{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T22:09:13Z","timestamp":1791929353457,"version":"4.3.4"},"reference-count":47,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2024,4,4]],"date-time":"2024-04-04T00:00:00Z","timestamp":1712188800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["19K08474"],"award-info":[{"award-number":["19K08474"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J of Gastro and Hepatol"],"published-print":{"date-parts":[[2024,6]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background and Aim<\/jats:title>\n                    <jats:p>Nonsteroidal anti\u2010inflammatory drugs (NSAIDs) damage the small intestine via neutrophil infiltration driven by the mucosal invasion of enterobacteria. The antimicrobial function of neutrophils is partially dependent on neutrophil extracellular traps (NETs). Excessive NET formation has been associated with several inflammatory diseases. Here, we aimed to investigate the role of NETs in NSAID\u2010induced small intestinal damage using human samples and an experimental mouse model.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Human small intestine specimens were obtained from NSAID users during double\u2010balloon enteroscopy. Wild\u2010type, protein arginine deiminase 4 (PAD4) knockout, and antibiotic\u2010treated mice were administered indomethacin to induce small intestinal injury. The expression of NET\u2010associated proteins, including PAD4, citrullinated histone H3 (CitH3), cell\u2010free DNA, and myeloperoxidase (MPO), was evaluated.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>The double\u2010positive stained area with CitH3 and MPO, which is specific for neutrophil\u2010derived extracellular traps, was significantly high in the injured small intestinal mucosa of NSAID users. In a mouse model, small intestinal damage developed at 6\u00a0h after indomethacin administration, accompanied by increased mRNA levels of interleukin\u20101\u03b2 and keratinocyte chemoattractant and elevated NET\u2010associated protein levels of PAD4, CitH3, and MPO in small intestine and serum levels of cell\u2010free DNA. Both genetic deletion and pharmacological inhibition of PAD4 attenuated this damage by reducing the mRNA expression of inflammatory cytokines and NET\u2010associated proteins. Furthermore, mice pretreated with antibiotics showed resistance to indomethacin\u2010induced small intestinal damage, with less NET formation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>These results suggest that NETs aggravate NSAID\u2010induced small intestinal injury. Therefore, NET inhibition could be a potential treatment for NSAID\u2010induced small intestinal injury.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/jgh.16543","type":"journal-article","created":{"date-parts":[[2024,4,5]],"date-time":"2024-04-05T02:50:19Z","timestamp":1712285419000},"page":"1123-1133","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Neutrophil extracellular trap formation and its implications in nonsteroidal anti\u2010inflammatory drug\u2010induced small intestinal injury"],"prefix":"10.1111","volume":"39","author":[{"given":"Eiji","family":"Moriyama","sequence":"first","affiliation":[{"name":"Department of Gastroenterology, Graduate School of Medicine Osaka city University  Osaka Japan"},{"name":"Department of Gastroenterology, Graduate School of Medicine Osaka Metropolitan University  Osaka 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