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Gastroesophageal reflux activates the NF-?B 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-?B pathway due to reflux. Significance analysis of microarrays revealed upregulation of NF-?B target genes. Overexpression of NF-?B subunits (p50 and p65) and NF-?B target genes (matrix metalloproteinases-3 and -9, IL-1?, IL-6, and IL-8) confirmed activation of the NF-?B 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-?B 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-?B-regulated cytokines. We conclude that gastroesophageal reflux activates the NF-?B pathway and impairs esophageal barrier function in mice and that targeting the NF-?B pathway may strengthen esophageal barrier function against reflux.

SUBMITTER: Fang Y

PROVIDER: S-EPMC3725692 | biostudies-literature | 2013 Jul

REPOSITORIES: biostudies-literature

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Gastroesophageal reflux activates the NF-κB pathway and impairs esophageal barrier function in mice.

Fang Yu Y Chen Hao H Hu Yuhui Y Djukic Zorka Z Tevebaugh Whitney W Shaheen Nicholas J NJ Orlando Roy C RC Hu Jianguo J Chen Xiaoxin X

American journal of physiology. Gastrointestinal and liver physiology 20130502 1

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 mix ...[more]

PMID: 23639809

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Project description:The histologic changes associated with acute gastroesophageal reflux disease (GERD) have not been studied prospectively in humans. Recent studies in animals have challenged the traditional notion that reflux esophagitis develops when esophageal surface epithelial cells are exposed to lethal chemical injury from refluxed acid.To evaluate histologic features of esophageal inflammation in acute GERD to study its pathogenesis.Patients from the Dallas Veterans Affairs Medical Center who had reflux esophagitis successfully treated with proton pump inhibitors (PPIs) began 24-hour esophageal pH and impedance monitoring and esophagoscopy (including confocal laser endomicroscopy [CLE]) with biopsies from noneroded areas of distal esophagus at baseline (taking PPIs) and at 1 week and 2 weeks after stopping the PPI medication. Enrollment began May 2013 and follow-up ended July 2015.PPIs stopped for 2 weeks.Twelve patients (men, 11; mean age, 57.6 year [SD, 13.1]) completed the study. Primary outcome was change in esophageal inflammation 2 weeks after stopping the PPI medication, determined by comparing lymphocyte, eosinophil, and neutrophil infiltrates (each scored on a 0-3 scale) in esophageal biopsies. Also evaluated were changes in epithelial basal cell and papillary hyperplasia, surface erosions, intercellular space width, endoscopic grade of esophagitis, esophageal acid exposure, and mucosal impedance (an index of mucosal integrity).At 1 week and 2 weeks after discontinuation of PPIs, biopsies showed significant increases in intraepithelial lymphocytes, which were predominantly T cells (median [range]: 0 (0-2) at baseline vs 1 (1-2) at both 1 week [P?=?.005] and 2 weeks [P?=?.002]); neutrophils and eosinophils were few or absent. Biopsies also showed widening of intercellular spaces (confirmed by CLE), and basal cell and papillary hyperplasia developed without surface erosions. Two weeks after stopping the PPI medication, esophageal acid exposure increased (median: 1.2% at baseline to 17.8% at 2 weeks; ?, 16.2% [95% CI, 4.4%-26.5%], P?=?.005), mucosal impedance decreased (mean: 2671.3 ? at baseline to 1508.4 ? at 2 weeks; ?, 1162.9 ? [95% CI, 629.9-1695.9], P?=?.001), and all patients had evidence of esophagitis.In this preliminary study of 12 patients with severe reflux esophagitis successfully treated with PPI therapy, stopping PPI medication was associated with T lymphocyte-predominant esophageal inflammation and basal cell and papillary hyperplasia without loss of surface cells. If replicated, these findings suggest that the pathogenesis of reflux esophagitis may be cytokine-mediated rather than the result of chemical injury.clinicaltrials.gov Identifier: NCT01733810.

Project description:HypothesisScreening for esophageal adenocarcinoma has focused on identifying Barrett esophagus (BE) in patients with severe, long-standing symptoms of gastroesophageal reflux disease (GERD). Unfortunately, 95% of patients who develop esophageal adenocarcinoma are unaware of the presence of BE before their cancer diagnosis, which means they never had been selected for screening. One possible explanation is that no correlation exists between the severity of GERD symptoms and cancer risk. We hypothesize that severe GERD symptoms are not associated with an increase in the prevalence of BE, dysplasia, or cancer in patients undergoing primary endoscopic screening.DesignCross-sectional study.SettingUniversity hospital.PatientsA total of 769 patients with GERD.InterventionsPrimary screening endoscopy performed from November 1, 2004, through June 7, 2007.Main outcomes measuresSymptom severity, proton pump inhibitor therapy, and esophageal adenocarcinogenesis (ie, BE, dysplasia, or cancer).ResultsEndoscopy revealed adenocarcinogenesis in 122 patients. An increasing number of severe GERD symptoms correlated positively with endoscopic findings of esophagitis (odds ratio, 1.05; 95% confidence interval, 1.01-1.09). Conversely, an increasing number of severe GERD symptoms were associated with decreased odds of adenocarcinogenesis (odds ratio, 0.94; 95% confidence interval, 0.89-0.98). Patients taking proton pump inhibitors were 61.3% and 81.5% more likely to have adenocarcinogenesis if they reported no severe typical or atypical GERD symptoms, respectively, compared with patients taking proton pump inhibitors, who reported that all symptoms were severe.ConclusionsMedically treated patients with mild or absent GERD symptoms have significantly higher odds of adenocarcinogenesis compared with medically treated patients with severe GERD symptoms. This finding may explain the failure of the current screening paradigm in which the threshold for primary endoscopic examination is based on symptom severity.

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Gastroesophageal reflux activates the NF-?B pathway and impairs esophageal barrier function in mice.

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Gastroesophageal reflux activates the NF-κB pathway and impairs esophageal barrier function in mice.

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