A model for the development and recovery from acid-induced esophagitis in the opossum: Changes in motor function and in the mucosal defensive repertoire

The pathogenesis of gastroesophageal reflux disease (GERD) is poorly understood. Two prevailing hypotheses propose that GERD is either an epithelial disease or is a result of altered motility. The development of esophagitis is, in fact, likely a consequence of failures of both motor function, allowing access of refluxate to the esophageal lumen, and of mucosal defenses that may be inadequate to resist the resulting acid exposure. This thesis describes an integrated series of studies that used a "subacute" model of esophagitis in anesthetized opossums to examine alterations in esophageal motor function and in epithelial and mucosal components of the defensive repertoire.; Changes in esophageal length and swallow-induced motor responses were recorded before and after three consecutive days of 45-minute luminal perfusion with saline or with physiologically relevant concentrations of acid. Electrical and mechanical longitudinal muscle (LM) responses were also assessed. Repeated acid challenge produced erosive esophagitis that was partially resolved over a subsequent one-week period. Acid-induced esophageal shortening was associated with enhanced LM responses to carbachol, depolarization of resting cell membrane potentials, and abnormal spike patterns. Lower esophageal sphincter resting pressure and swallow-induced peristalsis were unaffected, but acid did impair the deglutition reflex. The role of vagal afferent pathways in this deficit was established by its attenuation by bilateral cervical vagotomy.; Regional heterogeneity was described in epithelial thickness and in quantity and content of esophageal glands. Exposure to acid produced site-specific increases in the extent of gland secretion and changes in gland mucin composition. There were also decreases in mast cells, and changes in structure and integrity of the luminal epithelium. Damage was associated with increased glutathione peroxidase (GPx) and heat shock protein (HSP) 90, and with decreased reduced glutathione (GSH) and HSP72. Resolution of injury eight days after acid exposure was associated with distally decreased GPx and GSH.; These studies provide new insights into the pathogenesis of GERD and highlight the existence of certain site-specific structural and functional defenses against gastric refluxate. Esophageal shortening associated with LM hyperresponsiveness is identified as the earliest motor disorder induced by acid injury, while changes in antioxidant levels further support the involvement of free radicals in acid-induced esophagitis.