Cystic fibrosis, gene therapy, and lung inflammation: for better or worse?

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Abstract
CFTR mutations and cystic fibrosis lung pathophysiology. Cystic fibrosis is the most common autosomal recessive disorder in the Caucasian population, with a frequency of ∼1 in 2,500 live births. It is caused by defective function of the cftr gene product (14), which encodes a 170- to 180-kDa protein that functions as a cAMP-regulated chloride channel. The CFTR protein is expressed normally in those tissues affected in cystic fibrosis, including airway submucosal glands and airway epithelial cells. The cystic fibrosis respiratory disease phenotype includes thick mucus secretion and bacterial colonization of the lung with a select few bacterial pathogens, including Pseudomonas aeruginosa (13). Repeated P. aeruginosa infections compounded by an inability to clear this organism result in a profound neutrophil migration into the airways and secretion of a variety of inflammatory mediators, including neutrophil elastase, reactive oxygen species, and inflammatory cytokines, which cause irreversible damage to the airways and gas-exchange components.

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