Cystic fibrosis transmembrane conductance regulator in COPD: a role in respiratory epithelium and beyond

Abstract

The cystic fibrosis transmembrane conductance regulator (CFTR) is a crucial ion channel for transport of chloride and bicarbonate anions. Functional roles of CFTR have been identified in a broad range of cell types including epithelial, endothelial, immune, and structural cells. While CFTR has been investigated largely in the context of inborn dysfunction in cystic fibrosis (CF), recent evidence shows CFTR is also affected by acquired dysfunction in chronic obstructive pulmonary disease (COPD). In patients with COPD and smokers, CFTR impairment has been demonstrated in the upper and lower airways, sweat glands and intestines, suggesting both pulmonary and systemic defects. Cigarette smoke, a key factor in COPD development, is the major cause of acquired CFTR dysfunction. Inflammation, bacterial by-products, and reactive oxygen species can further impair CFTR expression and function. CFTR dysfunction could directly contribute to disease manifestation and progression of COPD including disturbed airway surface liquid homeostasis, airway mucus obstruction, pathogen colonisation and inflammation. Mucus plugging and neutrophilic inflammation contribute to tissue destruction, development of dysfunction at the level of the small airways and COPD progression. Acquired CFTR dysfunction in extra-pulmonary organs could add to common co-morbidities and the disease burden. This review explores how CFTR dysfunction may be acquired and its potential effects on patients with COPD, particularly those with chronic bronchitis. The development of CFTR potentiators and the probable benefits of CFTR potentiation to improve tissue homeostasis, reduce inflammation, improve host defence, and potentially reduce remodelling in the lungs will be discussed.

Comparison of a novel potentiator of CFTR channel activity to ivacaftor in ameliorating mucostasis caused by cigarette smoke in primary human bronchial airway epithelial cells

“…The current studies support the hypothesis that small molecule potentiators of CFTR channel activity have the potential to ameliorate mucus obstruction (38,39). Further, our findings show that the efficacy of small molecule potentiators to rescue Wt-CFTR channel activity in CSEexposed airway epithelial cells parallels efficacy in ameliorating CSE associated mucostasis.…”

Reflection confocal microscopy for quantitative assessment of airway surface liquid dysregulation and pharmacological rescue in cystic fibrosis under near-physiological conditions

“…In these patients, a personalized medicine approach including confocal reflection microscopy may help to determine response to therapy and provide access to approved CFTR modulator therapies (13,(56)(57)(58). Beyond CF, studies on ASL dysregulation may provide insights into the pathophysiology of other muco-obstructive lung diseases such as COPD and non-CF bronchiectasis (8,59). In this context, there is interest in targeting alternative ion channels such as ENaC and the alternative Clchannel TMEM16A to increase ASL volume and improve mucociliary clearance in these muco-obstructive lung diseases (8,20,(59)(60)(61).…”

“…Beyond CF, studies on ASL dysregulation may provide insights into the pathophysiology of other muco-obstructive lung diseases such as COPD and non-CF bronchiectasis (8,59). In this context, there is interest in targeting alternative ion channels such as ENaC and the alternative Clchannel TMEM16A to increase ASL volume and improve mucociliary clearance in these muco-obstructive lung diseases (8,20,(59)(60)(61). Quantitative assessment of effects of therapeutic approaches on ASL height on airway epithelial cultures under unperturbed conditions by confocal reflection microscopy may facilitate the discovery and preclinical development of novel therapies aiming to improve airway surface hydration and mucus clearance.…”

“…ENaC and the alternative Clchannel TMEM16A to increase ASL volume and improve mucociliary clearance in these muco-obstructive lung diseases(8,20,(59)(60)(61). Quantitative assessment of effects of therapeutic approaches on ASL height on airway epithelial cultures under unperturbed conditions by confocal reflection microscopy may facilitate the discovery and preclinical development of novel therapies aiming to improve airway surface hydration and mucus clearance.In summary, our study highlights the importance of considering the intricate mechanisms underlying the regulation of epithelial ion transport as well as regulation of the thin ASL covering airway surfaces for studies of the pathophysiology and the development of novel therapeutic strategies for mucoobstructive lung diseases.…”

Pharmacotherapies in Older Adults with COPD: Challenges and Opportunities

“…This risk is greater in older adults, in which advancing age is associated with a decline in the integrity of physical barriers and protection against pathogens, and age-related changes in the immune system are associated with increased susceptibility to infection [ 106 ]. Growing evidence is suggesting that dysfunction of the cystic fibrosis transmembrane conductance regulator (CFTR), an ion transporter that regulates the hydration and viscosity of mucous secretions in the airway, is related to the impaired bacterial phagocytosis and favors recurrent bacterial infections and airway inflammation [ 107 ]. Furthermore, an experimental study in mice has documented that reduced expression of CFTR contributes to airspace enlargement because of aging and in response to cigarette smoke [ 108 ].…”