Airway Epithelium Dysfunction in Cystic Fibrosis and COPD

Abstract

Cystic fibrosis is a genetic disease caused by mutations in the CFTR gene, whereas chronic obstructive pulmonary disease (COPD) is mainly caused by environmental factors (mostly cigarette smoking) on a genetically susceptible background. Although the etiology and pathogenesis of these diseases are different, both are associated with progressive airflow obstruction, airway neutrophilic inflammation, and recurrent exacerbations, suggesting common mechanisms. The airway epithelium plays a crucial role in maintaining normal airway functions. Major molecular and morphologic changes occur in the airway epithelium in both CF and COPD, and growing evidence suggests that airway epithelial dysfunction is involved in disease initiation and progression in both diseases. Structural and functional abnormalities in both airway and alveolar epithelium have a relevant impact on alteration of host defences, immune/inflammatory response, and the repair process leading to progressive lung damage and impaired lung function. In this review, we address the evidence for a critical role of dysfunctional airway epithelial cells in chronic airway inflammation and remodelling in CF and COPD, highlighting the common mechanisms involved in the epithelial dysfunction as well as the similarities and differences of the two diseases.

Figure 1

Similarities and differences between cystic fibrosis and COPD. Cystic fibrosis (CF) is a genetic disease caused by mutations in the CFTR gene, while COPD is a multifactorial-acquired disease of later onset predominantly associated with cigarette smoke exposure. Although the diseases are different in many aspects, they also share key phenotypical features. Recent evidence suggests that cigarette smoke induces an acquired CFTR dysfunction in COPD and that both CF and COPD have corresponding molecular phenotypes of CFTR dysfunction resulting in airway surface liquid (ASL) dehydration, mucostasis, bacterial colonization, chronic inflammation, and tissue damage. Airflow obstruction, recurrent infective exacerbations, and a progressive decline in lung function characterize both conditions.

Figure 2

Airway innate immunity. (a) The major pattern recognition receptor (PRR) is the Toll-like receptor (TLR) family which interact with microbial-derived factors or pathogen-associated molecular patterns (PAMPs) such as LPS from P. aeruginosa. LPS-induced activation of TLR induces an IL-8 response via a NF-κB pathway. (b) Important antiproteases and antimicrobial proteins in the lung include AAT, SLPI, elafin, the cathelicidin LL-37, lactoferrin, and the human beta defensins (HBDs); these can be cleaved and inactivated by neutrophil elastase in the CF lung. CBM: capillary basement membrane.

Figure 3

Pathophysiology of airway disease in cystic fibrosis. In cystic fibrosis, loss of normal CFTR function and overactivity of ENaC result in acidification (loss of HCO3⁻ secretion) and dehydration of the airway surface liquid layer (ASL) disrupting the normal mucociliary escalator. This results in an increase in ASL viscosity, mucus plugging, bacterial colonization, and neutrophil-dominated inflammation. An overabundance of bacterial and neutrophil derived proteases degrades important antiproteases and antimicrobial peptides in the CF airways further compounding an already-overwhelmed impaired innate immune system.

Figure 4

Effects of cigarette smoke on CFTR and pathophysiology of airway disease in COPD. Cigarette smoke components (e.g., acrolein and cadmium) can decrease expression and function of the CFTR protein by decreasing CFTR mRNA and protein levels, accelerated CFTR internalization, and decreased channel opening probability (P_o). Increased levels of neutrophil elastase in COPD may worsen CFTR dysfunction by degrading CFTR and upregulating ENaC expression. Loss of CFTR function results in ASL dehydration and acidification, mucus hypersecretion, and mucus plugging leading to reduced mucociliary clearance, chronic inflammation, impaired innate immunity, and infection.