Transepithelial Leak in Barrett’s Esophagus

Mullin, James M.; Valenzano, Mary Carmen; Trembeth, S.; Allegretti, Paul; Verrecchio, J. J.; Schmidt, J; Jain, Vishal; Meddings, Jonathan B.; Mercogliano, Giancarlo; Thornton, J. Douglas

doi:10.1007/s10620-006-9478-5

Cited by 29 publications

(22 citation statements)

References 51 publications

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“…Several previous reports have indicated that the disruption of barrier function is related to dislocalization and loss of TJ complexes between epithelial cells (2,7,8,10,21,27). Several distinct types of claudins have been reported to colocalize in various types of cells (8,35), and several reports including ours have indicated that claudin-1, claudin-4, claudin-7, JAM-A, occludin, and ZO-1 are expressed in the human esophagus (9,26,29).…”

Section: Discussionmentioning

confidence: 49%

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Acidic bile salts modulate the squamous epithelial barrier function by modulating tight junction proteins

Chen

Oshima²,

Tomita³

et al. 2011

American Journal of Physiology-Gastrointestinal and Liver Physi

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Experimental models for esophageal epithelium in vitro either suffer from poor differentiation or complicated culture systems. An air-liquid interface system with normal human bronchial epithelial cells can serve as a model of esophageal-like squamous epithelial cell layers. Here, we explore the influence of bile acids on barrier function and tight junction (TJ) proteins. The cells were treated with taurocholic acid (TCA), glycocholic acid (GCA), or deoxycholic acid (DCA) at different pH values, or with pepsin. Barrier function was measured by transepithelial electrical resistance (TEER) and the diffusion of paracellular tracers (permeability). The expression of TJ proteins, including claudin-1 and claudin-4, was examined by Western blotting of 1% Nonidet P-40-soluble and -insoluble fractions. TCA and GCA dose-dependently decreased TEER and increased paracellular permeability at pH 3 after 1 h. TCA (4 mM) or GCA (4 mM) did not change TEER and permeability at pH 7.4 or pH 4. The combination of TCA and GCA at pH 3 significantly decreased TEER and increased permeability at lower concentrations (2 mM). Pepsin (4 mg/ml, pH 3) did not have any effect on barrier function. DCA significantly decreased the TEER and increased permeability at pH 6, a weakly acidic condition. TCA (4 mM) and GCA (4 mM) significantly decreased the insoluble fractions of claudin-1 and claudin-4 at pH 3. In conclusion, acidic bile salts disrupted the squamous epithelial barrier function partly by modulating the amounts of claudin-1 and claudin-4. These results provide new insights for understanding the role of TJ proteins in esophagitis.

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Section: Discussionmentioning

confidence: 49%

“…TJs consist of occludin, claudins, junctional adhesion molecule (JAM), and scaffold proteins, which together are known as the zonula occludens (ZO). Among these TJ molecules, claudins are the major integral membrane proteins of TJ strands (2,7,8,10,21,27).…”

mentioning

confidence: 99%

Acidic bile salts modulate the squamous epithelial barrier function by modulating tight junction proteins

Chen

Oshima²,

Tomita³

et al. 2011

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…Although the levels of claudin-1 and -4 in soluble fractions were similar between days 3 and 7, those of claudin-4 in the insoluble fractions had markedly increased by day 7. Several previous reports have indicated that the disruption of barrier function is related to delocalization and loss of TJ complexes between epithelial cells (1,6,10,24,30). These findings suggest that the insoluble fraction of TJ proteins may relate to the TJ proteins that appeared as dots and whisker-like lines in the superficial layers.…”

Section: Discussionmentioning

confidence: 68%

Bile salts disrupt human esophageal squamous epithelial barrier function by modulating tight junction proteins

Chen

Oshima

Shan

et al. 2012

American Journal of Physiology-Gastrointestinal and Liver Physi

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of acid and bile acids contributes to epithelial tissue injury in gastro-esophageal reflux disease. However, the influence of refluxed material on human esophageal stratified epithelial barrier function and tight junction (TJ) proteins has not been fully elucidated. Here, we investigated the influence of acid and bile acids on barrier function and TJ protein distribution using a newly developed air-liquid interface (ALI) in vitro culture model of stratified squamous epithelium based on primary human esophageal epithelial cells (HEECs). Under ALI conditions, HEECs formed distinct epithelial layers on Transwell inserts after 7 days of culture. The epithelial layers formed TJ, and the presence of claudin-1, claudin-4, and occludin were detected by immunofluorescent staining. The NP-40-insoluble fraction of these TJ proteins was significantly higher by day 7 of ALI culture. Exposure of HEECs to pH 2, and taurocholic acid (TCA) and glycocholic acid (GCA) at pH 3, but not pH 4, for 1 h decreased transepithelial electrical resistance (TEER) and increased paracellular permeability. Exposure of cell layers to GCA (pH 3) and TCA (pH 3) for 1 h also markedly reduced the insoluble fractions of claudin-1 and -4. We found that deoxycholic acid (pH 7.4 or 6, 1 h) and pepsin (pH 3, 24 h) significantly decreased TEER and increased permeability. Based on these findings, ALIcultured HEECs represent a new in vitro model of human esophageal stratified epithelium and are suitable for studying esophageal epithelial barrier functions. Using this model, we demonstrated that acid, bile acids, and pepsin disrupt squamous epithelial barrier function partly by modulating TJ proteins. These results provide new insights into understanding the role of TJ proteins in esophagitis. esophageal epithelium; claudin; air-liquid interface THE HUMAN ESOPHAGUS IS LINED with a layer of nonkeratinizing stratified squamous epithelium, which serves as an effective barrier against the influx of luminal contents. The esophageal epithelium consists of the basal, suprabasal, and superficial layers (14). In the pathogenesis of reflux esophagitis, acids, bile acids, and pepsin play a major role in damaging the esophageal epithelium (34). However, the mechanisms by which the luminal contents affect the barrier function of the stratified epithelial cell layers remain unclear.Tight junctions (TJs) separate the apical and basolateral cell surface domains to establish cell polarity and establish barrier function. TJs are composed of several proteins, including occludin, claudins, junctional adhesion molecule (22), and the scaffold protein zonula occludens (ZO). Of these proteins, claudins, which form specialized cellular structures that regulate the permeability of cellular layers, are the most important structural and functional components of TJ strands (1,6,10,30). Claudins are an integral transmembrane protein family consisting of at least 27 subtypes in mammals (22,40) and are essential for establishing and maintaining epithelial cell polarity by controlling the m...

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“…16 Among various genetic events a disturbed balance of TJ proteins, which regulate tissue integrity and paracellular transport, is believed to promote the development of BC. [17][18][19] In line with this hypothesis complex alterations of TJ expression in BE and BC compared to esophageal squamous epithelium have been observed: claudin-1 and claudin-5 are downregulated in BE 19,20 whereas for claudin-2, -3, -4 and -7 an upregulation has been noted, in particular in highgrade IN and BC. 17,19,21 These data suggest that downregulated TJ proteins might facilitate inhibitory functions, whereas upregulated TJs may promote the progression of BE.…”

Section: Introductionmentioning

confidence: 69%

Expression and function of the coxsackie and adenovirus receptor in Barrett's esophagus and associated neoplasia

et al. 2009

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Cell surface presence of the coxsackie and adenovirus receptor (CAR) is considered a crucial prerequisite for the uptake of attenuated adenovirus. In cancers, however, a frequent loss of CAR has been noted potentially hampering the success of adenovirus-based therapy. In esophageal Barrett's carcinomas and its precursor lesions CAR presence has not been systematically determined yet. Immunohistochemical assessment in tissue specimens of 111 patients revealed CAR-positivity in all cases of Barrett's esophagus, including various degrees of intraepithelial neoplasia. In contrast, no considerable CAR presence was seen in squamous esophageal epithelium. Among Barrett's carcinomas, 93% displayed CAR presence, whereas CAR-negativity was observed preferentially in advanced cancers. Aiming to evaluate whether this loss of CAR impacts tumor-biologic properties of esophageal adenocarcinomas we studied cell lines OE19 and OE33 and observed an increased proliferation, migration and invasion upon siRNA-mediated functional CAR knock down. In conclusion, our results indicate that CAR may provide a valuable target for adenovirus-based therapy of Barrett's carcinomas and its precursor lesions. These data do also suggest that CAR does not contribute substantially to carcinogenesis in Barrett's esophagus, however, it may be speculated that loss of CAR promotes tumor progression in advanced stages of Barrett's carcinomas.

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Transepithelial Leak in Barrett’s Esophagus

Cited by 29 publications

References 51 publications

Acidic bile salts modulate the squamous epithelial barrier function by modulating tight junction proteins

Acidic bile salts modulate the squamous epithelial barrier function by modulating tight junction proteins

Bile salts disrupt human esophageal squamous epithelial barrier function by modulating tight junction proteins

Expression and function of the coxsackie and adenovirus receptor in Barrett's esophagus and associated neoplasia

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