Dilated intercellular spaces are a feature of reflux damage to human esophageal epithelium. As a morphological marker of increased paracellular permeability, its presence in patients without endoscopic abnormalities may help explain their development of heartburn.

In nonerosive acid-damaged esophageal epithelium DIS develop in association with and as a marker of reduced transepithelial resistance and increased shunt permeability. This change in shunt permeability upon acid or acid-pepsin exposure is substantial, permitting dextran molecules as large as 20 kD (33 A) to diffuse across the epithelium. Also, this shunt leak enables luminal EGF at 6 kD to diffuse across the acid-damaged epithelium and by so doing enables it to access its receptors on epithelial basal cells. We hypothesize that the shunt leak of EGF may in part account for the development of a reparative phenomenon on esophageal biopsy in patients with nonerosive reflux disease known as basal cell hyperplasia.

OBJECTIVES An early event in the pathogenesis of gastroesophageal reflux disease (GERD) is an acid-induced increase in junctional (paracellular) permeability in esophageal epithelium (EE). The molecular events that account for this change are unknown. E-cadherin is a junctional protein important in barrier function in EE. Therefore, defects in barrier function in EE were sought in GERD as well as whether their presence correlated with abnormalities in e-cadherin. METHODS Endoscopic biopsies of EE from GERD (n = 20; male 10; female 10; mean age 50 ± 10 years) and subjects with a healthy esophagus (controls; n = 23; male 11; female 12; mean age 51 ± 11 years) were evaluated in mini-Ussing chambers and by western blot and immunochemistry; and serum analyzed by enzyme-linked immunosorbent assay (ELISA). A role for e-cadherin was also assessed using a unique conditional knockout of e-cadherin in adult mouse esophagus. RESULTS EE from GERD patients had lower electrical resistance and higher fluorescein flux than EE from controls; and the findings in GERD associated with cleavage of e-cadherin. Cleavage of e-cadherin in GERD was documented in EE by the presence of a 35-kDa, C-terminal fragment of the molecule on western blot and by an increase in soluble N-terminal fragments of the molecule in serum. Activation of the membrane metalloproteinase, A Disintegrin And Metalloproteinase (ADAM-10), was identified as a likely cause for cleavage of e-cadherin by western blot and immunostaining and a role for e-cadherin in the increased junctional permeability in EE from GERD supported by showing increased permeability after deletion of e-cadherin in mouse EE. CONCLUSIONS The EE in GERD has increased junctional permeability and this is in association with proteolytic cleavage of e-cadherin. As loss of e-cadherin can, alone, account for the increase in junctional permeability, cleavage of e-cadherin likely represents a critical molecular event in the pathogenesis of GERD, and identification of cleaved fragments may, if confirmed in larger studies, be valuable as a biomarker of GERD.

Sodium ion and chloride transport was studied in vitro in small intestinal and colonic tissue from patients with cystic fibrosis (CF) and from non-CF control subjects matched as to age and sex. Normal histological appearance and substantial response to mucosal glucose (5 mM, ileum) or mucosal amiloride (10(-5) M, colon) indicated normal tissue viability in both control and CF tissues. Electroneutral NaCl absorption was demonstrated in the small intestine of control subjects and CF patients. Small intestinal and colonic tissues of control subjects responded to four secretagogues (theophylline, 5 mM; prostaglandin E2, 10(-6) M; calcium ionophore (A23187), 10(-5) M; bethanechol, 5 x 10(-5) M), with electrogenic chloride secretion. The tissues of CF patients, however, did not respond to any of the test secretagogues. These studies demonstrate that an abnormality in chloride transport is present in the small intestinal and colonic epithelia of CF patients. Unlike airway epithelia, which secrete chloride in response to Ca ionophore, the intestinal epithelia of CF patients do not respond to either cAMP- or Ca-mediated secretagogues. This abnormality in intestinal electrolyte transport may play a role in the pathogenesis of meconium impactions in CF patients.

These studies suggest that acidified pepsin plays a key role in the development of reflux esophagitis by producing an early irreversible lesion that results in an increase in paracellular permeability, which indirect evidence suggests is due to damage to the junctional complex. The irreversibility of the increase in paracellular permeability is likely to aid conversion of nonerosive to erosive damage to the epithelium by permitting luminal acid greater access to the basolateral membrane of esophageal epithelial cells, which is known to be acid permeable.

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Tobey NA, Argote CM, Vanegas XC, Barlow W, Orlando RC. Electrical parameters and ion species for active transport in human esophageal stratified squamous epithelium and Barrett's specialized columnar epithelium. Am J Physiol Gastrointest Liver Physiol 293: G264-G270, 2007. First published April 12, 2007; doi:10.1152/ajpgi.00047.2007.-The human esophagus is lined by stratified squamous epithelium (ESSE), and in some subjects with reflux disease the distal esophagus becomes lined by Barrett's specialized columnar epithelium (BSCE). ESSE and BSCE differ both histologically and functionally, the latter evident by differences in their in vivo transmural electrical potential difference (PD), ESSE averaging Ϫ15 mV and BSCE being greater than Ϫ25 mV. In this report we examine the basis for this difference in PD. This is done by mounting endoscopic biopsies of ESSE from 25 subjects without esophageal disease and BSCE from 19 with Barrett's esophagus in mini-Ussing chambers for electrical recordings basally and after bathing solution ion replacement. The results show that the PD of human ESSE reflects a low level of active ion transport (5.1 Ϯ 0.8 A/cm 2 ) combined with a high level of tissue (electrical) resistance (344 Ϯ 34 ⍀ ⅐ cm 2 ) and that of BSCE reflects a high level of active transport (43.6 Ϯ 11.6 A/cm 2 ) combined with a low level of resistance (69 Ϯ 8 ⍀ ⅐ cm 2 ). Furthermore, active transport in ESSE was principally due to sodium absorption whereas in BSCE it was equally divided between sodium absorption and anion (chloride/ bicarbonate) secretion, the latter through an apical membrane, 4-acetamido4Ј-isothiocyano-2,2Ј-stilbenedisulfonic acid-sensitive anion channel. As an anion-secreting tissue with bicarbonate secretory capacity more than fivefold greater than ESSE, BSCE is better suited than ESSE for defense of the esophagus against reflux disease. mini-Ussing chambers; ouabain; potential difference; short-circuit current; electrical resistance; gastroesophageal reflux disease; ethoxyzolamide; 4-acetamido4Ј-isothiocyano-2,2Ј-stilbenedisulfonic acid THE HUMAN ESOPHAGUS IS LINED by stratified squamous epithelium (ESSE), and in ϳ10% of subjects with gastroesophageal reflux disease the ESSE of distal esophagus is destroyed and replaced to a varying extent by a lining of Barrett's specialized columnar epithelium (BSCE) (19). ESSE and BSCE differ not only structurally, as the names imply, but also functionally, and one marker of this functional difference is reflected by differences in their in vivo transmural electrical potential difference (PD). The in vivo PD for ESSE averages Ϫ15 Ϯ 5 mV and the in vivo PD for BSCE is typically greater than Ϫ25 mV (11,22,24,30,39). Since the PD, according to Ohm's law, is the product of current times (electrical) resistance, such differences in PD for ESSE and BSCE indicate that these epithelia have fundamental differences in ion transport and/or barrier properties. The nature of these differences, however, remains elusive, principally because of limitations in electrical reco...

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