Airway Pathophysiology

The CFTR protein is a chloride channel which also transports bicarbonate, and regulates other transporters such as the epithelial sodium channel (ENaC) and other chloride channels. With the exception of the sweat gland, the absence or dysfunction of CFTR in other tissues results in an ionic imbalance leading in the secretion of thick, dehydrated mucus.

In the airways, CFTR plays a major role in determining the airway surface liquid volume and the hydration of mucus. Thus, it plays a major role in airway mucociliary clearance which is a primary innate defence mechanism: when the airway surface liquid volume is normal, it promotes normal ciliary beat and effective clearance of the overlying mucus gel layer in which bacteria are trapped. When the CFTR protein is defective, there is an imbalance between CFTR-dependent chloride secretion and ENaC-mediated sodium absorption. It leads to low volume and dehydration of airway surface liquid, impairing airway mucociliary clearance [Knowles and Boucher, 2002].

CFTR dysfunction also causes impaired bicarbonate secretion and reduced pH of the airway’s surface fluid. This is thought to interfere with the innate immune system's ability to kill bacteria [Pezzulo et al., 2012].

There is a broad agreement that inflammation is an early and important feature of cystic fibrosis lung disease with chronic neutrophilic airway inflammation contributing to injury and remodelling over time [Stoltz et al., 2015]. However it is unclear whether inflammation in the cystic fibrosis lung is due to a primary defect resulting from loss of CFTR function or a secondary consequence of infection. Some data support the hypothesis that mutations in CFTR make epithelial cells intrinsically more pro-inflammatory compared with healthy cells [Stoltz et al., 2015; Cohen-Cymberknoh et al., 2013]. Moreover, recent studies in newborn cystic fibrosis pigs suggest that acute inflammatory responses of airway epithelia are different in the absence of functional CFTR [Bartlett et al., 2016].

These CFTR-related defects in the innate immunity of the airways and the abnormal inflammatory responses trigger a chain of events including mucus stasis and plugging, airway obstruction and chronic infection and inflammation, leading to bronchiectasis and respiratory failure [Stoltz et al., 2015; Mall and Boucher, 2014].

Figure above demonstrates common cystic fibrosis disease pathophysiology Key: PCL, perciliary liquid layer; NL, normal lung; CF, cystic fibrosis.

Figure above demonstrates common cystic fibrosis disease pathophysiology
Key: PCL, perciliary liquid layer; NL, normal lung; CF, cystic fibrosis. [adapted from Ratjen et al., 2009; Knowles & Boucher, 2002].