The role of pepsin in acid injury to esophageal epithelium

OBJECTIVES: The development of reflux esophagitis in humans is a process re sulting from esophageal exposure to refluxed gastric contents. There is no doubt that damage to the esophageal epithelium requires exposure to gastric acid; however, the role of refluxed pepsin as contributor to this damage s eems to be underappreciated. METHODS: The role of physiological concentrations of pepsin was examined in Ussing chambered rabbit esophageal epithelium and in cultured esophageal e pithelial cells. RESULTS: The results of this investigation reaffirmed the ability of pepsin to increase the rate and degree of esophageal cell and tissue damage at ac idic pH, although the range of activity was limited to pH < 3.0. Moreover, the increased rate of tissue damage by acidified pepsin rapidly (within 15 min) produced a lesion that was irreversible, whereas, in a similar time fr ame, acid alone produced a lesion that was completely reversible. This earl y lesion by acidified pepsin was localized by performance of mannitol fluxe s in apparently undamaged esophageal epithelium on light microscopy to the intercellular junctional complex. Further acid produced similar degrees of cell killing as acidified pepsin at pH < 3.0 in rabbit esophageal epithelia l cells in suspension but not when growing on coverslips or present within intact epithelium. CONCLUSIONS: These studies suggest that acidified pepsin plays a key role i n the development of reflux esophagitis by producing an early irreversible lesion that results in an increase in paracellular permeability, which indi rect evidence suggests is due to damage to the junctional complex. The irre versibility of the increase in paracellular permeability is likely to aid c onversion of nonerosive to erosive damage to the epithelium by permitting l uminal acid greater access to the basolateral membrane of esophageal epithe lial cells, which is known to be acid permeable. (C) 2001 by Am. Coll. of G astroenterology.