{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,3]],"date-time":"2026-11-03T07:53:33Z","timestamp":1793692413070,"version":"4.5.1"},"reference-count":54,"publisher":"Oxford University Press (OUP)","issue":"10","license":[{"start":{"date-parts":[[2019,5,8]],"date-time":"2019-05-08T00:00:00Z","timestamp":1557273600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"DFG Collaborative Research Center","award":["SFB 900 TP8"],"award-info":[{"award-number":["SFB 900 TP8"]}]},{"name":"DFG Priority Program","award":["SPP1656\/2"],"award-info":[{"award-number":["SPP1656\/2"]}]},{"name":"Infect-ERA Consortium","award":["031L0093B"],"award-info":[{"award-number":["031L0093B"]}]},{"name":"Canadian Academy of Health Sciences Foundation","award":["148408"],"award-info":[{"award-number":["148408"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2019,9,18]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Intestinal fibrosis is a common and serious complication of Crohn\u2019s disease characterized by the accumulation of fibroblasts, deposition of extracellular matrix, and formation of scar tissue. Although many factors including cytokines and proteases contribute to the development of intestinal fibrosis, the initiating mechanisms and the complex interplay between these factors remain unclear.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Chronic infection of mice with Salmonella enterica serovar Typhimurium was used to induce intestinal fibrosis. A murine protease-specific CLIP-CHIP microarray analysis was employed to assess regulation of proteases and protease inhibitors. To confirm up- or downregulation during fibrosis, we performed quantitative real-time polymerase chain reaction (PCR) and immunohistochemical stainings in mouse tissue and tissue from patients with inflammatory bowel disease. In vitro infections were used to demonstrate a direct effect of bacterial infection in the regulation of proteases.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Mice develop severe and persistent intestinal fibrosis upon chronic infection with Salmonella enterica serovar Typhimurium, mimicking the pathology of human disease. Microarray analyses revealed 56 up- and 40 downregulated proteases and protease inhibitors in fibrotic cecal tissue. Various matrix metalloproteases, serine proteases, cysteine proteases, and protease inhibitors were regulated in the fibrotic tissue, 22 of which were confirmed by quantitative real-time PCR. Proteases demonstrated site-specific staining patterns in intestinal fibrotic tissue from mice and in tissue from human inflammatory bowel disease patients. Finally, we show in vitro that Salmonella infection directly induces protease expression in macrophages and epithelial cells but not in fibroblasts.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>In summary, we show that chronic Salmonella infection regulates proteases and protease inhibitors during tissue fibrosis in vivo and in vitro, and therefore this model is well suited to investigating the role of proteases in intestinal fibrosis.<\/jats:p><\/jats:sec>","DOI":"10.1093\/ibd\/izz070","type":"journal-article","created":{"date-parts":[[2019,5,8]],"date-time":"2019-05-08T10:31:14Z","timestamp":1557311474000},"page":"1629-1643","source":"Crossref","is-referenced-by-count":25,"title":["Persistent Salmonella enterica Serovar Typhimurium Infection Induces Protease Expression During Intestinal Fibrosis"],"prefix":"10.1093","volume":"25","author":[{"given":"Katrin","family":"Ehrhardt","sequence":"first","affiliation":[{"name":"Institute of Medical Microbiology and Hospital Epidemiology and German Center for Infection Research (DZIF), Partner Site Hannover, Hannover Medical School, Hannover, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalie","family":"Steck","sequence":"additional","affiliation":[{"name":"Institute for Experimental Medicine, Christian-Albrechts University of Kiel, Kiel, Germany, and Research Center Borstel, Borstel, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Reinhild","family":"Kappelhoff","sequence":"additional","affiliation":[{"name":"Department of Oral Biological and Medical Sciences, Centre for Blood Research, Faculty of Dentistry, University of British Columbia, Vancouver, BC, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephanie","family":"Stein","sequence":"additional","affiliation":[{"name":"Institute for Experimental Medicine, Christian-Albrechts University of Kiel, Kiel, Germany, and Research Center Borstel, Borstel, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Florian","family":"Rieder","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Hepatology and Nutrition, Digestive Diseases and Surgery Institute"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ilyssa O","family":"Gordon","sequence":"additional","affiliation":[{"name":"Department of Pathology, Pathology and Laboratory Medicine Institute, Cleveland Clinic Foundation, Cleveland, Ohio, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erin C","family":"Boyle","sequence":"additional","affiliation":[{"name":"Department of Cardiothoracic, Transplantation, and Vascular Surgery, Hannover Medical School, Hannover, Germany"},{"name":"Institute for Laboratory Animal Science, Hannover Medical School, Hannover, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Braubach","sequence":"additional","affiliation":[{"name":"Institute for Pathology, Hannover Medical School, Hannover, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher M","family":"Overall","sequence":"additional","affiliation":[{"name":"Department of Oral Biological and Medical Sciences, Centre for Blood Research, Faculty of Dentistry, University of British Columbia, Vancouver, BC, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"B Brett","family":"Finlay","sequence":"additional","affiliation":[{"name":"Michael Smith Laboratories, University of British Columbia, Vancouver, BC, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3718-2090","authenticated-orcid":false,"given":"Guntram A","family":"Grassl","sequence":"additional","affiliation":[{"name":"Institute of Medical Microbiology and Hospital Epidemiology and German Center for Infection Research (DZIF), Partner Site Hannover, Hannover Medical School, Hannover, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2019,5,9]]},"reference":[{"key":"2019091808542886000_CIT0001","doi-asserted-by":"crossref","first-page":"242","DOI":"10.2174\/138945010790309984","article-title":"Intestinal fibrosis in Crohn\u2019s disease: medical treatment or surgery?","volume":"11","author":"Spinelli","year":"2010","journal-title":"Curr Drug Targets."},{"key":"2019091808542886000_CIT0002","doi-asserted-by":"crossref","first-page":"228","DOI":"10.1038\/nrgastro.2009.31","article-title":"Intestinal fibrosis in IBD\u2014a dynamic, multifactorial process","volume":"6","author":"Rieder","year":"2009","journal-title":"Nat Rev Gastroenterol 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