Update in Cystic Fibrosis 2008

Cystic fibrosis (CF) is caused by mutations in the cystic fibrosis transmembrane regulator (CFTR) gene, and more than 1,500 distinct mutations with different functional consequences have been reported in the CFTR database (1). Multiple organs are involved in the disease process, but lung disease continues to account for the majority of morbidity and mortality in patients with CF. Knowledge about the pathophysiology of cystic fibrosis has greatly increased in recent years and CF has evolved into a model demonstrating how a better understanding of the underlying defect can lead to novel therapeutic approaches. However, complex interactions exist between CFTR and other regulatory proteins and all of the relevant components that cause disease manifestations both in the lung and in other organ systems are still incompletely understood. A large body of evidence supports the concept that airway surface liquid depletion is a key component in the development of CF lung disease. This is thought to be the consequence of an imbalance in defective chloride secretion and enhanced sodium absorption that has been consistently observed in studies of CF epithelium. The net fluid loss on the airway surface leads to the collapse of cilia and impaired mucociliary transport. However, regulation of mucociliary clearance is a dynamic process involving other epithelial channels that are thought to play an important role in stress-induced increases in airway surface liquid (ASL) height (2). These CFTR independent pathways are functional in CF and can be up-regulated by both external and internal stimuli, such as ATP, which may explain why mucociliary clearance is reduced but not absent in patients with CF (2). Improving airway surface hydration either with pharmacological agents or osmotic agents, such as hypertonic saline, has become an important therapeutic target in CF (3, 4).