Abstract
The arrival of cystic fibrosis transmembrane conductance regulator (CFTR) modulators as a new class of treatment for cystic fibrosis (CF) in 2012 represented a pivotal advance in disease management, as these small molecules directly target the upstream underlying protein defect. Further advancements in the development and scope of these genotype-specific therapies have been transformative for an increasing number of people with CF (PWCF). Despite clear improvements in CFTR function and clinical endpoints such as lung function, body mass index (BMI), and frequency of pulmonary exacerbations, current evidence suggests that CFTR modulators do not prevent continued decline in lung function, halt disease progression, or ameliorate pathogenic organisms in those with established lung disease. Furthermore, it remains unknown whether their restorative effects extend to dysfunctional CFTR expressed in phagocytes and other immune cells, which could modulate airway inflammation. In this review, we explore the effects of CFTR modulators on airway inflammation, infection, and their influence on the impaired pulmonary host defences associated with CF lung disease. We also consider the role of inflammation-directed therapies in light of the widespread clinical use of CFTR modulators and identify key areas for future research.
Highlights
Cystic fibrosis (CF) is a genetic disease caused by mutations in the CF transmembrane conductance regulator (CFTR) gene, resulting in dysfunctional or absent CFTR protein on the apical membrane of epithelial cells
We examine the pathophysiology of CF inflammation and explore the capacity of CFTR modulators to improve dysregulated inflammation and impaired host responses exhibited by people with CF (PWCF)
These and other unidentified intrinsic abnormalities may contribute to the immune response characteristic of CF, and they are likely to be exacerbated by pro-inflammatory priming that comes from the pathogen as well as the pathogen-associated molecular patterns (PAMP)/damage-associated molecular patterns (DAMP) and cytokine-rich environment of the CF lung
Summary
Cystic fibrosis (CF) is a genetic disease caused by mutations in the CF transmembrane conductance regulator (CFTR) gene, resulting in dysfunctional or absent CFTR protein on the apical membrane of epithelial cells. While CFTR modulators are successful in improving epithelial CFTR expression and function, as evidenced by the near-normalisation of sweat chloride levels and improved clinical outcomes, findings to date suggest that they do not prevent the continued decline in lung function, halt disease progression, or decrease the burden of pathogenic organisms in those with established lung disease [14]. It remains unknown whether their restorative effects extend to dysfunctional CFTR expressed in phagocytes and other immune cells. We consider the potential role for anti-inflammatory therapies in light of the widespread clinical use of CFTR modulators and identify some key areas for future research
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