Dilated intercellular spaces and shunt permeability in nonerosive acid-damaged esophageal epithelium

Am J Gastroenterol. 2004 Jan;99(1):13-22. doi: 10.1046/j.1572-0241.2003.04018.x.


Objectives: It has recently been established that patients with nonerosive reflux disease have on biopsy within esophageal epithelium a lesion known as dilated intercellular spaces (DIS).

Methods: To further explore the nature and implications of this lesion, in vitro models of nonerosive acid and acid-pepsin damage were created in Ussing chamber-mounted rabbit esophageal epithelium. Using these models circuit analysis and permeability studies were carried out, the latter using dextran of varying size and human epidermal growth factor (EGF).

Results: Luminal HCl, pH 1.1, or HCl, pH 2.0 + pepsin, 1 mg/ml, for 30 min significantly reduced transepithelial electrical resistance (RT) but produced no gross erosions or histologic evidence of cell necrosis. Transmission electron microscopy, however, documented the presence of DIS. Circuit analysis on healthy esophageal epithelium showed that shunt resistance (RS) was much lower than apical membrane, basolateral membrane and transcellular resistances (Ra, Rb, and Rcell, respectively) and approached that of RT. Further, circuit analysis on acid and acid-pepsin damaged tissues showed that the declines in RT resulted from declines in RS. Moreover, the declines in RT (and so RS) were associated with a linear increase in permeability to 4 kD dextrans as well as an increase in permeability to 6 kD EGF and dextrans as large as 20 kD.

Conclusions: 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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Dextrans / pharmacokinetics
  • Electric Conductivity
  • Epidermal Growth Factor / pharmacokinetics
  • Epithelium / diagnostic imaging
  • Epithelium / metabolism
  • Esophagitis, Peptic / pathology*
  • Esophagitis, Peptic / physiopathology
  • Esophagus / diagnostic imaging*
  • Esophagus / metabolism
  • Extracellular Space / diagnostic imaging*
  • In Vitro Techniques
  • Male
  • Microscopy, Electron
  • Permeability
  • Rabbits
  • Ultrasonography


  • Dextrans
  • Epidermal Growth Factor