of Thoracic and Cardiovascular Surgery, Department of Surgery, Box 310, University of Virginia Health Sciences Center, Charlottesville, VA 22908.

Abstract

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° 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. (J THORAC CARDIOVASC SURG 1996;112:607-13)

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