Cystic fibrosis (CF) is the most common lethal genetic disease in Caucasians (1 in 2500 live births). It involves the lungs, sweat glands, pancreas, intestine, liver, and reproductive system, but pulmonary disease causes 90% of the deaths in CF patients. CF is characterized by abnormally thick mucous secretion, which impairs mucociliary transport in the airways and leaves the lungs vulnerable to bacterial infections. Chronic airway infection leads to abnormalities in gas exchange and the pulmonary circulation and ultimately to death by respiratory failure. Treating gastrointestinal complications and enhancing nutrition is important for preserving pulmonary function in CF. Improved treatment of infections has increased the life expectancy for CF patients from infancy to young adulthood, but recent results offer the promise for curing CF with gene therapy.
Abnormal chloride transport occurs in all tissues affected by CF, and this is explained by mutations in the CF transmembrane conductance regulator (CFTR). CFTR is involved in several aspects of mucous secretion in the airways: (1) Normal CFTR acts as a channel for chloride secretion at the apical surface of airway epithelial cells and (2) normal CFTR regulates sodium conductance through different channels by an unknown cell-signaling mechanism. Figure 15 shows that NaCl and water are normally absorbed out of the airways, but secretagogues can stimulate NaCl and mucous secretion into the airways. Normally the NaCl pulls water into the sol layer of the mucus so it is not too sticky and ciliary motion is efficient; this process is impaired in CF.
An autosomal recessive mutation results in deletion of a single amino acid from CFTR in 70% of CF patients. This mutant CFTR does not fold properly in the endoplasmic reticulum and it is catabolized before it can be inserted in the cell membrane. New therapeutic trials have tried (1) correcting ion transport by blocking sodium absorption or stimulating sodium secretion with non-CFTR mechanisms, (2) reducing the stickiness of mucus with enzymes, and (3) rescuing mutant CFTR from defective cell trafficking and stimulating normal membrane insertion. However, the most exciting possibility is that of introducing a normal copy of the CFTR gene into the airway in early life. Lung epithelial cells are easily accessible to gene transfer agents and adenoviruses have been used to deliver normal CFTR and restore chloride secretion in the nasal mucosa of patients for up to 3 weeks. Airway submucosal glands, which are normally rich in CFTR, are not as accessible to such gene transfer. Hence, the future of this therapy depends on delivering the gene to enough cells in the respiratory tract to normalize function throughout the airways and on lengthening the duration of expression of the normal gene product.
defend against oxidant injury, presumably because Po2 is so high in the airways compared to other body compartments.
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