Do Tight Junction Structure and Function Play a Role in the Acid Resistance of Barrett’s Esophagus?

Abstract

Barrett’s esophagus (BE) is a lesion characterized by specialized columnar epithelium lining the distal esophagus. It develops in subjects with acid reflux disease as replacement for destroyed esophageal stratified squamous epithelium (SqE) – presumably because it is more acid resistant than SqE. How BE resists acid injury is complex but one means may involve alteration in the structure and function of its tight junctions. To address this question, expression profiles were performed for 21 claudin genes by quantitative RT-PCR and highly expressed claudin proteins immunolocalized by fluorescence microscopy on endoscopic biopsies from BE and from healthy SqE from subjects without esophageal disease. The results showed that all 21 claudins were expressed in BE while 19 claudins were expressed in SqE. Further, claudins 3, 4, 12, 15, 18 and 23 were overexpressed in BE compared to SqE, and claudin 18 notable for being both the most highly expressed in BE and absent in SqE. Immunolocalization studies in BE reveled that several claudins were localized to the tight junctions including 4, 7, 8, 10, 15, and, importantly, 18. Given the uniqueness of claudin 18 in BE, this claudin was expressed in MDCK II cells and shown to selectively increase junctional resistance to cations (Na+) compared to standard MDCK II cells. These results suggest that the alterations in tight junction structure and function in BE is one means for its greater acid resistance than SqE (Support: NIH grants DK036013, DK063669 and DK45134).