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.

Oxidative stress, autophagy and airway ion transport

“…Persistent low-dose CSE exposure, however, caused a gradual decrease in CFTR expression and function (233). This result was similar to previously reported effects of CSE on airway epithelial cells that caused CFTR internalization and a reduction in CFTR-C22 OXIDATIVE STRESS, AUTOPHAGY AND AIRWAY ION TRANSPORT dependent anion secretion (33,203). However, internalized CFTR did not colocalize with lysosomes but, instead, associated with intermediate filament proteins that were ultimately transported into perinuclear aggresome-like structures, similar to those in cells expressing ⌬F508-CFTR mutant channels (33,98).…”

“…A link between oxidative stress and autophagy has been described in studies involving the effects of CS on the airway epithelium (162,185,250). CS is a robust source of oxidants capable of producing oxidative stress and inhibition of anion secretion resulting from loss of CFTR function (203). In experiments where CSE was used to produce acquired CFTR dysfunction, treatment with GSNO or S-nitrosoglutathione reductase inhibitor significantly prevented the decrease in plasma membrane CFTR expression.…”

“…Moreover, there is evidence that oxidizing conditions directly slow the rate of CFTR gating and decrease the frequency of subconductance openings by a mechanism involving oxidation of cysteine residues within the nucleotide-binding domains (78). Oxidant stress also diminishes CFTR mRNA and protein expression following several hours of sublethal oxidant exposure, producing a more sustained reduction in anion secretion (21,23,203). Furthermore, experiments testing the effects of a cell-free filtrate of Pseudomonas aeruginosa demonstrated inhibition of anion secretion in human airway epithelial cells resulting from decreased endocytic recycling of CFTR that was associated with an overall decrease in channel expression in the apical membrane (209).…”

“…Airborne pollutants, tobacco smoke, and various environmental allergens are known to induce oxidative stress and alter the ion transport properties of the airway epithelium. A direct effect of tobacco smoke, for example, at low concentrations was a biphasic effect on ion transport, initially stimulating anion secretion, while chronic exposure or higher dosages inhibit apical expression of ion channels (e.g., CFTR and C25 OXIDATIVE STRESS, AUTOPHAGY AND AIRWAY ION TRANSPORT KCa1.1/KCNMA1) that directly participate in production of ASL (33,187,203,233). The acute increase in anion secretion was shown to be ROS-dependent and to stimulate autocrine signaling, similar to the effects of oxidative stress following allergen exposure, although different signaling molecules are involved.…”

“…However, the acquired inhibition of CFTR-dependent anion secretion associated with oxidative stress results from decreases in CFTR gene expression (23), internalization, and aggresomal accumulation (33). The disruption of normal autophagy associated with acquired CFTR dysfunction is comparable to observations with cells expressing the ⌬F508-CFTR mutation, where restoration of autophagy with cysteamine, a compound with antioxidant, antimicrobial, and mucolytic properties, has been shown to be effective in facilitating CFTR trafficking to the apical membrane (132,203). The antioxidant properties of cysteamine may also suppress activation of ANO6, thus potentially limiting phospholipid scrambling and Cl Ϫ channel function linked to volume changes and cell death.…”