Diseases of the Airway Epithelia Cystic Fibrosis

Cystic fibrosis (CF) is a life-threatening autosomal recessive disorder caused by mutant cystic fibrosis transmembrane conductance regulator (CFTR), a cAMPregulated chloride channel (Gadsby et al. 2006; Soferman 2006). Patients with CF

have a predisposition to subsequent chronic colonization and infection with bacteria, especially P. aeruginosa, leading to progressive lung destruction. It was postulated that the activity of antimicrobial molecules is compromised by changes in the composition of the airway surface liquid in lungs of CF patients (Smith et al. 1996). The high salt concentration in CF airway fluid, caused by the lack of functional chloride channels, was shown to inhibit salt-sensitive antimicrobial peptides, such as the defensins, from killing bacteria, and subsequently leading to increased susceptibility to infections (Guggino 2001).

Furthermore, it was demonstrated that hBD-2 and hBD-3 are susceptible to degradation and inactivation by the cysteine proteases cathepsins B, L, and S (Taggart et al. 2003). These three cathepsins are present and active in CF bronchoalveolar lavage and incubation of hBD-2 and -3 with CF lavage leads to the degradation of the antimicrobial molecules. These results show that any potential use of host-derived AMP for the treatment of CF should consider the potential inactivation of these proteins by endogenous and bacterial proteases.

Overexpression of LL-37 in CF xenografts was shown to increase the antimicrobial activity of airway surface fluid and to restore bacterial killing (Bals et al. 1999), providing an alternative genetic approach for the treatment of CF based on enhanced expression of an endogenous antimicrobial peptide. LL-37 was also investigated for its role in the regulation of wound closure of the airway epithelium. LL-37 stimulated the healing of mechanically induced wounds and induced cell proliferation and the migration of airway epithelial cells (Shaykhiev et al. 2005).

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