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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2019,8,20]]},"abstract":"<jats:p>Intestinal epithelial cell (IEC) shedding is a fundamental response to intestinal damage, yet underlying mechanisms and functions have been difficult to define. Here we model chronic intestinal damage in zebrafish larvae using the nonsteroidal antiinflammatory drug (NSAID) Glafenine. Glafenine induced the unfolded protein response (UPR) and inflammatory pathways in IECs, leading to delamination. Glafenine-induced inflammation was augmented by microbial colonization and associated with changes in intestinal and environmental microbiotas. IEC shedding was a UPR-dependent protective response to Glafenine that restricts inflammation and promotes animal survival. Other NSAIDs did not induce IEC delamination; however, Glafenine also displays off-target inhibition of multidrug resistance (MDR) efflux pumps. We found a subset of MDR inhibitors also induced IEC delamination, implicating MDR efflux pumps as cellular targets underlying Glafenine-induced enteropathy. These results implicate IEC delamination as a protective UPR-mediated response to chemical injury, and uncover an essential role for MDR efflux pumps in intestinal homeostasis.<\/jats:p>","DOI":"10.1073\/pnas.1902596116","type":"journal-article","created":{"date-parts":[[2019,8,7]],"date-time":"2019-08-07T19:15:36Z","timestamp":1565205336000},"page":"16961-16970","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":8,"title":["Epithelial delamination is protective during pharmaceutical-induced enteropathy"],"prefix":"10.1073","volume":"116","author":[{"given":"Scott T.","family":"Espenschied","sequence":"first","affiliation":[{"name":"Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, NC 27710;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark R.","family":"Cronan","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, NC 27710;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Molly A.","family":"Matty","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, NC 27710;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olaf","family":"Mueller","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, NC 27710;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew R.","family":"Redinbo","sequence":"additional","affiliation":[{"name":"Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599;"},{"name":"Department of Biochemistry, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599;"},{"name":"Department of Microbiology and Immunology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3465-5518","authenticated-orcid":false,"given":"David M.","family":"Tobin","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, NC 27710;"},{"name":"Department of Medicine, Duke University School of Medicine, Durham, NC 27710;"},{"name":"Department of Immunology, Duke University School of Medicine, Durham, NC 27710"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5976-5206","authenticated-orcid":false,"given":"John F.","family":"Rawls","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, NC 27710;"},{"name":"Department of Medicine, Duke University School of Medicine, Durham, NC 27710;"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2019,8,7]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.1111\/febs.13575"},{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1124\/dmd.118.083402"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrmicro.2016.17"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.3109\/03602532.2011.560607"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1186\/1479-7364-3-3-281"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1742-4658.2009.07485.x"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.2174\/1567201043480036"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1093\/carcin\/18.11.2171"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1159\/000338121"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2011.02.012"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1136\/flgastro-2013-100316"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.mayocp.2014.07.015"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.1093\/toxsci\/kfs310"},{"key":"e_1_3_4_14_2","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2017.10.049"},{"key":"e_1_3_4_15_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.aag2770"},{"key":"e_1_3_4_16_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2014.07.002"},{"key":"e_1_3_4_17_2","doi-asserted-by":"publisher","DOI":"10.3109\/00498254.2013.811314"},{"key":"e_1_3_4_18_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1191175"},{"key":"e_1_3_4_19_2","first-page":"146","article-title":"Glafenine-induced intestinal injury in zebrafish is ameliorated by \u03bc-opioid signaling via enhancement of Atf6-dependent cellular stress responses","volume":"6","author":"Goldsmith J. 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