H2O2 stimulates cystic fibrosis transmembrane conductance regulator through an autocrine prostaglandin pathway, using multidrug-resistant protein-4

Gregory E. Conner, Pedro Ivonnet, Murline Gelin, Philip Whitney, Matthias Salathe

Research output: Contribution to journalArticle

13 Scopus citations

Abstract

Cystic fibrosis transmembrane conductance regulator (CFTR) activity is essential for the maintenance of airway surface liquid depth, and therefore mucociliary clearance. Reactive oxygen species, increased during inflammatory airway diseases, alter CFTR activity. Here, H2O2 levels in the surface liquid ofnormalhumanbronchial epithelial cultures differentiated at the air-liquid interface were estimated, and H2O2- mediated changes in CFTR activitywere examined. In Ussing chambers, H 2O2-induced anion currents were sensitive to the CFTR inhibitors CFTRinh172 and GlyH-101. These currents were absent in cells from patients with cystic fibrosis. Responses to greater than 500 μM H2O2 were transient. Cyclooxygenase inhibitors blocked the H2O2 response, as did EP1 and EP4 receptor antagonists. Amultidrug-resistant protein (MRP) inhibitor and short hairpin RNA directed againstMRP4 blocked H2O2 responses. EP1 and EP4 agonists mimicked H2O2 in both control andMRP4 knockdown cells. Thus, H2O2 activates the synthesis, export, and binding of prostanoids via EP4 and, interestingly, EP1 receptors in normal, differentiated human airway epithelial cells to activate cyclic adenosine monophosphate pathways that in turn activate CFTR channels in the apicalmembrane.

Original languageEnglish (US)
Pages (from-to)672-679
Number of pages8
JournalAmerican journal of respiratory cell and molecular biology
Volume49
Issue number4
DOIs
StatePublished - Oct 1 2013

    Fingerprint

Keywords

  • CFTR
  • EP1
  • EP4
  • HO
  • MRP4

ASJC Scopus subject areas

  • Cell Biology
  • Pulmonary and Respiratory Medicine
  • Molecular Biology
  • Clinical Biochemistry

Cite this