Methods
Measuring duodenal epithelial intracellular pH (pH_i), blood flow and mucus gel thickness (MGT), we studied duodenal defense mechanisms in vivo so as to more fully understand the response to luminal acid.

Results
Exposure of the mucosa to physiologic acid solutions promptly lowered pH_i, followed by recovery after acid removal, indicating that acid readily diffuses into, but does not damage epithelial cells. Cellular acid then exits the cell via an amiloride-inhibitable process, presumably sodium-proton exchange (NHE). MGT and blood flow increase promptly during acid perfusion; both decrease after acid challenge and are inhibited by vanilloid receptor antagonists or by sensory afferent denervation. Bicarbonate secretion, measured by a CO₂ electrode, is not affected by acid challenge but increases after challenge. Inhibition of cellular base loading lowers pH_i and enhances acid-induced injury, whereas inhibition of apical base extrusion alkalinizes pH_i and attenuates injury.

Conclusions
These observations support the following hypothesis: luminal acid diffuses into the epithelial cells, lowering pH_i. Acidic pH_i increases the activity of a basolateral NHE, acidifying the submucosal space and increasing cellular base loading. The acidic submucosal space activates capsaicin receptors on afferent nerves, increasing MGT and blood flow. With continued acid exposure, a new steady state with thickened mucus gel, increased blood flow, and a higher cellular buffering power protects against acid injury. After acid challenge, mucus secretion decreases, blood flow slows, and pH_i returns to normal, the latter occurring via apical bicarbonate extrusion, increasing bicarbonate secretion. Through these integrated mechanisms, the epithelial cells are protected from damage due to repeated pulses of concentrated gastric acid.