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New therapeutic approaches for cystic fibrosis lung disease.

Cystic fibrosis (CF) results from a variety of mutations in the gene encoding the CF transmembrane conductance regulator (CFTR) protein, a cAMP-regulated chloride channel in epithelial cells1–3. Dysfunction of CFTR is due either to lack of production, failure of the protein to reach its site of action on the apical membrane of the cell, or to defects in function4. The end result is abnormal ion transport at the apical surface of epithelial cells. Although CFTR protein is expressed in many organs, the clinical picture is dominated by disease in the respiratory, gastrointestinal and reproductive tracts, relating in each of these sites to impaired clearance and obstruction by viscous secretions. Of these sites, pulmonary disease accounts for most of the morbidity associated with CF, and is the cause of death in over 90% of patients5. The hallmarks of CF lung disease are persistent infection with a relatively narrow range of bacteria and early, severe and sustained neutrophil-mediated inflammation6. The relationship between the underlying molecular defect and the clinical picture of CF is complex and incompletely understood. The lungs in CF are thought to be normal at birth7 but begin to show microscopic inflammatory changes in early infancy8. Some studies have detected such inflammation in the absence of culturable pathogens9, which has led to much interest in the possibility that the CFTR defect in itself is somehow pro-inflammatory. This remains, however, highly controversial, with other well-conducted clinical and laboratory studies failing to support this hypothesis10. Resolving this issue is of importance, as much interest has focused recently on an anti-inflammatory approach to treatment. Within the CF airway, bacterial infection occurs early and is difficult to eradicate. Several explanations for the predisposition of the CF airway to infection have been postulated, the simplest being those related to airway surface liquid (ASL). Here again, two opposing theories exist regarding the nature and effects of such abnormalities. In the low-volume hypothesis, the thin layer of ASL is depleted due to sodium and water hyperabsorption, leading to defective mucociliary clearance11. Mucus plugs build up within which, due to the increased metabolic activity of CF cells, a hypoxic environment ensues, which may favour the survival of bacteria such as Pseudomonas aeruginosa, and the switching on of genes such as those leading to the mucoid phenotype and those involved in biofilm formation. In an alternative hypothesis, the high-salt theory, the levels of both chloride and sodium in the ASL are high with respect to plasma12, leading to dysfunction of saltsensitive antibacterial defence proteins including bdefensins, lysozyme and lactoferrin. Available in vivo data in CF subjects favours the former hypothesis, as ASL electrolyte levels do not differ from non-CF values13. In addition to chloride and sodium ion transport, CFTR function has also been shown to be important in the transport of the antioxidant glutathione14, sulphation of mucins15 and sialylation of cell surface glycoconjugates16. The asialylated form of cell surface glycolipids, which are found more frequently on the surface of CF cells, act as receptors for both P. aeruginosa and Staphylococcus aureus, pathogens important in the progression of CF lung disease17. Another study has reported that CFTR binds and internalizes bacteria, leading to defective elimination of organisms by the CF airway18. However, the relevance of each of these postulated mechanisms is unclear.