Pathophysiology

CFTR is an anion channel that functions in the regulation of ion transport. It plays multiple roles in fluid and electrolyte transport, including salt absorption, fluid absorption, and anion-mediated fluid secretion (11). Defects in this protein, as described earlier, lead to CF, the morbidity of which is initiated by a breach in host defenses and propagated by an inability to clear the resultant infections (12). Because inflammatory exacerbations precipitate irreversible lung damage, the innate immune system plays an important role in the pathogenesis of CF.

Respiratory epithelial cells containing the CFTR gene also provide a crucial environmental interface for a variety of inhaled insults. The local mucosal mechanism of defense involves mucociliary clearance that relies upon the presence and constituents of airway surface liquid (ASL). The high salt in the ASL of CF patients is found to interfere with the natural antibiotics present in ASL, such as defensins and lysozyme (13). Bales et al. categorizes the role of CFTR in the pathogenesis of CF lung disease into two groups (12). The first describes defects in CFTR that result in altered salt and water concentrations of airway secretions. This then affects host defenses and creates a milieu for infection. The second is associted with CFTR deficiency that results in biologically and intrinsically abnormal respiratory epithelia. These abnormal epithelial cells fail as a mechanical barrier, enhancing the presence of pathogenic bacteria by providing receptors and binding sites or failing to produce functional antimicrobials.

Through multiple mechanisms, the CF patient is compromised in their ability to clear airway colonization and infection. Whereas understanding which immunologic abnormalities are responsible for the disease manifestations leads to more effective therapies, correction of the CFTR defect by gene transfer could ultimately prevent the occurrence or progression of the infectious and inflammatory consequences.

Fig. 1. Schematic illustration of the Invader assay (Third Wave Technologies, Madison, WI).

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