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

Gastroesophageal Reflux Disease Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02579460
• Other study ID #: 15-022
• Secondary ID: 1R01DK103598-01A
• Status: Completed
• Phase: N/A
• Start date: November 2015
• Est. completion date: November 2017

Study information

• Verified date: September 2023
• Source: Dallas VA Medical Center
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 15
• Est. completion date: November 2017
• Est. primary completion date: November 2017
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 80 Years

Eligibility

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

Related Conditions & MeSH terms

• Barrett Esophagus
• Barrett's Esophagus
• Gastroesophageal Reflux
• Gastroesophageal Reflux Disease

Intervention

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.

Locations

Country	Name	City	State
United States	Dallas VA Medical Center	Dallas	Texas

Sponsors (2)

Lead Sponsor	Collaborator
Dallas VA Medical Center	National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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