Inhibition of elastase-induced acute inflammation and pulmonary emphysema in hamsters by a novel neutrophil elastase inhibitor FR901277.
OBJECTIVE
A neutrophil elastase inhibitor FR901277 was examined for its inhibitory effect on degradation of natural substrate elastin in vitro, and on acute inflammatory states and pulmonary emphysema in vivo.


METHODS
Elastin-congo red was used as a substrate for elastin degradation assay. Paw edema in male C57BL mice (6 weeks old) and pulmonary hemorrhage in female golden hamsters (5 weeks old) were induced by topical injection of human neutrophil elastase (HNE). Pulmonary emphysema in male golden Syrian hamsters (10 weeks old) was provoked by intratracheal instillation of porcine pancreatic elastase. In all in vivo experiments. FR901277 was administered prior to elastase treatment.


METHODS
Elastin degradation by HNE was monitored spectrophotometrically with elastin-congo red. Foot swelling was measured by calipers. Pulmonary hemorrhage was assessed by hemoglobin concentration in bronchoalveolar lavage fluid. As emphysematous parameters, quasi-static lung compliance and vital capacity were measured.


RESULTS
FR901277 inhibited HNE-induced elastin degradation. Systemic treatment with FR901277 significantly inhibited paw edema and pulmonary hemorrhage. Intratracheal treatment with FR901277 significantly ameliorated changes in pulmonary function.


CONCLUSIONS
These results suggest that FR901277 inhibits the elastase activity potently both in vitro and in vivo, and that elastase may play a role at least in part in pathogenesis of pulmonary emphysema.
Fujie
K
K
Exploratory Research Laboratories, Fujisawa Pharmaceutical Co. Ltd., Ibaraki, Japan. keiko_fujie@po.fujisawa.co.jp
Shinguh
Y
Y
Yamazaki
A
A
Hatanaka
H
H
Okamoto
M
M
Okuhara
M
M
D000577:Amides / Q000627:therapeutic use*; D000818:Animals; D006224:Cricetinae; D004487:Edema / Q000139:chemically induced / Q000517:prevention & control; D004549:Elastin / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D005260:Female; D006470:Hemorrhage / Q000139:chemically induced / Q000517:prevention & control; D006801:Humans; D007249:Inflammation / Q000139:chemically induced / Q000517:prevention & control*; D019272:Leukocyte Elastase / Q000037:antagonists & inhibitors*; D008171:Lung Diseases / Q000139:chemically induced / Q000517:prevention & control; D008297:Male; D008647:Mesocricetus; D051379:Mice; D008810:Mice, Inbred C57BL; D010196:Pancreatic Elastase; D011656:Pulmonary Emphysema / Q000139:chemically induced / Q000517:prevention & control*; D013552:Swine
D000577:Amides; D004791:Enzyme Inhibitors; C120193:FR 901277; D004549:Elastin; D010196:Pancreatic Elastase; D019272:Leukocyte Elastase