title: Sivelestat reduces reperfusion injury of lungs harvested from endotoxin-primed rats by inhibition of neutrophil-mediated inflammation.
abstract: 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.
authors.affiliation: Department of Thoracic Surgery, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan. satoshisuzuki@idac.tohoku.ac.jp
authors.forename: Satoshi
authors.initials: S
authors.lastname: Suzuki
authors.forename: Takafumi
authors.initials: T
authors.lastname: Sugawara
authors.forename: Toshiharu
authors.initials: T
authors.lastname: Tabata
authors.forename: Hisashi
authors.initials: H
authors.lastname: Oishi
authors.forename: Hiromichi
authors.initials: H
authors.lastname: Niikawa
authors.forename: Takashi
authors.initials: T
authors.lastname: Kondo
mesh_terms: 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
chemical_list: D016207:Cytokines; D004731:Endotoxins; D016209:Interleukin-8; D013449:Sulfonamides; D014409:Tumor Necrosis Factor-alpha; C069195:sivelestat; D019272:Leukocyte Elastase; D005998:Glycine