Elastase inhibition reduced death associated with acid aspiration-induced lung injury in hamsters.
This study examined whether the specific inhibition of neutrophil elastase by sivelestat sodium hydrate (sivelestat) reduced deaths associated with severe acute lung injury after hydrochloric acid (HCl) aspiration in hamsters. Animals that received a single intratracheal instillation of HCl (0.2 N, 200 microL) time-dependently died by occlusion of their trachea with inflammatory exudate. In a time course study, these animals developed severe lung injury, peaking 12 to 24 h after HCl instillation, as indicated by hemorrhage and a massive increase in the protein concentration of bronchoalveolar lavage fluid. These changes were closely correlated with neutrophil elastase activity in bronchoalveolar lavage fluid. Sivelestat (0.01, 0.1 and 1 mg/kg/h), when intravenously infused during the first 48 h post-HCl instillation, dose-dependently reduced death in HCl-instilled hamsters. In a separate experiment, analysis of bronchoalveolar lavage fluid parameters and partial pressure of arterial oxygen (PaO(2)) 8 h post-HCl instillation showed that sivelestat at 1 mg/kg/h, i.v. significantly improved both bronchoalveolar lavage fluid parameters and PaO(2) levels with evidence of the inhibition of neutrophil elastase activity in bronchoalveolar lavage fluid. These results suggest that neutrophil elastase plays a significant role in this type of severe acute lung injury that leads to death by respiratory failure.
Hagio
Tetsuya
T
Minase Research Institute, Ono Pharmaceutical Co., Ltd., 3-1-1, Sakurai, Shimamoto, Mishima, Osaka 618-8585, Japan.
Matsumoto
Shigeru
S
Nakao
Shintaro
S
Abiru
Taira
T
Ohno
Hiroyuki
H
Kawabata
Kazuhito
K
D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D006224:Cricetinae; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D005998:Glycine / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D006470:Hemorrhage / Q000473:pathology; D006851:Hydrochloric Acid; D066298:In Vitro Techniques; D007958:Leukocyte Count; D019272:Leukocyte Elastase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008168:Lung / Q000473:pathology; D008297:Male; D008647:Mesocricetus; D009504:Neutrophils / Q000473:pathology; D009195:Peroxidase / Q000378:metabolism; D011015:Pneumonia, Aspiration / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D012131:Respiratory Insufficiency / Q000209:etiology / Q000517:prevention & control; D013449:Sulfonamides / Q000627:therapeutic use*; D016019:Survival Analysis
D004791:Enzyme Inhibitors; D013449:Sulfonamides; C069195:sivelestat; D009195:Peroxidase; D019272:Leukocyte Elastase; D006851:Hydrochloric Acid; D005998:Glycine