H2O2 Stimulates Cystic Fibrosis Transmembrane Conductance Regulator through an Autocrine Prostaglandin Pathway, Using Multidrug-Resistant Protein–4
| Autor: | Philip L. Whitney, Gregory E. Conner, Matthias Salathe, Pedro I. Ivonnet, Murline Gelin |
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| Rok vydání: | 2013 |
| Předmět: |
Anions
Pulmonary and Respiratory Medicine medicine.medical_specialty Cystic Fibrosis Clinical Biochemistry EP4 Receptor Cystic Fibrosis Transmembrane Conductance Regulator Prostaglandin Bronchi Biology Cystic fibrosis Small hairpin RNA chemistry.chemical_compound Internal medicine Cyclic AMP medicine Humans Cyclooxygenase Inhibitors Cyclic adenosine monophosphate Receptor Molecular Biology Cells Cultured Cell Membrane Epithelial Cells Hydrogen Peroxide Articles Cell Biology respiratory system Apical membrane medicine.disease Receptors Prostaglandin E EP1 Subtype Cystic fibrosis transmembrane conductance regulator Cell biology Endocrinology chemistry Prostaglandin-Endoperoxide Synthases biology.protein lipids (amino acids peptides and proteins) Multidrug Resistance-Associated Proteins Receptors Prostaglandin E EP4 Subtype |
| Zdroj: | American Journal of Respiratory Cell and Molecular Biology. 49:672-679 |
| ISSN: | 1535-4989 1044-1549 |
| Popis: | 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 of normal human bronchial epithelial cultures differentiated at the air–liquid interface were estimated, and H2O2-mediated changes in CFTR activity were examined. In Ussing chambers, H2O2-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. A multidrug-resistant protein (MRP) inhibitor and short hairpin RNA directed against MRP4 blocked H2O2 responses. EP1 and EP4 agonists mimicked H2O2 in both control and MRP4 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 apical membrane. |
| Databáze: | OpenAIRE |
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