Regulation of alveolar epithelial Na + channels by ERK1/2 in chlorine-breathing mice

Academic Article


  • The mechanisms by which the exposure of mice to Cl 2 decreases vectorial Na + transport and fluid clearance across their distal lung spaces have not been elucidated. We examined the biophysical, biochemical, and physiological changes of rodent lung epithelial Na + channels (ENaCs) after exposure to Cl 2, and identified the mechanisms involved. We measured amiloride-sensitive short-circuit currents (I amil) across isolated alveolar Type II (ATII) cell monolayers and ENaC single-channel properties by patching ATII and ATI cells in situ. α-ENaC, γ-ENaC, total and phosphorylated extracellular signalrelated kinase (ERK)1/2, and advanced products of lipid peroxidation in ATII cells weremeasured byWestern blot analysis. Concentrations of reactive intermediates were assessed by electron spin resonance (ESR). Amiloride-sensitive Na 1 channels with conductances of 4.5 and 18 pS were evident in ATI and ATII cells in situ of air-breathing mice. At 1 hour and 24 hours after exposure to Cl 2, the open probabilities of these two channels decreased. This effect was prevented by incubating lung slices with inhibitors of ERK1/2 or of proteasomes and lysosomes. The exposure of ATII cell monolayers to Cl2 increased concentrations of reactive intermediates, leading to ERK1/2 phosphorylation and decreased I amil and α-ENaC concentrations at 1 hour and 24 hours after exposure. The administration of antioxidants to ATII cells before and after exposure to Cl 2 decreased concentrations of reactive intermediates and ERK1/2 activation, which mitigated the decrease in I amil and ENaC concentrations. The reactive intermediates formed during and after exposure to Cl 2 activated ERK1/2 in ATII cells in vitro andin vivo, leading to decreased ENaC concentrations and activity. Copyright © 2012 by the American Thoracic Society.
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    Author List

  • Lazrak A; Chen L; Jurkuvenaite A; Doran SF; Liu G; Li Q; Lancaster JR; Matalon S
  • Start Page

  • 342
  • End Page

  • 354
  • Volume

  • 46
  • Issue

  • 3