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

<!DOCTYPE html> <html lang="en" class="no-js"> <head> <meta charset="UTF-8"> <meta http-equiv="X-UA-Compatible" content="IE=edge"> <meta name="applicable-device" content="pc,mobile"> <meta name="viewport" content="width=device-width, initial-scale=1"> <meta name="robots" content="max-image-preview:large"> <meta name="access" content="No"> <meta name="360-site-verification" content="1268d79b5e96aecf3ff2a7dac04ad990" /> <title>Inhibition of neutrophil elastase prevents the development of murine dextran sulfate sodium-induced colitis | Journal of Gastroenterology </title> <meta name="twitter:site" content="@SpringerLink"/> <meta name="twitter:card" content="summary_large_image"/> <meta name="twitter:image:alt" content="Content cover image"/> <meta name="twitter:title" content="Inhibition of neutrophil elastase prevents the development of murine dextran sulfate sodium-induced colitis"/> <meta name="twitter:description" content="Journal of Gastroenterology - Neutrophil elastase (NE) is a major secretory product from activated neutrophils and a major contributor to tissue destruction. However, little is known about the..."/> <meta name="twitter:image" content="https://media.springernature.com/full/springer-static/cover-hires/journal/535"/> <meta name="journal_id" content="535"/> <meta name="dc.title" content="Inhibition of neutrophil elastase prevents the development of murine dextran sulfate sodium-induced colitis"/> <meta name="dc.source" content="Journal of Gastroenterology 2006 41:4"/> <meta name="dc.format" content="text/html"/> <meta name="dc.publisher" content="Springer"/> <meta name="dc.type" content="OriginalPaper"/> <meta name="dc.language" content="En"/> <meta name="dc.copyright" content="2006 Springer-Verlag Tokyo"/> <meta name="dc.rights" content="2006 Springer-Verlag Tokyo"/> <meta name="dc.rightsAgent" content="journalpermissions@springernature.com"/> <meta name="dc.description" content="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. 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. 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. 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."/> <meta name="prism.issn" content="1435-5922"/> <meta name="prism.publicationName" content="Journal of Gastroenterology"/> <meta name="prism.volume" content="41"/> <meta name="prism.number" content="4"/> <meta name="prism.section" content="OriginalPaper"/> <meta name="prism.startingPage" content="318"/> <meta name="prism.endingPage" content="324"/> <meta name="prism.copyright" content="2006 Springer-Verlag Tokyo"/> <meta name="prism.rightsAgent" content="journalpermissions@springernature.com"/> <meta name="prism.url" content="https://link.springer.com/article/10.1007/s00535-005-1768-8"/> <meta name="prism.doi" content="doi:10.1007/s00535-005-1768-8"/> <meta name="citation_pdf_url" content="https://link.springer.com/content/pdf/10.1007/s00535-005-1768-8.pdf"/> <meta name="citation_fulltext_html_url" content="https://link.springer.com/article/10.1007/s00535-005-1768-8"/> <meta name="citation_journal_title" content="Journal of Gastroenterology"/> <meta name="citation_journal_abbrev" content="J Gastroenterol"/> <meta name="citation_publisher" content="Springer-Verlag"/> <meta name="citation_issn" content="1435-5922"/> <meta name="citation_title" content="Inhibition of neutrophil elastase prevents the development of murine dextran sulfate sodium-induced colitis"/> <meta name="citation_volume" content="41"/> <meta name="citation_issue" content="4"/> <meta name="citation_publication_date" content="2006/04"/> <meta name="citation_firstpage" content="318"/> <meta name="citation_lastpage" content="324"/> <meta name="citation_article_type" content="Article"/> <meta name="citation_language" content="en"/> <meta name="dc.identifier" content="doi:10.1007/s00535-005-1768-8"/> <meta name="DOI" content="10.1007/s00535-005-1768-8"/> <meta name="size" content="82111"/> <meta name="citation_doi" content="10.1007/s00535-005-1768-8"/> <meta name="citation_springer_api_url" content="http://api.springer.com/xmldata/jats?q=doi:10.1007/s00535-005-1768-8&api_key="/> <meta name="description" content="Neutrophil elastase (NE) is a major secretory product from activated neutrophils and a major contributor to tissue destruction. However, little is known ab"/> <meta name="dc.creator" content="Morohoshi, Yuichi"/> <meta name="dc.creator" content="Matsuoka, Katsuyoshi"/> <meta name="dc.creator" content="Chinen, Hiroshi"/> <meta name="dc.creator" content="Kamada, Nobuhiko"/> <meta name="dc.creator" content="Sato, Toshiro"/> <meta name="dc.creator" content="Hisamatsu, Tadakazu"/> <meta name="dc.creator" content="Okamoto, Susumu"/> <meta name="dc.creator" content="Inoue, Nagamu"/> <meta name="dc.creator" content="Takaishi, Hiromasa"/> <meta name="dc.creator" content="Ogata, Haruhiko"/> <meta name="dc.creator" content="Iwao, Yasushi"/> <meta name="dc.creator" content="Hibi, Toshifumi"/> <meta name="dc.subject" content="Gastroenterology"/> <meta name="dc.subject" content="Hepatology"/> <meta name="dc.subject" content="Abdominal Surgery"/> <meta name="dc.subject" content="Colorectal Surgery"/> <meta name="dc.subject" content="Surgical Oncology"/> <meta name="citation_reference" content="citation_journal_title=N Engl J Med; 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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."/> <meta property="og:image" content="https://media.springernature.com/full/springer-static/cover-hires/journal/535"/> <meta name="format-detection" content="telephone=no"> <link rel="apple-touch-icon" sizes="180x180" href=/oscar-static/img/favicons/darwin/apple-touch-icon-92e819bf8a.png> <link rel="icon" type="image/png" sizes="192x192" href=/oscar-static/img/favicons/darwin/android-chrome-192x192-6f081ca7e5.png> <link rel="icon" type="image/png" sizes="32x32" href=/oscar-static/img/favicons/darwin/favicon-32x32-1435da3e82.png> <link rel="icon" type="image/png" sizes="16x16" href=/oscar-static/img/favicons/darwin/favicon-16x16-ed57f42bd2.png> <link rel="shortcut icon" data-test="shortcut-icon" href=/oscar-static/img/favicons/darwin/favicon-c6d59aafac.ico> <meta name="theme-color" content="#e6e6e6">   <link rel="stylesheet" media="print" href=/oscar-static/app-springerlink/css/print-b8af42253b.css> <style> 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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. 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. 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. 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.","datePublished":"","dateModified":"","pageStart":"318","pageEnd":"324","sameAs":"https://doi.org/10.1007/s00535-005-1768-8","keywords":["ulcerative colitis","neutrophil elastase","dextran sulfate sodium-induced colitis","ONO-5046","Gastroenterology","Hepatology","Abdominal Surgery","Colorectal Surgery","Surgical Oncology"],"image":[],"isPartOf":{"name":"Journal of Gastroenterology","issn":["1435-5922","0944-1174"],"volumeNumber":"41","@type":["Periodical","PublicationVolume"]},"publisher":{"name":"Springer-Verlag","logo":{"url":"https://www.springernature.com/app-sn/public/images/logo-springernature.png","@type":"ImageObject"},"@type":"Organization"},"author":[{"name":"Yuichi Morohoshi","affiliation":[{"name":"Keio University","address":{"name":"Department of Internal Medicine, School of Medicine, Keio University, Tokyo, Japan","@type":"PostalAddress"},"@type":"Organization"}],"@type":"Person"},{"name":"Katsuyoshi Matsuoka","affiliation":[{"name":"Keio University","address":{"name":"Department of Internal Medicine, School of Medicine, Keio University, Tokyo, Japan","@type":"PostalAddress"},"@type":"Organization"}],"@type":"Person"},{"name":"Hiroshi Chinen","affiliation":[{"name":"Keio University","address":{"name":"Department of Internal Medicine, School of Medicine, Keio University, Tokyo, Japan","@type":"PostalAddress"},"@type":"Organization"}],"@type":"Person"},{"name":"Nobuhiko Kamada","affiliation":[{"name":"Keio University","address":{"name":"Department of Internal Medicine, School of Medicine, Keio University, Tokyo, Japan","@type":"PostalAddress"},"@type":"Organization"}],"@type":"Person"},{"name":"Toshiro Sato","affiliation":[{"name":"Keio University","address":{"name":"Department of Internal Medicine, School of Medicine, Keio University, Tokyo, Japan","@type":"PostalAddress"},"@type":"Organization"}],"@type":"Person"},{"name":"Tadakazu Hisamatsu","affiliation":[{"name":"Keio University","address":{"name":"Department of Internal Medicine, School of Medicine, Keio University, Tokyo, Japan","@type":"PostalAddress"},"@type":"Organization"}],"@type":"Person"},{"name":"Susumu Okamoto","affiliation":[{"name":"Keio University","address":{"name":"Department of Internal Medicine, School of Medicine, Keio University, Tokyo, Japan","@type":"PostalAddress"},"@type":"Organization"}],"@type":"Person"},{"name":"Nagamu Inoue","affiliation":[{"name":"Keio University","address":{"name":"Center for Comprehensive and Advanced Medicine, Keio University, Tokyo, Japan","@type":"PostalAddress"},"@type":"Organization"}],"@type":"Person"},{"name":"Hiromasa Takaishi","affiliation":[{"name":"Keio University","address":{"name":"Center for Comprehensive and Advanced Medicine, Keio University, Tokyo, 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Gastroenterology</span> </a> <a href="https://link.springer.com/journal/535/aims-and-scope" class="app-article-masthead__submission-link" data-track="click_aims_and_scope" data-track-action="aims and scope" data-track-context="article page" data-track-label="link"> Aims and scope <svg width="16" height="16" focusable="false" role="img" aria-hidden="true" class="u-icon"><use xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#icon-eds-i-arrow-right-medium"></use></svg> </a> <a href="https://www.editorialmanager.com/joga" class="app-article-masthead__submission-link" data-track="click_submit_manuscript" data-track-context="article masthead on springerlink article page" data-track-action="submit manuscript" data-track-label="link"> Submit manuscript <svg width="16" height="16" focusable="false" role="img" aria-hidden="true" class="u-icon"><use xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#icon-eds-i-arrow-right-medium"></use></svg> </a> </div> </div> </div> </section> <div class="c-article-main u-container u-mt-24 u-mb-32 l-with-sidebar" id="main-content" data-component="article-container"> <main class="u-serif js-main-column" data-track-component="article body"> <div class="c-article-header"> <header> <ul class="c-article-author-list c-article-author-list--short" data-test="authors-list" data-component-authors-activator="authors-list"><li class="c-article-author-list__item"><a data-test="author-name" data-track="click" data-track-action="open author" data-track-label="link" href="#auth-Yuichi-Morohoshi-A1" data-author-popup="auth-Yuichi-Morohoshi-A1" data-author-search="Morohoshi, Yuichi">Yuichi Morohoshi</a><sup class="u-js-hide"><a href="#A1">1</a></sup>, </li><li class="c-article-author-list__item"><a data-test="author-name" data-track="click" data-track-action="open author" data-track-label="link" href="#auth-Katsuyoshi-Matsuoka-A1" data-author-popup="auth-Katsuyoshi-Matsuoka-A1" data-author-search="Matsuoka, Katsuyoshi">Katsuyoshi Matsuoka</a><sup 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href="#auth-Toshiro-Sato-A1" data-author-popup="auth-Toshiro-Sato-A1" data-author-search="Sato, Toshiro">Toshiro Sato</a><sup class="u-js-hide"><a href="#A1">1</a></sup>, </li><li class="c-article-author-list__item c-article-author-list__item--hide-small-screen"><a data-test="author-name" data-track="click" data-track-action="open author" data-track-label="link" href="#auth-Tadakazu-Hisamatsu-A1" data-author-popup="auth-Tadakazu-Hisamatsu-A1" data-author-search="Hisamatsu, Tadakazu">Tadakazu Hisamatsu</a><sup class="u-js-hide"><a href="#A1">1</a></sup>, </li><li class="c-article-author-list__item c-article-author-list__item--hide-small-screen"><a data-test="author-name" data-track="click" data-track-action="open author" data-track-label="link" href="#auth-Susumu-Okamoto-A1" data-author-popup="auth-Susumu-Okamoto-A1" data-author-search="Okamoto, Susumu">Susumu Okamoto</a><sup class="u-js-hide"><a href="#A1">1</a></sup>, </li><li class="c-article-author-list__item c-article-author-list__item--hide-small-screen"><a data-test="author-name" data-track="click" data-track-action="open author" data-track-label="link" href="#auth-Nagamu-Inoue-A2" data-author-popup="auth-Nagamu-Inoue-A2" data-author-search="Inoue, Nagamu">Nagamu Inoue</a><sup class="u-js-hide"><a href="#A2">2</a></sup>, </li><li class="c-article-author-list__item c-article-author-list__item--hide-small-screen"><a data-test="author-name" data-track="click" data-track-action="open author" data-track-label="link" href="#auth-Hiromasa-Takaishi-A2" data-author-popup="auth-Hiromasa-Takaishi-A2" data-author-search="Takaishi, Hiromasa">Hiromasa Takaishi</a><sup class="u-js-hide"><a href="#A2">2</a></sup>, </li><li class="c-article-author-list__item c-article-author-list__item--hide-small-screen"><a data-test="author-name" data-track="click" data-track-action="open author" data-track-label="link" href="#auth-Haruhiko-Ogata-A3" data-author-popup="auth-Haruhiko-Ogata-A3" data-author-search="Ogata, Haruhiko">Haruhiko Ogata</a><sup class="u-js-hide"><a href="#A3">3</a></sup>, </li><li class="c-article-author-list__item c-article-author-list__item--hide-small-screen"><a data-test="author-name" data-track="click" data-track-action="open author" data-track-label="link" href="#auth-Yasushi-Iwao-A2" data-author-popup="auth-Yasushi-Iwao-A2" data-author-search="Iwao, Yasushi">Yasushi Iwao</a><sup class="u-js-hide"><a href="#A2">2</a></sup> & </li><li class="c-article-author-list__show-more" aria-label="Show all 12 authors for this article" title="Show all 12 authors for this article">…</li><li class="c-article-author-list__item"><a data-test="author-name" data-track="click" data-track-action="open author" data-track-label="link" href="#auth-Toshifumi-Hibi-A1-A2" data-author-popup="auth-Toshifumi-Hibi-A1-A2" data-author-search="Hibi, Toshifumi">Toshifumi Hibi</a><sup class="u-js-hide"><a href="#A1">1</a>,<a href="#A2">2</a></sup> </li></ul><button aria-expanded="false" class="c-article-author-list__button"><svg width="16" height="16" focusable="false" role="img" aria-hidden="true" class="u-icon"><use xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#icon-eds-i-chevron-down-medium"></use></svg><span>Show authors</span></button> <div data-test="article-metrics"> <ul class="app-article-metrics-bar u-list-reset"> <li class="app-article-metrics-bar__item"> <p class="app-article-metrics-bar__count"><svg class="u-icon app-article-metrics-bar__icon" width="24" height="24" aria-hidden="true" focusable="false"> <use xlink:href="#icon-eds-i-accesses-medium"></use> </svg>756 <span class="app-article-metrics-bar__label">Accesses</span></p> </li> <li class="app-article-metrics-bar__item"> <p class="app-article-metrics-bar__count"><svg class="u-icon app-article-metrics-bar__icon" width="24" height="24" aria-hidden="true" focusable="false"> <use xlink:href="#icon-eds-i-altmetric-medium"></use> </svg>6 <span class="app-article-metrics-bar__label">Altmetric</span></p> </li> <li class="app-article-metrics-bar__item app-article-metrics-bar__item--metrics"> <p class="app-article-metrics-bar__details"><a href="/article/10.1007/s00535-005-1768-8/metrics" data-track="click" data-track-action="view metrics" data-track-label="link" rel="nofollow">Explore all metrics <svg class="u-icon app-article-metrics-bar__arrow-icon" width="24" height="24" aria-hidden="true" focusable="false"> <use xlink:href="#icon-eds-i-arrow-right-medium"></use> </svg></a></p> </li> </ul> </div> <div class="u-mt-32"> </div> </header> </div> <div data-article-body="true" data-track-component="article body" class="c-article-body"> <section aria-labelledby="Abs1" data-title="Abstract" lang="en"><div class="c-article-section" id="Abs1-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="Abs1">Abstract</h2><div class="c-article-section__content" id="Abs1-content"><h3 class="c-article__sub-heading" data-test="abstract-sub-heading">Background</h3><p>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.</p><h3 class="c-article__sub-heading" data-test="abstract-sub-heading">Methods</h3><p>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.</p><h3 class="c-article__sub-heading" data-test="abstract-sub-heading">Results</h3><p>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.</p><h3 class="c-article__sub-heading" data-test="abstract-sub-heading">Conclusions</h3><p>ONO-5046, a specific NE inhibitor, prevented the development of DSS-induced colitis in mice. 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