Sivelestat reduces reperfusion injury of lungs harvested from endotoxin-primed rats by inhibition of neutrophil-mediated inflammation.
BACKGROUND
Although liberalization of donor criteria may be one of the solutions to the current serious lung donor shortage, the use of non-standard donor lungs would increase the risk of post-operative complications. In the present study, we investigated the effect of sivelestat, a neutrophil elastase inhibitor, on reperfusion injury of a donor lung that was harvested from endotoxin-primed animals in a rat lung transplantation model.


METHODS
Donor rats received an intraperitoneal injection of Escherichia coli endotoxin (5 mg/kg) 2 hours before lung harvesting. The donor lungs were flushed with an organ preservation solution with or without sivelestat (300 microg/ml), and the left lung was immediately transplanted to the recipient by the cuff technique.


RESULTS
Endotoxin priming did not cause significant lung injury before harvesting. Although these lungs looked normal macroscopically, they were found to contain numerous neutrophils in the alveolar capillaries, even after lung flushing. There was no significant difference in the neutrophil count between the lungs flushed with and without sivelestat. The endotoxin-primed donor lung without sivelestat treatment became edematous immediately after reperfusion. In addition, the recipient's native right lungs were also pathologic. Treatment with sivelestat significantly reduced injury in both the donor and the recipient's native lungs. Treatment with sivelestat also inhibited the increase in tumor necrosis factor-alpha and cytokine-induced neutrophil chemoattractant-1 levels in the recipient circulation after reperfusion.


CONCLUSIONS
We conclude that sivelestat could reduce lung injury after transplantation by inhibiting the deleterious burst of inflammatory reactions that are initiated by reperfusion of the lungs from endotoxin-primed rats.
Suzuki
Satoshi
S
Department of Thoracic Surgery, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan. satoshisuzuki@idac.tohoku.ac.jp
Sugawara
Takafumi
T
Tabata
Toshiharu
T
Oishi
Hisashi
H
Niikawa
Hiromichi
H
Kondo
Takashi
T
D000818:Animals; D016207:Cytokines / Q000378:metabolism; D004731:Endotoxins / Q000008:administration & dosage / Q000494:pharmacology*; D004926:Escherichia coli / Q000378:metabolism; D005998:Glycine / Q000031:analogs & derivatives* / Q000494:pharmacology; D007274:Injections, Intraperitoneal; D016209:Interleukin-8 / Q000037:antagonists & inhibitors / Q000097:blood; D019272:Leukocyte Elastase / Q000037:antagonists & inhibitors; D008168:Lung / Q000098:blood supply* / Q000187:drug effects / Q000473:pathology; D016040:Lung Transplantation; D008297:Male; D009504:Neutrophils; D011014:Pneumonia / Q000209:etiology / Q000517:prevention & control*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000473:pathology / Q000517:prevention & control*; D013449:Sulfonamides / Q000494:pharmacology*; D020858:Tissue and Organ Harvesting; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D016207:Cytokines; D004731:Endotoxins; D016209:Interleukin-8; D013449:Sulfonamides; D014409:Tumor Necrosis Factor-alpha; C069195:sivelestat; D019272:Leukocyte Elastase; D005998:Glycine