Neutrophil elastase inhibitor, sivelestat, attenuates acute lung injury after cardiopulmonary bypass in the rabbit endotoxemia model.
BACKGROUND
Neutrophil elastase probably contributes to the development of acute lung injury after cardiopulmonary bypass (CPB) in patients with infection or shock. We evaluated whether pretreatment with sivelestat sodium hydrate, a neutrophil elastase inhibitor (EI), can prevent acute lung injury caused by CPB.


METHODS
Rabbits were assigned four groups: CPB for 60 minutes, control CPB group; low-dose lipopolysaccharide (LPS) administration without CPB, LPS group; CPB after lipopolysaccharide administration, LPS+CPB group; or preparation with continuous infusion of sivelestat and CPBs after lipopolysaccharide administration, EI group. Blood samples to determine blood gas concentration, plasma elastase activity, and plasma interleukin-8 levels were obtained. Histopathologic examinations of the lung were performed.


RESULTS
The decreased arterial oxygen pressure at the end of CPB was observed in the LPS+CPB group only, but was suppressed in the EI group (p < 0.01). Elastase activity was markedly elevated at 120 minutes after CPB, and interleukin-8 levels were markedly elevated at 180 minutes in the LPS+CPB group but were much lower (p < 0.05) in the EI group. Histopathology demonstrated accumulation of polymorphonuclear neutrophils in bronchoalveolar areas in the LPS+CPB group (p < 0.01). Pulmonary myeloperoxidase activity was significantly lower in the LPS+CPB group than in the other groups (p < 0.01). These changes were minimal in the EI group.


CONCLUSIONS
The combination of low dose LPS+60 minutes of CPB, but neither intervention alone, produced evidence of acute lung injury in a rabbit model. This did not occur when the animals were pretreated with sivelestat.
Wakayama
Fuminori
F
First Department of Surgery, Hirosaki University School of Medicine, Aomori, Japan.
Fukuda
Ikuo
I
Suzuki
Yasuyuki
Y
Kondo
Norihiro
N
D000818:Animals; D002315:Cardiopulmonary Bypass / Q000009:adverse effects*; D005998:Glycine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D016209:Interleukin-8 / Q000097:blood; D019272:Leukocyte Elastase / Q000037:antagonists & inhibitors* / Q000502:physiology; D008070:Lipopolysaccharides / Q000633:toxicity*; D009504:Neutrophils / Q000502:physiology; D009195:Peroxidase / Q000378:metabolism; D011817:Rabbits; D012128:Respiratory Distress Syndrome / Q000517:prevention & control*; D013449:Sulfonamides / Q000627:therapeutic use*
D016209:Interleukin-8; D008070:Lipopolysaccharides; D013449:Sulfonamides; C069195:sivelestat; D009195:Peroxidase; D019272:Leukocyte Elastase; D005998:Glycine