Reflux-Induced Oxidative Stress in Barrett's Esophagus: Response, Repair, and Epithelial-Mesenchymal-Transition

Reflux-Induced Oxidative Stress in Barrett's Esophagus: Response, Repair, and Epithelial-Mesenchymal-Transition

Reflux-Induced Oxidative Stress in Barrett's Esophagus: Response, Repair, and Epithelial-Mesenchymal-Transition

The purpose of this study is to elucidate mechanisms whereby oxidative stress induced by acute reflux esophagitis: 1) activates p38 to regulate proteins that control the G1/S cell cycle checkpoint, and 2) activates HIFs (hypoxia inducible factors) to cause autocrine VEGF (vascular endothelial growth factor) signaling that triggers the EMT (epithelial-mesenchymal-transition) program in Barrett's esophagus.

Gastroesophageal reflux disease (GERD) and its complication, Barrett's esophagus (BE), are risk factors for esophageal adenocarcinoma. In BE, GERD causes inflammation with oxidative DNA damage and genomic instability that contributes to carcinogenesis. In BE, one response to oxidative stress is p38 pathway activation, which might protect against cancer development by initiating G1 arrest and enabling repair of DNA damage. Inflammation and oxidative stress also might induce epithelial-mesenchymal transition (EMT), the process in which epithelial cells acquire mesenchymal characteristics including the ability to migrate. This study will elucidate mechanisms whereby the oxidative stress of acute reflux esophagitis in BE activates p38 to regulate proteins controlling the G1/S cell cycle checkpoint, and activates HIFs to cause autocrine vascular endothelial growth factor (VEGF) signaling that triggers the EMT program.

Patients with Barrett's Esophagus will be enrolled. The intervention is cessation of acid-suppressing medications. Biopsies will be taken during endoscopy at Day 0, 7, and 14.

Acid suppressing medications are stopped for all participants the day after baseline assessment. Subsequent evaluations are performed while the participant is not on acid-suppressing medications. Endoscopy with biopsies will be performed in all patients on day 0, 7, and 14.

Change in esophageal mucosal inflammation using histopathological assessment from baseline to 14 days

Inflammation of the esophageal mucosa will be measured at baseline, 7 days, and at 14 days. Esophageal mucosal inflammation will be measured using esophageal mucosal biopsy specimens, and histopatholgical grading. Mucosal infiltration with inflammatory cells (neutrophils, eosinophils, and lymphocytes) will be measured.

p38 and components of the p38 pathway will be measured in the esophageal mucosa at baseline, 7 days, and at 14 days

miRNAs will be measured in the esophageal mucosa and in exosomes isolated from the blood at baseline, day 7, and day 14

Inclusion Criteria: U.S. Veteran Barrett's Esophagus Exclusion Criteria: Inability to provide informed consent Pregnancy or breastfeeding Esophageal varices Warfarin use Coagulopathy that precludes safe biopsy of the esophagus Comorbidity that precludes safe participation in the study