Inhibition of neutrophil elastase activity attenuates complement-mediated lung injury in the hamster.
The role of neutrophil elastase in complement-mediated lung injury was examined in hamsters using a specific neutrophil elastase inhibitor, sodium N-[2-[4-(2,2 dimethylpropionyloxy)phenylsulfonylamino]benzoyl]aminoacetate tetrahydrate (sivelestat). Intravenous injection with cobra venom factor (CVF) into hamsters transiently increased plasma neutrophil elastase activity by about 10-fold. This increase was followed by a sustained increase in lung vascular [125I]bovine serum albumin permeability peaking 30 min after CVF injection. The increase in lung vascular permeability was associated with neutrophil accumulation in lung tissue and an increase in protein concentration in the bronchoalveolar lavage fluid. Inhibition of the elevated plasma neutrophil elastase activity (36.5%, 66.9% and 104.3%) by continuous i.v. infusion with sivelestat (0.1, 0.3 and 1 mg/kg/h), dose-dependently attenuated the increase in lung vascular permeability 30 min after CVF injection. Furthermore, sivelestat at 1 mg/kg/h almost totally prevented the increase in protein concentration in the bronchoalveolar lavage fluid without affecting lung neutrophil accumulation. These results suggest that neutrophil elastase is an important mediator in complement-mediated acute lung injury.
Hagio
T
T
Minase Research Institute, Discovery Laboratories II, Ono Pharmaceutical Co., Ltd., 3-1-1 Sakurai, Shimamoto, Mishima, 618-8585, Osaka, Japan.
Nakao
S
S
Matsuoka
H
H
Matsumoto
S
S
Kawabata
K
K
Ohno
H
H
D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D002199:Capillary Permeability / Q000187:drug effects; D002374:Catalase / Q000494:pharmacology; D003167:Complement Activation / Q000187:drug effects / Q000502:physiology*; D006224:Cricetinae; D004305:Dose-Response Relationship, Drug; D004546:Elapid Venoms / Q000008:administration & dosage; D005998:Glycine / Q000031:analogs & derivatives / Q000494:pharmacology*; D019272:Leukocyte Elastase / Q000037:antagonists & inhibitors* / Q000097:blood; D008168:Lung / Q000098:blood supply / Q000187:drug effects / Q000473:pathology; D008171:Lung Diseases / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D008297:Male; D008647:Mesocricetus; D009504:Neutrophils / Q000187:drug effects / Q000473:pathology; D009195:Peroxidase / Q000187:drug effects / Q000378:metabolism; D011506:Proteins / Q000187:drug effects / Q000378:metabolism; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology*; D013449:Sulfonamides / Q000494:pharmacology*; D013997:Time Factors
D004546:Elapid Venoms; D011506:Proteins; D015842:Serine Proteinase Inhibitors; D013449:Sulfonamides; C016310:cobra venom factor; C069195:sivelestat; D002374:Catalase; D009195:Peroxidase; D019272:Leukocyte Elastase; D005998:Glycine