Human Cellular Models for the Investigation of Lung Inflammation and Mucus Production in Cystic Fibrosis

Figure 1

Pathophysiology of CF lung disease. (a) In the healthy state, the CFTR protein inhibits the epithelial sodium channel (ENaC), thereby regulating the absorption of sodium and water from the airway lumen, providing the adequate airway surface homeostasis with effective transport of mucus extruding from the airway surface goblet cells and submucosal glands. Physiological bicarbonate and pH regulation facilitates the formation of an airway surface liquid (ASL) that optimizes mucociliary clearance. Moreover, CFTR regulates transepithelial reduced glutathione (GSH) transport, maintaining the redox potential in the airways. (b) In CF, the absence of CFTR on the apical membrane leads to hyperactivity of ENaC, resulting in hyperabsorption of Na⁺ and water and consequently in reduction of the periciliary liquid (PCL) layer. Mucus transport slows down due to the incapacity of cilia beating with disruption of mucociliary clearance, contributing to mucus stasis also given by goblet cell hyperplasia and submucosal gland hypertrophy. Decreased bicarbonate transport contributes to an acidic pH. Moreover, lower levels of GSH contribute to increased concentration of reactive oxygen species (ROS). This oxidative stress leads to a heightened NF-κB translocation in the nuclei of airway epithelial cells. These events contribute to a proinflammatory airway environment characterized by a massive neutrophil infiltration. Dysregulated macrophages contribute to the high inflammatory burden.