Cigarette smoke and CFTR: implications in the pathogenesis of COPD

Abstract

Chronic obstructive pulmonary disease (COPD) is a progressive respiratory disorder consisting of chronic bronchitis and/or emphysema. COPD patients suffer from chronic infections and display exaggerated inflammatory responses and a progressive decline in respiratory function. The respiratory symptoms of COPD are similar to those seen in cystic fibrosis (CF), although the molecular basis of the two disorders differs. CF is a genetic disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene encoding a chloride and bicarbonate channel (CFTR), leading to CFTR dysfunction. The majority of COPD cases result from chronic oxidative insults such as cigarette smoke. Interestingly, environmental stresses including cigarette smoke, hypoxia, and chronic inflammation have also been implicated in reduced CFTR function, and this suggests a common mechanism that may contribute to both the CF and COPD. Therefore, improving CFTR function may offer an excellent opportunity for the development of a common treatment for CF and COPD. In this article, we review what is known about the CF respiratory phenotype and discuss how diminished CFTR expression-associated ion transport defects may contribute to some of the pathological changes seen in COPD.

Keywords: CFTR; COPD; calcium-activated chloride channel; cystic fibrosis; epithelial sodium channel (ENaC); mucus stasis; respiratory infections.

Fig. 1.

Environmental effects on airway surface liquid and therapeutic approaches for correcting these defects. Chronic obstructive pulmonary disease is often caused by years of cigarette smoke or exposure to environmental pollutants. These environmental insults lead to decreases in the periciliary layer (PCL) that lines the lungs and increases in mucus production that lead to compromised bacterial clearance, hyperinflammatory responses, and chronic bacterial infections. Mounting evidence also suggests that ion channels, including the chloride channel defective in cystic fibrosis, are decreased in cigarette smokers. Potential therapies are directed toward 1) breaking up the elevated mucus with mucolytics, 2) treatments with antioxidants to diminish the harmful effects of free radicals, 3) the use of bronchodilators and corticosteroids to open up the airways and decrease inflammation, and, most recently, 4) the concept of increasing chloride channel function to increase airway hydration.