title: Role of E-cadherin in the pathogenesis of gastroesophageal reflux disease.
abstract: OBJECTIVE
  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.
authors: Division of Gastroenterology and Hepatology, Department of Medicine, University of North Carolina, Chapel Hill, North Carolina, USA. bjovov@med.unc.edu
authors: Biljana
authors: B
authors: Jovov
authors: Jianwen
authors: J
authors: Que
authors: Nelia A
authors: NA
authors: Tobey
authors: Zorka
authors: Z
authors: Djukic
authors: Brigid L M
authors: BL
authors: Hogan
authors: Roy C
authors: RC
authors: Orlando
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D015415:Biomarkers / Q000032:analysis / Q000378:metabolism; D001707:Biopsy, Needle; D015153:Blotting, Western; D015820:Cadherins / Q000032:analysis / Q000378:metabolism*; D016022:Case-Control Studies; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D004943:Esophagogastric Junction / Q000473:pathology / Q000503:physiopathology; D004945:Esophagoscopy / Q000379:methods; D004947:Esophagus / Q000473:pathology*; D005260:Female; D005455:Fluorescent Antibody Technique; D005764:Gastroesophageal Reflux / Q000378:metabolism* / Q000473:pathology* / Q000503:physiopathology; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D011379:Prognosis; D012016:Reference Values; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012680:Sensitivity and Specificity; D012720:Severity of Illness Index
chemical_list: D015415:Biomarkers; D015820:Cadherins