Unravelling salt transport in cystic fibrosis

Cystic fibrosis (CF) lung disease is characterised by thick viscid airway secretions, the development of progressive airways obstruction and bronchiectasis, and colonisation with specific bacteria, notably Pseudomonas aeruginosa.¹ Although the precise pathogenic pathways in CF are still debated (see below), airway epithelial ion transport has been known to be defective in CF for two decades. This can be assessed in the airway in vivo by measuring potential difference (PD)—that is, the voltage generated across an electrically tight epithelium by the active transport of charged sodium and chloride ions.² In patients with CF the magnitude of sodium absorption across airway epithelia and the response to the sodium channel blocker amiloride are substantially increased compared with normal subjects, coupled with an inability to secrete chloride ions.³ In the 1990s the putative gene (the cystic fibrosis transmembrane conductance regulator (CFTR) gene) was cloned⁴ and the affected protein was identified as a gated chloride channel,⁵ supporting the hypothesis that CF is linked to abnormal transepithelial ion transport.

Despite this clear link between abnormal ion transport and CF, the pathogenesis of lung disease in CF is complex, and much effort has been expended trying to elucidate the pathways involved in the development of airways disease. One hypothesis suggests that lung disease in CF develops in large part because of the deranged ion transport, resulting in a reduction in airway surface liquid volume and compromised mucociliary clearance.⁶ These abnormal mechanisms set up a cycle of retained airway secretions, accumulation of mucus with infection and inflammation in the airways, ultimately leading to airway destruction, respiratory failure, and death from lung disease.

Recent in vitro studies on airway cell cultures grown to confluence with an air/liquid interface have yielded further insights …