The effects of a neutrophil elastase inhibitor (ONO-5046.Na) and neutrophil depletion using a granulotrap (G-1) column on lung reperfusion injury in dogs.
BACKGROUND
Activated neutrophils are reported to be closely involved in ischemia-reperfusion injury after lung transplantation. We investigated the beneficial effects of a new recombinant specific neutrophil elastase inhibitor, ONO-5046.Na, and an extracorporeal-type granulotrap (G-1) column on ischemia-reperfusion lung injury, by using an in situ warm lung ischemia model in dogs.


METHODS
Warm ischemia was induced for 3 hours by clamping the pulmonary arteries and veins. The left main bronchus was bisected and reanastomosed prior to reperfusion. The left lung was collapsed for 3 hours. A total of 27 adult mongrel dogs were divided into three groups: the control group (n = 9) treated with a saline vehicle; the ONO group (n = 9), in which ONO-5046.Na was continuously administrated from before induced ischemia and to ending 2 hours after reperfusion; and the G-1 group (n = 9), in which a G-1 column was applied for 90 minutes starting 30 minutes before reperfusion under passive bypass support.


RESULTS
Circulating neutrophils in the G-1 group decreased significantly (p<.05) compared to preischemia, and significantly decreased compared with the other groups after reperfusion. Oxygenation was improved actually and pulmonary vascular resistance was kept lower level after the administration of ONO-5046.Na. The increase of lung weight was significantly ameliorated in both the G-1 and ONO groups. In the histopathological study, lungs from the control group demonstrated diffuse alveolar edema, neutrophil infiltration, massive alveolar exudate and hemorrhage, and thickening of the interstitium. Lungs from the G-1 group showed mild swelling of the alveolar wall and neutrophil infiltration. Lungs from the ONO group showed virtually no abnormalities.


CONCLUSIONS
This study demonstrated that a neutrophil elastase inhibitor and neutrophil depletion prevented lung reperfusion injury. These treatments may prevent ischemia and reperfusion injury in lung transplantation.
Tomizawa
N
N
Second Department of Surgery, Gunma University School of Medicine, Maebashi, Japan.
Ohwada
S
S
Ohya
T
T
Takeyoshi
I
I
Ogawa
T
T
Kawashima
Y
Y
Adachi
M
M
Morishita
Y
Y
D000818:Animals; D004285:Dogs; D004353:Drug Evaluation, Preclinical; D005998:Glycine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D006439:Hemodynamics / Q000187:drug effects; D007937:Leukapheresis / Q000295:instrumentation* / Q000379:methods; D019272:Leukocyte Elastase / Q000037:antagonists & inhibitors*; D008168:Lung / Q000098:blood supply* / Q000473:pathology; D009504:Neutrophils; D009929:Organ Size / Q000187:drug effects; D011897:Random Allocation; D011994:Recombinant Proteins / Q000494:pharmacology / Q000627:therapeutic use; D015427:Reperfusion Injury / Q000097:blood / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D013449:Sulfonamides / Q000494:pharmacology / Q000627:therapeutic use*; D013997:Time Factors
D011994:Recombinant Proteins; D015842:Serine Proteinase Inhibitors; D013449:Sulfonamides; C069195:sivelestat; D019272:Leukocyte Elastase; D005998:Glycine