| The traditional concept that GERD develops as a caustic chemical injury was proposed by Asher Winkelstein in 1935. According to this concept, refluxed acid and pepsin destroy esophageal epithelial cells directly, producing an acid “burn” that starts at the epithelial surface and later progresses into deeper layers of the esophageal wall. This caustic injury was assumed to trigger the infiltration of granulocytes (neutrophils and eosinophils), and the death of surface cells was thought to induce basal cell hyperplasia, a manifestation of basal cells proliferating to replace surface cells that had been destroyed by acid. This traditional notion of GERD pathogenesis went largely unchallenged until 2009, when my research group published a histological study on the development of reflux esophagitis in rats that had reflux induced by esophago-duodenostomy. We found that reflux esophagitis in those animals began with an infiltration of T-lymphocytes (not granulocytes) in the esophageal submucosa, with basal cell hyperplasia developing before any surface cell damage, which was not apparent until several weeks after the reflux-inducing operation. In accompanying experiments, we found that human esophageal squamous cells exposed to acid and bile in concentrations and durations typical of reflux episodes did not die, but did dramatically increase their secretion of pro-inflammatory cytokines. We confirmed these findings in a study of 12 patients who had severe reflux esophagitis healed by proton pump inhibitors (PPIs). We induced acute reflux esophagitis in those patients by interrupting their PPI therapy for 2 weeks, during which reflux esophagitis developed just as it did in our rat model, starting with infiltration of the esophageal mucosa by T-lymphocytes, and with basal cell hyperplasia preceding surface cell damage. Based on these findings, we proposed that reflux esophagitis develops as a cytokine-mediated injury in which the reflux of acid and bile does not destroy epithelial cells directly, but rather induces them to secrete pro-inflammatory cytokines that attract lymphocytes first, while also inducing the basal cell proliferation characteristic of GERD. Ultimately, it is inflammatory cells that mediate the epithelial injury of reflux esophagitis, not the direct caustic effects of refluxed gastric acid. Presently, GERD treatment focuses on elimination of acid reflux by medical or surgical means, but our studies have identified other potential therapeutic targets (e.g. inflammatory cytokines), and we anticipate that future GERD therapies might focus on those targets. |
