{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:48:04Z","timestamp":1787028484591,"version":"build-2736575974"},"reference-count":78,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2022,9,8]],"date-time":"2022-09-08T00:00:00Z","timestamp":1662595200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"the National Institutes of Health\/National Institute of Diabetes and Digestive and Kidney Diseases","award":["AS R01DK118065"],"award-info":[{"award-number":["AS R01DK118065"]}]},{"name":"the National Institutes of Health\/National Institute of Diabetes and Digestive and Kidney Diseases","award":["NIH P30 DK048522"],"award-info":[{"award-number":["NIH P30 DK048522"]}]},{"name":"the USC Research Center for Liver Diseases","award":["AS R01DK118065"],"award-info":[{"award-number":["AS R01DK118065"]}]},{"name":"the USC Research Center for Liver Diseases","award":["NIH P30 DK048522"],"award-info":[{"award-number":["NIH P30 DK048522"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Subepithelial human esophageal myofibroblasts (HEMFs) in gastroesophageal reflux disease (GERD) are exposed to luminal contents via impaired squamous epithelium barrier integrity. The supernatant of HEMFs treated with acidic bile salts reflective of in vivo reflux increases squamous epithelial thickness. We aimed to identify the involved mechanisms using an unbiased approach. Acidic-bile-salt-treated primary HEMF cultures (n = 4) were submitted for RNA-Seq and analyzed with Partek Flow followed by Ingenuity Pathway Analysis (IPA). A total of 1165 molecules (579 downregulated, 586 upregulated) were differentially expressed, with most top regulated molecules either extracellular or in the plasma membrane. Increases in HEMF CXCL-8, IL-6, AREG, and EREG mRNA, and protein secretion were confirmed. Top identified canonical pathways were agranulocyte and granulocyte adhesion and diapedesis, PI3K\/AKT signaling, CCR5 signaling in macrophages, and the STAT3 pathway. Top diseases and biological functions were cellular growth and development, hematopoiesis, immune cell trafficking, and cell-mediated response. The targets of the top upstream regulator ErbB2 included CXCL-8, IL-6, and AREG and the inhibition of CXCL-8 in the HEMF supernatant decreased squamous epithelial proliferation. Our work shows an inflammatory\/immune cell and proliferative pathways activation in HEMFs in the GERD environment and identifies CXCL-8 as a HEMF-derived chemokine with paracrine proliferative effects on squamous epithelium.<\/jats:p>","DOI":"10.3390\/ijms231810371","type":"journal-article","created":{"date-parts":[[2022,9,8]],"date-time":"2022-09-08T07:05:56Z","timestamp":1662620756000},"page":"10371","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Inflammatory and Proliferative Pathway Activation in Human Esophageal Myofibroblasts Treated with Acidic Bile Salts"],"prefix":"10.3390","volume":"23","author":[{"given":"Madhura","family":"Patankar","sequence":"first","affiliation":[{"name":"Department of Internal Medicine, Division of Gastrointestinal and Liver Diseases, Keck School of Medicine of USC, Los Angeles, CA 90033, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meng","family":"Li","sequence":"additional","affiliation":[{"name":"USC Libraries Bioinformatics Services, University of Southern California, Los Angeles, CA 90007, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Atousa","family":"Khalatbari","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Division of Gastrointestinal and Liver Diseases, Keck School of Medicine of USC, Los Angeles, CA 90033, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joshua D.","family":"Castle","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Division of Gastrointestinal and Liver Diseases, Keck School of Medicine of USC, Los Angeles, CA 90033, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liping","family":"Hu","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Division of Gastrointestinal and Liver Diseases, Keck School of Medicine of USC, Los Angeles, CA 90033, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunying","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Division of Gastrointestinal and Liver Diseases, Keck School of Medicine of USC, Los Angeles, CA 90033, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anisa","family":"Shaker","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Division of Gastrointestinal and Liver Diseases, Keck School of Medicine of USC, Los Angeles, CA 90033, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,9,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"871","DOI":"10.1136\/gutjnl-2012-304269","article-title":"Update on the epidemiology of gastro-oesophageal reflux disease: A systematic review","volume":"63","author":"Sweet","year":"2014","journal-title":"Gut"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"767","DOI":"10.1016\/j.cgh.2019.07.015","article-title":"Phenotypes of Gastroesophageal Reflux Disease: Where Rome, Lyon, and Montreal Meet","volume":"18","author":"Katzka","year":"2020","journal-title":"Clin. 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