Duodenal intracellular bicarbonate and the 'CF paradox'.
HCO(3)(-) secretion, which is believed to neutralize acid within the mucus gel, is the most studied duodenal defense mechanism. In general, HCO(3)(-) secretion rate and mucosal injury susceptibility correlate closely. Recent studies suggest that luminal acid can lower intracellular pH (pH(i)) of duodenal epithelial cells and that HCO(3)(-) secretion is unchanged during acid stress. Furthermore, peptic ulcers are rare in cystic fibrosis (CF), although, with impaired HCO(3)(-) 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 pH(i) regulation rather than by neutralization of acid by HCO(3)(-) in the pre-epithelial mucus. Cellular acidification during luminal acid perfusion, and unchanged HCO(3)(-) secretion during acid stress are inconsistent with pre-epithelial acid neutralization by secreted HCO(3)(-). Furthermore, inhibition of HCO(3)(-) secretion by 5-nitro-2-(3-phenylpropylamino) benzoic acid (NPPB) despite preservation of pH(i) and protection from acid-induced injury further question the pre-epithelial acid neutralization hypothesis. This decoupling of HCO(3)(-) secretion and injury susceptibility by NPPB (and possibly by CF) further suggest that cellular buffering, rather than HCO(3)(-) exit into the mucus, is of primary importance for duodenal mucosal protection, and may account for the lack of peptic ulceration in CF patients.
Kaunitz
J D
JD
Greater Los Angeles Veterans Affairs Healthcare System, CURE: Digestive Diseases Research Center, Los Angeles, CA 90072, USA. jake@ucla.edu
Akiba
Y
Y
D000818:Animals; D001639:Bicarbonates / Q000378:metabolism*; D003550:Cystic Fibrosis / Q000150:complications / Q000378:metabolism*; D004381:Duodenal Ulcer / Q000209:etiology / Q000378:metabolism*; D004386:Duodenum / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007424:Intracellular Fluid / Q000378:metabolism*; D010437:Peptic Ulcer / Q000209:etiology / Q000378:metabolism*
D001639:Bicarbonates