title: Gastroesophageal reflux activates the NF-κB pathway and impairs esophageal barrier function in mice.
abstract: The barrier function of the esophageal epithelium is a major defense against gastroesophageal reflux disease. Previous studies have shown that reflux damage is reflected in a decrease in transepithelial electrical resistance associated with tight junction alterations in the esophageal epithelium. To develop novel therapies, it is critical to understand the molecular mechanisms whereby contact with a refluxate impairs esophageal barrier function. In this study, surgical models of duodenal and mixed reflux were developed in mice. Mouse esophageal epithelium was analyzed by gene microarray. Gene set enrichment analysis showed upregulation of inflammation-related gene sets and the NF-κB pathway due to reflux. Significance analysis of microarrays revealed upregulation of NF-κB target genes. Overexpression of NF-κB subunits (p50 and p65) and NF-κB target genes (matrix metalloproteinases-3 and -9, IL-1β, IL-6, and IL-8) confirmed activation of the NF-κB pathway in the esophageal epithelium. In addition, real-time PCR, Western blotting, and immunohistochemical staining also showed downregulation and mislocalization of claudins-1 and -4. In a second animal experiment, treatment with an NF-κB inhibitor, BAY 11-7085 (20 mg·kg⁻¹·day⁻¹ ip for 10 days), counteracted the effects of duodenal and mixed reflux on epithelial resistance and NF-κB-regulated cytokines. We conclude that gastroesophageal reflux activates the NF-κB pathway and impairs esophageal barrier function in mice and that targeting the NF-κB pathway may strengthen esophageal barrier function against reflux.
authors: Department of Cardiovascular and Thoracic Surgery, Second Xiangya Hospital, Central South University, Changsha, Hunan Province, China.
authors: Yu
authors: Y
authors: Fang
authors: Hao
authors: H
authors: Chen
authors: Yuhui
authors: Y
authors: Hu
authors: Zorka
authors: Z
authors: Djukic
authors: Whitney
authors: W
authors: Tevebaugh
authors: Nicholas J
authors: NJ
authors: Shaheen
authors: Roy C
authors: RC
authors: Orlando
authors: Jianguo
authors: J
authors: Hu
authors: Xiaoxin
authors: X
authors: Chen
mesh_terms: D000818:Animals; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004848:Epithelium / Q000502:physiology; D004947:Esophagus / Q000502:physiology*; D005764:Gastroesophageal Reflux / Q000378:metabolism*; D005786:Gene Expression Regulation; D019278:Matrix Metalloproteinase 3 / Q000235:genetics / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D009570:Nitriles / Q000494:pharmacology; D020411:Oligonucleotide Array Sequence Analysis; D013450:Sulfones / Q000494:pharmacology
chemical_list: C416282:BAY 11-7085; D016207:Cytokines; D016328:NF-kappa B; D009570:Nitriles; D013450:Sulfones; D019278:Matrix Metalloproteinase 3; D020780:Matrix Metalloproteinase 9
keywords: NF-κB; barrier function; gastroesophageal reflux; mouse model; tight junction
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