Inhibition of NHE-1 Increases Smoke-Induced Proliferative Activity of Barrett's Esophageal Cell Line

Int J Mol Sci. 2021 Sep 30;22(19):10581. doi: 10.3390/ijms221910581.


Several clinical studies indicate that smoking predisposes its consumers to esophageal inflammatory and malignant diseases, but the cellular mechanism is not clear. Ion transporters protect esophageal epithelial cells by maintaining intracellular pH at normal levels. In this study, we hypothesized that smoking affects the function of ion transporters, thus playing a role in the development of smoking-induced esophageal diseases. Esophageal cell lines were treated with cigarettesmoke extract (CSE), and the viability and proliferation of the cells, as well as the activity, mRNA and protein expression of the Na+/H+ exchanger-1 (NHE-1), were studied. NHE-1 expression was also investigated in human samples. For chronic treatment, guinea pigs were exposed to tobacco smoke, and NHE-1 activity was measured. Silencing of NHE-1 was performed by using specific siRNA. CSE treatment increased the activity and protein expression of NHE-1 in the metaplastic cells and decreased the rate of proliferation in a NHE-1-dependent manner. In contrast, CSE increased the proliferation of dysplastic cells independently of NHE-1. In the normal cells, the expression and activity of NHE-1 decreased due to in vitro and in vivo smoke exposure. Smoking enhances the function of NHE-1 in Barrett's esophagus, and this is presumably a compensatory mechanism against this toxic agent.

Keywords: Barrett’s esophagus; NHE-1; esophagus; ion transport; smoking.

MeSH terms

  • Animals
  • Barrett Esophagus / genetics*
  • Barrett Esophagus / metabolism
  • Barrett Esophagus / pathology
  • Cell Line
  • Cell Proliferation / genetics*
  • Cell Survival
  • Epithelial Cells / metabolism
  • Esophagus / metabolism*
  • Esophagus / pathology
  • Gene Expression
  • Guinea Pigs
  • Humans
  • Hydrogen-Ion Concentration
  • Male
  • Middle Aged
  • RNA Interference*
  • Smoke*
  • Smoking
  • Sodium-Hydrogen Exchanger 1 / genetics*
  • Sodium-Hydrogen Exchanger 1 / metabolism
  • Tobacco / chemistry


  • SLC9A1 protein, human
  • Smoke
  • Sodium-Hydrogen Exchanger 1