Esophagitis as the outcome of progressive failures of the defensive repertoire

Abstract

Pre-epithelial defences include the coordinated actions of the lower esophageal sphincter and the esophageal muscles, which minimize reflux of gastric contents and promote clearance of refluxed material. The esophageal epithelium also possesses innate resistance to luminal damaging agents and may be protected luminally by a mucus or 'mucus bicarbonate' barrier and possibly a layer of hydrophobic surfactants. These components are derived from submucosal glands located in the submucosal connective tissue and from salivary secretions that may bind to the esophageal surface. Epithelial defences include the glycocalyx, permeability properties of the epithelial cell plasma membrane, junctional barriers to proton permeation through the paracellular pathway and ion transport processes for regulation of intracellular pH. Subepithelial defences involve mainly regulation of blood supply via responses of nerves, mast cells and blood vessels to influxing protons. Although the epithelium can withstand prolonged exposure to physiologically relevant concentrations of acid, the presence of pepsin or bile salts may overcome the permeability barrier, which probably resides in the superficial layers of epithelial cells. Focal destruction of these cells allows access of luminal acid and other aggressive agents to the vulnerable basolateral cell membranes and to the submucosa. The result is lesion production, although an efflux of alkaline plasma may protect the underlying submucosa and allow healing. Salivary-derived epidermal growth factor (EGF) is present in the luminal fluid, and lesion development may also provide access of EGF to receptors within the epithelium and in the underlying vasculature. Accelerated cell proliferation would then contribute to healing. Inflammation and healing should also be viewed as defensive responses, as can the development of Barrett's esophagus, in which the stratified squamous epithelium is replaced by a potentially acid-resistant columnar epithelium. Chronic inflammation and esophagitis only result when this multilayered set of defences is overcome. The challenge for research is to identify those components of the defensive repertoire that are defective in individuals who suffer from chronic esophagitis.