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.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
BASIC_SCIENCE
Masking
NONE
Enrollment
15
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.
Dallas VA Medical Center
Dallas, Texas, United States
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.
Time frame: 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
Time frame: day 0, day 7, and day 14
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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: day 0, day 7, and day 14
change in NPM1 from baseline to 14 days
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NPM-1 will be measured in the esophageal mucosa at baseline, day 7, and at day 14
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: day 0, day 7, and day 14