Cystic fibrosis: to ion transport and beyond

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The measurement of sweat electrolytes successfully diagnoses all but a tiny minority of patients with cystic fibrosis (CF). The discovery of a gene for CF, encoding the cystic fibrosis transmembrane conductance regulator (CFTR), has led to the understanding that CFTR is a chloride channel (hence the utility of the measurement of sweat electrolytes) and also regulates other ion channels, in particular the sodium transporter, ENaC. Measurement of transepithelial potential differences suggested that ENaC overactivity is pivotal in CF lung disease 1. The CF mouse was found to have a poor lower airway phenotype for human CF lung disease, but the ENaC β-subunit overexpressing mouse was a much better model for the devastating human CF lower airway disease 2. Indeed, CFTR dysfunction, perhaps induced by tobacco smoke exposure, has been implicated in chronic obstructive pulmonary disease (COPD) 3. After some controversy, a mechanism linking ion transport to CF lung disease was proposed 4; the airway surface liquid (ASL) height was found to be equal in CF and normal airway cell monolayers if they were subjected to phasic contraction and relaxation, but in the presence of infection with respiratory syncytial virus, CF monolayers had reduced ASL height, and thus impaired mucociliary clearance 5, presumably accounting for the susceptibility to airway infection, inflammation and ultimately death by respiratory failure. So, CF and spin-off CFTR …