Cystic fibrosis transmembrane conductance regulator protein: what is its role in cystic fibrosis?

Cystic fibrosis (CF) is a disease involving many organs including sweat glands, pancreas, gastrointestinal tract and airways. Disordered airway function is the main cause of illness and death in the increasing numbers of CF sufferers who survive infancy. At one time it was thought that a circulating CF factor or factors might cause the airway malfunction, but studies of normal lungs transplanted into CF patients have called this into question. Airways in normal lungs transplanted into CF patients have a normal epithelial potential difference and show only the same rate of infection with Pseudomonas aeruginosa and Staphylococcus aureus as do lungs transplanted into non-CF recipients [1]. Thus, the airway lesions in CF seem to depend in large part on the local expression of a disordered gene, probably within the mucosa. It is now just over three years since the gene locus responsible for CF was found and its gene cloned and sequenced [2, 3, 4]. The gene product is a membranespanning protein, cystic fibrosis transmembrane conductance regulator (CFTR), which acts as a chloride channel regulated via the cyclic AMP (cAMP) pathway [5]. In cells from CF patients, stimulation of cAMP release fails to open the channel. However, introduction of DNA coding for the correct protein into these cells restores their ability to conduct chloride via this channel [6]. This and other observations led to the hypothesis that lack of functional CFTR protein in the apical membrane of the epithelium leads to the abnormalities seen in CF lungs [7]. Surface epithelium reabsorbs sodium ions from the liquid in the airway lumen and can secrete chloride into it. In man Na+ reabsorption is the chief ion movement. Water moves along the osmotic gradient created by ion movements. In patients with CF, chloride movement into the lumen cannot be stimulated by cAMP and sodium reabsorption is greater than normal, though the reason for this is unknown. It has been suggested that these abnormalities would dehydrate mucus, giving it abnormal physical properties, and reduce the layer of periciliary fluid, both of which would slow mucociliary clearance. This in turn might explain why CF airways are liable to infection. This hypothesis is seductive but cannot explain the entire pathophysiology of the CF airway. For example, patients with 'immotile cilia syndrome'