Inhibition of neutrophil elastase prevents the development of murine dextran sulfate sodium-induced colitis |
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Authors: | Yuichi Morohoshi Katsuyoshi Matsuoka Hiroshi Chinen Nobuhiko Kamada Toshiro Sato Tadakazu Hisamatsu Susumu Okamoto Nagamu Inoue Hiromasa Takaishi Haruhiko Ogata Yasushi Iwao Toshifumi Hibi |
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Institution: | (1) Department of Internal Medicine, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan;(2) Center for Comprehensive and Advanced Medicine, Keio University, Tokyo, Japan;(3) Center for Diagnostic and Therapeutic Endoscopy, Keio University, Tokyo, Japan |
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Abstract: | 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. |
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Keywords: | ulcerative colitis neutrophil elastase dextran sulfate sodium-induced colitis ONO-5046 |
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