Cigarette smoke activates CFTR through ROS-stimulated cAMP signaling in human bronchial epithelial cells.

Abstract

Air pollution stimulates airway epithelial secretion through a cholinergic reflex that is unaffected in cystic fibrosis (CF), yet a strong correlation is observed between passive smoke exposure in the home and impaired lung function in CF children. Our aim was to study the effects of low smoke concentrations on cystic fibrosis transmembrane conductance regulator (CFTR) function in vitro. Cigarette smoke extract stimulated robust anion secretion that was transient, mediated by CFTR, and dependent on cAMP-dependent protein kinase activation. Secretion was initiated by reactive oxygen species (ROS) and mediated by at least two distinct pathways: autocrine activation of EP4 prostanoid receptors and stimulation of Ca2+ store-operated cAMP signaling. The response was absent in cells expressing the most common disease-causing mutant F508del-CFTR. In addition to the initial secretion, prolonged exposure of non-CF bronchial epithelial cells to low levels of smoke also caused a gradual decline in CFTR functional expression. F508del-CFTR channels that had been rescued by the CF drug combination VX-809 (lumacaftor) + VX-770 (ivacaftor) were more sensitive to this downregulation than wild-type CFTR. The results suggest that CFTR-mediated secretion during acute cigarette smoke exposure initially protects the airway epithelium while prolonged exposure reduces CFTR functional expression and reduces the efficacy of CF drugs.

• Authors: Francis H Wong, Asmahan AbuArish, Elizabeth Matthes, Mark J Turner, Lana E Greene, Alexandre Cloutier, Renaud Robert, David Y Thomas, Gonzalo Cosa, André M Cantin, John W Hanrahan
• Journal: American journal of physiology. Cell physiology (Am J Physiol Cell Physiol) Vol. 314 Issue 1 Pg. C118-C134 (01 01 2018) ISSN: 1522-1563 [Electronic] United States
• PMID: 28978522 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Aminophenols
• Aminopyridines
• Benzodioxoles
• CFTR protein, human
• PTGER4 protein, human
• Quinolones
• Reactive Oxygen Species
• Receptors, Prostaglandin E, EP4 Subtype
• Tobacco Smoke Pollution
• Cystic Fibrosis Transmembrane Conductance Regulator
• ivacaftor
• Cyclic AMP
• lumacaftor

Topics

• Aminophenols (pharmacology)
• Aminopyridines (pharmacology)
• Autocrine Communication (drug effects)
• Benzodioxoles (pharmacology)
• Bronchi (drug effects, metabolism, pathology)
• Calcium Signaling (drug effects)
• Cell Line
• Cyclic AMP (metabolism)
• Cystic Fibrosis (drug therapy, genetics, metabolism, pathology)
• Cystic Fibrosis Transmembrane Conductance Regulator (agonists, genetics, metabolism)
• Epithelial Cells (drug effects, metabolism, pathology)
• Humans
• Mutation
• Oxidative Stress (drug effects)
• Quinolones (pharmacology)
• Reactive Oxygen Species (metabolism)
• Receptors, Prostaglandin E, EP4 Subtype (agonists, metabolism)
• Second Messenger Systems (drug effects)
• Secretory Pathway (drug effects)
• Tobacco Smoke Pollution (adverse effects)