To increase our understanding of the pathophysiology of reflux esophagitis, we sought the early sequence of changes in mucosal structure and function in acutely acid-damaged rabbit esophagus. Using a perfused catheter technique esophageal potential difference (PD) profiles were obtained in anesthetized rabbits before, during, and after perfusion of the lower one-half of the esophagus with phosphate-buffered saline or 80 mM HCl-80 mM NaCl. When acid perfusion reduced the lower esophageal PD by 40-50% or 80-100% of the initial values, the esophagus was removed, sectioned, and the mucosa studied with light microscopy, transmission electron microscopy, and Ussing chamber technique for evaluation of sodium and mannitol transport. The earlier stage of acid damage (PD ↓ 40-50%) was associated with reduced mucosal resistance from 2,180±199 to 673±157 ohm .cm2 and increased passive transport of sodium (0.10±0.06 to 1.82±0.48 μeq/h.cm2) and mannitol (0.008±0.003 to 0.051±0.012 μM/h.cm2) (P < 0.05). There was no significant change in short circuit current (0.35±0.05 to 0.35±0.04) or net sodium transport (0.32±0.06 to 0.37±0.12) at this stage, and the only morphologic finding was dilated intercellular spaces on electron microscopy. The later stage of acid damage (PD ↓ 80-100%) exhibited a further reduction in resistance to 299±65 ohm.cm2 (P < 0.05), a finding now accompanied by a reduction in short circuit current (0.35±0.05 to 0.21±0.04 μeq/h.cm2) and complete inhibition of net sodium transport (0.32±0.06 to 0.01±0.13) (P < 0.05). Morphologic studies at this time revealed cellular necrosis, edema, and vesicle formation in the stratum spinosum. Both gross mucosal changes and transmural necrosis were notably absent. When esophageal perfusion was performed with a comination of acid (80 mM HCl-80 mM NaCl) and pepsin (100 μg/ml), the morphologic and physiologic findings were essentially the same as with acid alone; however, the time of perfusion to reach either the 50 or 100% reduction in PD was shortened. The findings in this model can be explained on an initial increase in cellular and/or paracellular permeability followed by inhibition of active sodium transport. The resulting loss of osmolar regulation leads to cell necrosis in the stratum spinosum.
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