Reflux-Induced Oxidative Stress in Barrett's Esophagus: Response, Repair, and Epithelial-Mesenchymal-Transition
Study Details
Study Description
Brief 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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
N/A |
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 Design
Arms and Interventions
| 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.
|
Outcome Measures
Primary Outcome Measures
- Change in esophageal mucosal inflammation using histopathological assessment from baseline to 14 days [day 0, day 7, and day 14]
Inflammation of the esophageal mucosa will be measured at baseline 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.
Secondary Outcome Measures
- change in p38 pathway from baseline to 14 days [day 0, day 7, and day 14]
p38 and components of the p38 pathway will be measured in the esophageal mucosa at baseline and at 14 days
- change in phosoho-p38 from baseline to 14 days [day 0, day 7, and day 14]
phospho-p38 will be measured in the esophageal mucosa at baseline, day 7, and at day 14
- Show oxidative DNA damage associated with p38 activation [day 0, day 7, and day 14]
OxiSelect Oxidative DNA Damage ELISA assay of Barrett's mucosa at baseline, day 7, and day 14
- change in VEGF from baseline to 14 days [day 0, day 7, and day 14]
VEGF will be measured in the esophageal mucosa at baseline and at day 14
- change in APE-1 from baseline to 14 days [day 0, day 7, and day 14]
APE-1 will be measured in the esophageal mucosa at baseline, day 7, and at day 14
- change in NPM1 from baseline to 14 days [day 0, day 7, and day 14]
NPM-1 will be measured in the esophageal mucosa at baseline, day 7, and at day 14
- change in phospho-NPM1 from baseline to 14 days [day 0, day 7, and day 14]
phospho-NPM1 will be measured in the esophageal mucosa at baseline, day 7, and at day 14
Eligibility Criteria
Criteria
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
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Dallas VA Medical Center | Dallas | Texas | United States | 75216 |
Sponsors and Collaborators
- Dallas VA Medical Center
- National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Investigators
- Principal Investigator: Stuart J Spechler, MD, Dallas VA Medical Center
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- 15-022
- 1R01DK103598-01A1