Potency of truncated secretory leukoprotease inhibitor assessed in acute lung injury models in hamsters.
We evaluated the potency of truncated secretory leukoprotease inhibitor (truncated SLPI) in a human sputum elastase (HSE)-induced lung injury model and in a specific neutrophil-mediated acute lung injury model in hamsters. Intratracheal administration of HSE induced acute lung hemorrhage that could be measured by determination of the hemoglobin content in the bronchoalveolar lavage fluid. Intratracheal administration of truncated SLPI 1 hr before HSE administration inhibited acute lung hemorrhage in a dose-dependent manner (ED50 = 46.8 microg/kg), as did i.v. injection of the inhibitor given 2 min before HSE administration (ED50 = 14.7 mg/kg). Intratracheal administration of endotoxin (lipopolysaccharide) induced pulmonary neutrophilia. Twenty-four hours after lipopolysaccharide administration, the addition of formyl-methionyl-leucyl-phenylalanine resulted in a neutrophil-dependent acute lung injury that expressed an increase in hemoglobin content and in elastase-like activity in bronchoalveolar lavage fluids. In this model, lung injury was significantly attenuated by i.v. and intratracheal administration of truncated SLPI. These results suggest that truncated SLPI appears to be a good candidate inhibitor for the treatment of destructive lung diseases due to neutrophils.
Mitsuhashi
H
H
Teijin Institute for Bio-Medical Research, Hino, Tokyo, Japan.
Asano
S
S
Nonaka
T
T
Masuda
K
K
Kiyoki
M
M
D000818:Animals; D001992:Bronchoalveolar Lavage Fluid; D006224:Cricetinae; D004195:Disease Models, Animal; D008070:Lipopolysaccharides / Q000633:toxicity; D008171:Lung Diseases / Q000139:chemically induced / Q000201:enzymology* / Q000473:pathology; D008297:Male; D008647:Mesocricetus; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000633:toxicity; D010196:Pancreatic Elastase / Q000633:toxicity; D053491:Proteinase Inhibitory Proteins, Secretory; D011506:Proteins / Q000494:pharmacology*; D053481:Secretory Leukocyte Peptidase Inhibitor
D008070:Lipopolysaccharides; D053491:Proteinase Inhibitory Proteins, Secretory; D011506:Proteins; C506814:SLPI protein, human; D053481:Secretory Leukocyte Peptidase Inhibitor; D009240:N-Formylmethionine Leucyl-Phenylalanine; D010196:Pancreatic Elastase