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.

Study Overview

• Status: Completed
• Conditions: Gastroesophageal Reflux Disease; Barrett's Esophagus
• Intervention / Treatment: Other: Cessation of Acid Suppressing Medications

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 15
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Texas
    • Dallas, Texas, United States, 75216
      • Dallas VA Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Barrett's esophagus patients; 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.	Other: Cessation of Acid Suppressing Medications; 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	day 0, day 7, and day 14

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
change in phosoho-p38 from baseline to 14 days	phospho-p38 will be measured in the esophageal mucosa at baseline, day 7, and at day 14	day 0, day 7, and day 14
Show oxidative DNA damage associated with p38 activation	OxiSelect Oxidative DNA Damage ELISA assay of Barrett's mucosa at baseline, day 7, and day 14	day 0, day 7, and day 14
change in APE-1 from baseline to 14 days	APE-1 will be measured in the esophageal mucosa at baseline, day 7, and at day 14	day 0, day 7, and day 14
change in NPM1 from baseline to 14 days	NPM-1 will be measured in the esophageal mucosa at baseline, day 7, and at day 14	day 0, day 7, and day 14
change in phospho-NPM1 from baseline to 14 days	phospho-NPM1 will be measured in the esophageal mucosa at baseline, day 7, and at day 14	day 0, day 7, and day 14
change in p38 pathway from baseline to 14 days	p38 and components of the p38 pathway will be measured in the esophageal mucosa at baseline, 7 days, and at 14 days	day 0, day 7, and day 14
change in VEGF from baseline to 14 days	VEGF will be measured in the esophageal mucosa at baseline, 7 days, and at day 14	day 0, day 7, and day 14
change in miRNA expression from baseline to 14 days	miRNAs will be measured in the esophageal mucosa and in exosomes isolated from the blood at baseline, day 7, and day 14	day 0, day 7, and day 14
change in HIF expression from baseline to 14 days	HIF expression will be measured in the esophageal mucosa at baseline, day 7, and day 14	day 0, day 7, and day 14

Collaborators and Investigators

• Sponsor: Dallas VA Medical Center
• Collaborators: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
• Investigators: Principal Investigator: Stuart J Spechler, MD, Dallas VA Medical Center

Study record dates

Study Major Dates

• Study Start (Actual): November 1, 2015
• Primary Completion (Actual): November 1, 2017
• Study Completion (Actual): November 1, 2017

Study Registration Dates

• First Submitted: October 14, 2015
• First Submitted That Met QC Criteria: October 15, 2015
• First Posted (Estimated): October 19, 2015

Study Record Updates

• Last Update Posted (Actual): September 11, 2023
• Last Update Submitted That Met QC Criteria: September 7, 2023
• Last Verified: September 1, 2023

More Information

Terms related to this study

• Keywords: Gastroesophageal Reflux Disease; Barrett's esophagus
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Gastrointestinal Diseases; Esophageal Motility Disorders; Deglutition Disorders; Esophageal Diseases; Precancerous Conditions; Gastroesophageal Reflux; Barrett Esophagus
• Other Study ID Numbers: 15-022; 1R01DK103598-01A1 (U.S. NIH Grant/Contract)