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

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 neutrophi 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.

• Authors: O A Binns, N F DeLima, S A Buchanan, M C Mauney, J T Cope, S D Thies, K S Shockey, C G Tribble, I L Kron
• Journal: The Journal of thoracic and cardiovascular surgery (J Thorac Cardiovasc Surg) Vol. 112 Issue 3 Pg. 607-13 (Sep 1996) ISSN: 0022-5223 [Print] United States
• PMID: 8800146 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Euro-Collins' solution
• Glycoproteins
• Hypertonic Solutions
• Protease Inhibitors
• Serine Proteinase Inhibitors
• Trypsin Inhibitors
• Cathepsins
• Serine Endopeptidases
• Cathepsin G
• Pancreatic Elastase
• Leukocyte Elastase
• urinastatin

Topics

• Animals
• Blood Pressure (drug effects)
• Cathepsin G
• Cathepsins (antagonists & inhibitors)
• Female
• Glycoproteins (therapeutic use)
• Hypertonic Solutions
• Hypothermia, Induced
• Leukocyte Elastase
• Lung Compliance (drug effects)
• Lung Transplantation (physiology)
• Male
• Neutrophils (enzymology)
• Organ Preservation
• Oxygen Consumption (drug effects)
• Pancreatic Elastase (antagonists & inhibitors)
• Protease Inhibitors (therapeutic use)
• Pulmonary Artery
• Rabbits
• Reperfusion
• Reperfusion Injury (prevention & control)
• Serine Endopeptidases
• Serine Proteinase Inhibitors (therapeutic use)
• Trypsin Inhibitors (therapeutic use)