Inhibition of neutrophil elastase prevents the development of murine dextran sulfate sodium-induced colitis.
BACKGROUND
Neutrophil elastase (NE) is a major secretory product from activated neutrophils and a major contributor to tissue destruction. However, little is known about the pathogenic contribution of NE to ulcerative colitis (UC). This study was designed to investigate the contribution of NE by measuring NE activity in plasma and colonic mucosal tissue from UC patients and a murine acute colitis model, and to elucidate the therapeutic effect of the NE-specific inhibitor ONO-5046.


METHODS
The NE enzyme activities in plasma and colonic mucosal tissue from UC patients were directly measured using an enzyme-substrate reaction. Acute colitis was induced in mice by administration of 1.5% dextran sulfate sodium (DSS) for 5 days. DSS-induced colitis mice were then treated with ONO-5046 (50 mg/kg body weight) intraperitoneally twice a day.


RESULTS
In UC patients, the NE enzyme activity was significantly elevated in both the plasma and colonic mucosal tissue compared with healthy controls. In DSS-induced colitis mice, the NE enzyme activity increased in parallel with the disease development. ONO-5046 showed therapeutic effects in DSS-treated mice by significantly reducing weight loss and histological score. ONO-5046 suppressed the NE enzyme activities in both plasma and culture supernatant of colonic mucosa from DSS-induced colitis mice.


CONCLUSIONS
ONO-5046, a specific NE inhibitor, prevented the development of DSS-induced colitis in mice. NE therefore represents a promising target for the treatment of UC patients.
Morohoshi
Yuichi
Y
Department of Internal Medicine, School of Medicine, Keio University, Tokyo 160-8582, Japan.
Matsuoka
Katsuyoshi
K
Chinen
Hiroshi
H
Kamada
Nobuhiko
N
Sato
Toshiro
T
Hisamatsu
Tadakazu
T
Okamoto
Susumu
S
Inoue
Nagamu
N
Takaishi
Hiromasa
H
Ogata
Haruhiko
H
Iwao
Yasushi
Y
Hibi
Toshifumi
T
D000328:Adult; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002478:Cells, Cultured; D003092:Colitis / Q000139:chemically induced / Q000201:enzymology / Q000517:prevention & control*; D003093:Colitis, Ulcerative / Q000201:enzymology / Q000517:prevention & control; D016264:Dextran Sulfate / Q000633:toxicity; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D005998:Glycine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D006801:Humans; D007413:Intestinal Mucosa / Q000201:enzymology / Q000473:pathology; D019272:Leukocyte Elastase / Q000037:antagonists & inhibitors*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D015842:Serine Proteinase Inhibitors / Q000627:therapeutic use*; D013449:Sulfonamides / Q000627:therapeutic use*
D015415:Biomarkers; D015842:Serine Proteinase Inhibitors; D013449:Sulfonamides; D016264:Dextran Sulfate; C069195:sivelestat; D019272:Leukocyte Elastase; D005998:Glycine