Airway surface hyperviscosity and defective mucociliary transport by IL-17/TNF-? are corrected by ?-adrenergic stimulus br

The fluid covering the surface of airway epithelia represents a first barrier against pathogens. The chemical and physical properties of the airway surface fluid are controlled by the activity of ion channels and transporters. In cystic fibrosis (CF), loss of CFTR chloride channel function causes airway surface dehydration, bacterial infection, and inflammation. We investigated the effects of IL-17A plus TNF-alpha, 2 cytokines with relevant roles in CF and other chronic lung diseases. Transcriptome analysis revealed a profound change with upregulation of several genes involved in ion transport, antibacterial defense, and neutrophil recruitment. At the functional level, bronchial epithelia treated in vitro with the cytokine combination showed upregulation of ENaC channel, ATP12A proton pump, ADRB2 beta-adrenergic receptor, and SLC26A4 anion exchanger. The overall result of IL-17A/TNF-alpha treatment was hyperviscosity of the airway surface, as demonstrated by fluorescence recovery after photobleaching (FRAP) experiments. Importantly, stimulation with a beta-adrenergic agonist switched airway surface to a low-viscosity state in non-CF but not in CF epithelia. Our study suggests that CF lung disease is sustained by a vicious cycle in which epithelia cannot exit from the hyperviscous state, thus perpetuating the proinflammatory airway surface condition.

Automated summary

The activity of ion channels and transporters controls the chemical and physical properties of the fluid on the surface of airway epithelia. In cystic fibrosis (CF), loss of CFTR chloride channel function leads to airway surface dehydration, bacterial infection, and inflammation. IL-17A and TNF-alpha cytokines have been found to upregulate genes related to ion transport, antibacterial defense, and neutrophil recruitment. Treatment with these cytokines also upregulates specific channels and transporters in bronchial epithelia. Importantly, a beta-adrenergic agonist is able to switch the airway surface to a low-viscosity state in non-CF epithelia but not in CF epithelia.