Effects of lecithinized superoxide dismutase and a neutrophil elastase inhibitor (ONO-5046) on hyperoxic lung injury in rat.
Reactive oxygen and neutrophil metabolites have been implicated in the development of hyperoxic lung injury. We determined the protective effects of either a superoxide dismutase or neutrophil elastase inhibitor and the combination of both agents on the development of hyperoxic lung injury in rats. Two drugs (lecithinized superoxide dismutase and ONO-5046) were used in the present study. Lecithinized superoxide dismutase, a lecithin derivative bound to recombinant CuZn superoxide dismutase, has a higher affinity for cells such as polymorphonuclear leukocytes and endothelial cells than recombinant human superoxide dismutase. N-[2-[4-2,2-dimethylpropionyloxy) phenylsulfonylamino] benzoyl]¿ aminoacetic acid (ONO-5046), a specific neutrophil elastase inhibitor, which was developed as a low-molecular weight inhibitor, showed protective effects against various lung injuries. Rats were exposed to over 90% oxygen for 72 h, and bronchoalveolar lavage was performed to evaluate the permeability and neutrophil accumulation in the lungs. Rats were treated with lecithinized superoxide dismutase (30,000 U/day, intravenously n=7) or ONO-5046 (10 mg/kg, intramuscularly twice a day, n=7) or a combination of both drugs (n=7). Albumin concentration and neutrophil counts in bronchoalveolar lavage fluid were compared between animals with and without drug treatment. Either lecithinized superoxide dismutase or ONO-5046 treatment significantly decreased albumin concentration and neutrophil counts in bronchoalveolar lavage fluid compared to those in the animals of the hyperoxia-alone group (n=9). However, albumin leakage and neutrophil accumulation in the rat lung treated with combined agents were identical to that of either the lecithinized superoxide dismutase or ONO-5046 treatment. These findings suggest that lecithinized superoxide dismutase and ONO-5046 are useful drugs to protect against hyperoxic lung injury in rats. However, there were no additive effects by the combination in preventing hyperoxic lung injury.
Yamamoto
H
H
First Department of Medicine, Shinshu University School of Medicine, 3-1-1 Asahi Matsumoto, 390-8621, Japan.
Koizumi
T
T
Kaneki
T
T
Hanaoka
M
M
Kubo
K
K
D000418:Albumins / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D002452:Cell Count; D005998:Glycine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D018496:Hyperoxia / Q000503:physiopathology*; D019272:Leukocyte Elastase / Q000037:antagonists & inhibitors*; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008171:Lung Diseases / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D009504:Neutrophils / Q000166:cytology / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D013449:Sulfonamides / Q000494:pharmacology*; D013482:Superoxide Dismutase / Q000494:pharmacology*
D000418:Albumins; D013449:Sulfonamides; C069195:sivelestat; D013482:Superoxide Dismutase; D019272:Leukocyte Elastase; D005998:Glycine