CFTR dysfunction in cystic fibrosis and chronic obstructive pulmonary disease

Abstract

Obstructive lung diseases such as cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD) are causes of high morbidity and mortality worldwide. CF is a multiorgan genetic disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene and is characterized by progressive chronic obstructive lung disease. Most cases of COPD are a result of noxious particles, mainly cigarette smoke but also other environmental pollutants. Areas covered: Although the pathogenesis and pathophysiology of CF and COPD differ, they do share key phenotypic features and because of these similarities there is great interest in exploring common mechanisms and/or factors affected by CFTR mutations and environmental insults involved in COPD. Various molecular, cellular and clinical studies have confirmed that CFTR protein dysfunction is common in both the CF and COPD airways. This review provides an update of our understanding of the role of dysfunctional CFTR in both respiratory diseases. Expert commentary: Drugs developed for people with CF to improve mutant CFTR function and enhance CFTR ion channel activity might also be beneficial in patients with COPD. A move toward personalized therapy using, for example, microRNA modulators in conjunction with CFTR potentiators or correctors, could enhance treatment of both diseases.

The Potential Role and Regulatory Mechanisms of MUC5AC in Chronic Obstructive Pulmonary Disease

“…In CFTR, the interactions of ATP and CFTR’s nucleotide-binding domains control the opening and closing of the channel, rather than driving solute transport. Deletion of F508 on CFTR causes its retention in the endoplasmic reticulum, reducing CFTR open probability, and its residence time in the plasma membrane [ 81 , 82 ]. Upon CFTR activation, Cl − and HCO 3 − are extruded into the airway lumen, with Na + and H 2 O following passively through the paracellular pathway.…”

“…CFTR mutations cause cystic fibrosis (CF), an airway disease that phenotypically resembles COPD and is characterized by chronic bronchitis. Acquired CFTR dysfunction may influence COPD pathogenesis, making CFTR a potential anti-COPD target [ 81 , 82 ]. Ivacaftor, a CFTR activator, reverses CFTR dysfunction in vitro by activating wild-type CFTR-dependent, short circuit current following chronic exposure.…”

The Potential Role and Regulatory Mechanisms of MUC5AC in Chronic Obstructive Pulmonary Disease

“…In CFTR, the interactions of ATP and CFTR's nucleotide-binding domains control the opening and closing of the channel, rather than driving solute transport. Deletion of F508 on CFTR causes its retention in the endoplasmic reticulum, reducing CFTR open probability, and its residence time in the plasma membrane [81,82]. Upon CFTR activation, Cland HCO3are extruded into the airway lumen, with Na + and H2O following passively through the paracellular pathway.…”

Acquired cystic fibrosis transmembrane conductance regulator dysfunction

“…Chronic bronchitis, like CF, is characterized by overproduction, poor clearance, and accumulation of hyperviscous mucus within the small airways. 30 , 42 , 43 Sloane et al 31 revealed reduced CFTR activity measured by nasal potential difference (NPD) was also predictive of the severity of bronchitis symptoms, even when controlled for cigarette smoking, indicating a significant association with the chronic bronchitis phenotype. Individuals with smoking related COPD exhibited a decreased CFTR expression (mRNA levels) and reduced activity, (approximately 50%) measured by NPD in the upper and lower airway.…”