Restoring airway epithelial homeostasis in Cystic Fibrosis

Abstract

Cystic fibrosis (CF), the most common life-threatening genetic disorder in Caucasians, is caused by recessive mutations in the Cystic Fibrosis Transmembrane Regulator (CFTR) gene encoding a chloride ion channel. Aberrant function of CFTR involves mucus- and sweat-producing epithelia affecting multiple organs, including airways and lungs. This condition facilitates the colonization of fungi, bacteria, or viruses. Recurrent antibiotic administration is commonly used to treat pathogen infections leading to the insurgence of resistant bacteria and to a chronic inflammatory state that jeopardizes airway epithelium repair. The phenotype of patients carrying CFTR mutations does not always present a strict correlation with their genotype, suggesting that the disease may occur because of multiple additive effects. Among them, the frequent microbiota dysbiosis observed in patients affected by CF, might be one cause of the discrepancy observed in their genotype-phenotype correlation. Interestingly, the abnormal polarity of the CF airway epithelium has been observed also under non-infectious and non-inflammatory conditions, suggesting that CFTR dysfunction "per se" perturbs epithelial homeostasis. New pathogen- or host-directed strategies are thus needed to counteract bacterial infections and restore epithelial homeostasis in individuals with CF. In this review, we summarized alternative cutting-edge approaches to high-efficiency modulator therapy that might be promising for these patients.

Keywords: Antimicrobials; Cystic fibrosis; Epithelial homeostasis; Inflammation; Phage therapy.