Role of tight junction proteins in gastroesophageal reflux disease

Abstract

Background: Gastroesophageal reflux disease (GERD) is associated with impaired epithelial barrier function that is regulated by cell-cell contacts. The aim of the study was to investigate the expression pattern of selected components involved in the formation of tight junctions in relation to GERD. Methods: Eighty-four patients with GERD-related symptoms with endoscopic signs (erosive: n = 47) or without them (non-erosive: n = 37) as well as 26 patients lacking GERD-specific symptoms as controls were included. Endoscopic and histological characterization of esophagitis was performed according to the Los Angeles and adapted Ismeil-Beigi criteria, respectively. Mucosal biopsies from distal esophagus were taken for analysis by histopathology, immunohistochemistry and quantitative reverse-transcription polymerase chain reaction (RT-PCR) of five genes encoding tight junction components [Occludin, Claudin-1, -2, Zona occludens (ZO-1, -2)]. Results: Histopathology confirmed GERD-specific alterations as dilated intercellular spaces in the esophageal mucosa of patients with GERD compared to controls (P < 0.05). Claudin-1 and −2 were 2-to 6-fold upregulation on transcript (P < 0.01) and in part on protein level (P < 0.015) in GERD, while subgroup analysis of revealed this upregulation for ERD only. In both erosive and non-erosive reflux disease, expression levels of Occludin and ZO-1,-2 were not significantly affected. Notably, the induced expression of both claudins did not correlate with histopathological parameters (basal cell hyperplasia, dilated intercellular spaces) in patients with GERD. Conclusions: Taken together, the missing correlation between the expression of tight junction-related components and histomorphological GERD-specific alterations does not support a major role of the five proteins studied in the pathogenesis of GERD.

Gastrointestinal mucosal barrier function and diseases

“…Although no change in occludin or ZO-1 expression has been reported in GERD patients, the expression of CLDN1 and CLDN2 mRNA and protein has been reported to be increased [34] and unchanged [35] in GERD, and the expression of CLDN1 and CLDN4 has been reported to be decreased in GERD [33]. The reason for these inconsistent results may be due to the fact that total CLDN protein was measured rather than a specific subpopulation of CLDNs.…”

Expression of claudin-3 in the esophagus and larynx of rat reflux model

“…Thirdly, there are many molecules associated with the integrity of esophageal and laryngeal epithelium in addition to claudin-3. Mö nkemü ller et al [22] reported the missing correlation between the expression of tight junction-related components [occludin, claudin-1, -2, zona occludens (ZO-1, -2)] and DIS of the esophageal epithelium in GERD patients. Further research is needed to evaluate the role of claudin-3 and other molecular markers in GERD and LPR.…”

Biomarkers of Reflux Disease

“…Animal and in vitro models of GERD have shown changes in expression and localization of Claudin-3 and -4 10, 11 . In human studies, expression of Claudin-1, -2 and -4, ZO-1, filaggrin and occludin are reportedly altered in GERD, but no correlation has been found with histopathological parameters such as DIS and basal cell hyperplasia 12–14 . NERD patients exhibit no change in the expression of these proteins 12 .…”

“…In human studies, expression of Claudin-1, -2 and -4, ZO-1, filaggrin and occludin are reportedly altered in GERD, but no correlation has been found with histopathological parameters such as DIS and basal cell hyperplasia 12–14 . NERD patients exhibit no change in the expression of these proteins 12 . Furthermore, direct correlation between acid exposure and pathology is lacking.…”