Cigarette Smoke-Induced Acquired Dysfunction of Cystic Fibrosis Transmembrane Conductance Regulator in the Pathogenesis of Chronic Obstructive Pulmonary Disease

Abstract

Chronic obstructive pulmonary disease (COPD) is a disease state characterized by airflow limitation that is not fully reversible. Cigarette smoke and oxidative stress are main etiological risks in COPD. Interestingly, recent studies suggest a considerable overlap between chronic bronchitis (CB) phenotypic COPD and cystic fibrosis (CF), a common fatal hereditary lung disease caused by genetic mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Phenotypically, CF and COPD are associated with an impaired mucociliary clearance and mucus hypersecretion, although they are two distinct entities of unrelated origin. Mechanistically, the cigarette smoke-increased oxidative stress-induced CFTR dysfunction is implicated in COPD. This underscores CFTR in understanding and improving therapies for COPD by altering CFTR function with antioxidant agents and CFTR modulators as a great promising strategy for COPD treatments. Indeed, treatments that restore CFTR function, including mucolytic therapy, antioxidant ROS scavenger, CFTR stimulator (roflumilast), and CFTR potentiator (ivacaftor), have been tested in COPD. This review article is aimed at summarizing the molecular, cellular, and clinical evidence of oxidative stress, particularly the cigarette smoke-increased oxidative stress-impaired CFTR function, as well as signaling pathways of CFTR involved in the pathogenesis of COPD, with a highlight on the therapeutic potential of targeting CFTR for COPD treatment.

Figure 1

Model of airway surface dehydration (mucus hyperconcentration) in chronic obstructive pulmonary disease (COPD). The healthy airway surface (left panel) is covered with a thin film of mucus able to entrap inhaled insults that are constantly removed from the lungs by mucociliary clearance. The proper function of this innate airway defense mechanism largely relies on the function of CFTR, ENaC, and other alternative Cl⁻ channels. In the COPD airway (right panel), the dysfunction of CFTR-mediated chloride channel leads net absorption of sodium leads to dehydration of airway surfaces, decreases ASL volume, and impairs mucus stasis and clearance.

Figure 2

Signaling of oxidative stress activated by cigarette smoke. Cigarette smoke induces oxidative signaling and inflammatory responses. In this respect, cigarette smoke induces ROS production and impairs CFTR function, which is also a trigger of oxidative stress to activate the dioxin receptor-mediated signaling pathway and induce ROS production and cell cycle arrest or apoptosis and other signaling pathways.

Figure 3

The cystic fibrosis transmembrane conductance regulator (CFTR) is a potential target for COPD treatment. The proper CFTR function is critical in maintaining the homeostasis of airway surface hydration and mucociliary clearance of normal airway epithelia. Cigarette smoke is able to induce excessive mucus secretion and has a negative impact on CFTR activation. The consequences of genetic and acquired CFTR dysfunction in patients with CB and COPD lead to a disreputable homeostasis of mucus and decreased ASL volume. The dehydrated mucus impairs the mucus clearance. Therefore, strategies that restore the CFTR function at different levels (mRNA and protein expression, stability, CFTR gating, and trafficking) using CFTR modulators (potentiator/corrector) and cAMP agonist (PDE inhibitors) may provide novel therapeutic approaches in obstructive pulmonary diseases, such as CB of COPD. The image on the left panel shows the cigarette smoke-induced CFTR dysfunction at different levels, and that in right the panel shows potential therapeutic interventions to restore CFTR function in cigarette smoke-exposed CFTR dysfunction. The red blocked line indicates an inhibition, and the green line with arrow represents an induction.