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 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.
Binns
O A
OA
Department of Surgery, University of Virginia Health Sciences Center, Charlottesville 22908, USA.
DeLima
N F
NF
Buchanan
S A
SA
Mauney
M C
MC
Cope
J T
JT
Thies
S D
SD
Shockey
K S
KS
Tribble
C G
CG
Kron
I L
IL
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D056649:Cathepsin G; D002403:Cathepsins / Q000037:antagonists & inhibitors; D005260:Female; D006023:Glycoproteins / Q000627:therapeutic use*; D006982:Hypertonic Solutions; D007036:Hypothermia, Induced; D019272:Leukocyte Elastase; D008170:Lung Compliance / Q000187:drug effects; D016040:Lung Transplantation / Q000502:physiology*; D008297:Male; D009504:Neutrophils / Q000201:enzymology; D009926:Organ Preservation; D010101:Oxygen Consumption / Q000187:drug effects; D010196:Pancreatic Elastase / Q000037:antagonists & inhibitors; D011480:Protease Inhibitors / Q000627:therapeutic use*; D011651:Pulmonary Artery; D011817:Rabbits; D015424:Reperfusion; D015427:Reperfusion Injury / Q000517:prevention & control*; D012697:Serine Endopeptidases; D015842:Serine Proteinase Inhibitors / Q000627:therapeutic use; D014361:Trypsin Inhibitors / Q000627:therapeutic use*
C037096:Euro-Collins' solution; D006023:Glycoproteins; D006982:Hypertonic Solutions; D011480:Protease Inhibitors; D015842:Serine Proteinase Inhibitors; D014361:Trypsin Inhibitors; D002403:Cathepsins; D012697:Serine Endopeptidases; D056649:Cathepsin G; D010196:Pancreatic Elastase; D019272:Leukocyte Elastase; C028665:urinastatin