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Inhibition of neutrophil elastase prevents the development of murine dextran sulfate sodium-induced colitis

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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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Authors and Affiliations

  1. Department of Internal Medicine, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan

    Yuichi Morohoshi, Katsuyoshi Matsuoka, Hiroshi Chinen, Nobuhiko Kamada, Toshiro Sato, Tadakazu Hisamatsu, Susumu Okamoto & Toshifumi Hibi

  2. Center for Comprehensive and Advanced Medicine, Keio University, Tokyo, Japan

    Nagamu Inoue, Hiromasa Takaishi, Yasushi Iwao & Toshifumi Hibi

  3. Center for Diagnostic and Therapeutic Endoscopy, Keio University, Tokyo, Japan

    Haruhiko Ogata

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  1. Yuichi Morohoshi
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  2. Katsuyoshi Matsuoka
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  3. Hiroshi Chinen
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  4. Nobuhiko Kamada
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  11. Yasushi Iwao
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  12. Toshifumi Hibi
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Morohoshi, Y., Matsuoka, K., Chinen, H. et al. Inhibition of neutrophil elastase prevents the development of murine dextran sulfate sodium-induced colitis. J Gastroenterol 41, 318–324 (2006). https://doi.org/10.1007/s00535-005-1768-8

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  • DOI: https://doi.org/10.1007/s00535-005-1768-8

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