Antireflux surgery normalizes cyclooxygenase-2 expression in squamous epithelium of the distal esophagus

In some patients GERD presents with heartburn and regurgitation symptoms but a relative paucity of endoscopic and clinical findings, while in others symptoms may be minor or absent yet there is significant mucosal damage on endoscopy including the presence of Barrett's esophagus. The initial injury of gastroesophageal reflux is to the squamous esophageal mucosa, but while substantial research has been devoted to determining which genes are involved in the progression of Barrett's to dysplasia and cancer, little is known about the gene expression alterations in the squamous mucosa of patients with reflux. We hypothesized that the expression of cyclooxygenase-2 (Cox-2) might be increased in the squamous esophageal mucosal of patients with reflux, and might be a molecular indicator of reflux injury. Further, we hypothesized that Cox-2 expression in the squamous mucosa would be reduced following the elimination of reflux with an antireflux operation.

Biopsies of the distal esophageal squamous mucosa were taken 3 cm above the squamocolumnar junction (SCJ) in 28 GERD patients before and after Nissen fundoplication. Following microdissection and RNA isolation, quantitative real-time PCR was used to measure Cox-2 gene expression in paraffin-embedded (N = 16) and fresh frozen (N = 12) tissue. Biopsies from patients (paraffin N = 15, frozen N = 14) with normal acid exposure and no evidence of mucosal injury were analyzed as controls.

Median Cox-2 expression in the squamous epithelium from paraffin embedded biopsies in patients with reflux disease was significantly increased compared to controls (p = 0.04). The presence of esophagitis or Barrett's esophagus did not significantly alter the expression of Cox-2 compared to patients with nonerosive reflux disease (NERD). After antireflux surgery median Cox-2 expression values were significantly reduced (p = 0.0003) and were normalized to levels similar to controls without reflux (p = 0.74). Similar results were observed in the prospectively obtained fresh frozen tissue.

Cox-2 gene expression is increased in the distal esophageal squamous mucosa of most patients with GERD, and the elevation was similar whether there was mucosal injury in the form of esophagitis or Barrett's or no visible mucosal injury. This suggests that increased Cox-2 expression may serve as a molecular marker of reflux disease. The increased Cox-2 expression in patients with reflux was usually normalized following antireflux surgery. These findings demonstrate for the first time that gene expression can be altered by surgical correction of reflux. Thus, in addition to symptom control and improvement in the quality of life, perhaps future studies assessing the efficacy of antireflux therapy should also focus on the impact of the therapy on gene expression in the esophageal squamous mucosa.