Abstract

HCO₃^- secretion, which is believed to neutralize acid within the mucus gel, is the most studied duodenal defense mechanism. In general, HCO₃^- secretion rate and mucosal injury susceptibility correlate closely. Recent studies suggest that luminal acid can lower intracellular pH (pHi) of duodenal epithelial cells and that HCO₃^- secretion is unchanged during acid stress. Furthermore, peptic ulcers are rare in cystic fibrosis (CF), although, with impaired HCO₃^- secretion, increased ulcer prevalence is predicted, giving rise to the ‘CF Paradox’. We thus tested the hypothesis that duodenal epithelial cell protection occurs as the result of pHi regulation rather than by neutralization of acid by HCO₃^- in the pre-epithelial mucus. Cellular acidification during luminal acid perfusion, and unchanged HCO₃^- secretion during acid stress are inconsistent with preepithelial acid neutralization by secreted HCO₃- . Furthermore, inhibition of HCO₃^- secretion by 5-nitro-2-(3-phenylpropylamino) benzoic acid (NPPB) despite preservation of pHi and protection from acid-induced injury further question the pre-epithelial acid neutralization hypothesis. This decoupling of HCO₃^- secretion and injury susceptibility by NPPB (and possibly by CF) further suggest that cellular buffering, rather than HCO₃^- exit into the mucus, is of primary importance for duodenal mucosal protection, and may account for the lack of peptic ulceration in CF patients.