Effects of airway surface liquid pH on host defense in cystic fibrosis

Abstract

Cystic fibrosis is a lethal genetic disorder characterized by viscous mucus and bacterial colonization of the airways. Airway surface liquid represents a first line of pulmonary defense. Studies in humans and animal models of cystic fibrosis indicate that the pH of airway surface liquid is reduced in the absence of cystic fibrosis transmembrane conductance regulator function. Many aspects of the innate host defense system of the airways are pH sensitive, including antimicrobial peptide/protein activity, the rheological properties of secreted mucins, mucociliary clearance, and the activity of proteases. This review will focus on how changes in airway surface liquid pH may contribute to the host defense defect in cystic fibrosis soon after birth. Understanding how changes in pH impact mucosal immunity may lead to new therapies that can modify the airway surface liquid environment, improve airway defenses, and alter the disease course.

Keywords: ASL; Airway surface liquid; Antimicrobials; Cystic fibrosis.

Figure 1. A simplified model of the airway epithelium

The airway epithelium has two compartments, the surface epithelium and the submucosal gland (SMG) epithelium. The airway surface epithelium includes ciliated and non-ciliated cells, goblet cells, and basal cells (not shown). SMG epithelium includes ciliated duct cells, mucus cells, and serous cells that secrete antimicrobial proteins. ASL provides a barrier between the epithelium and inspired air. ASL is composed of two layers, a mucus (gel) layer and periciliary liquid. The periciliary liquid covers the cilia, providing an environment for the beating of the cilia and ASL clearance when pathogens become trapped. Various antimicrobials are found in ASL.

Figure 2. Schematic of proteins contributing to acid and base transport across the apical membrane of the airway epithelium

H⁺ and HCO₃⁻ secretion help regulate ASL pH. CFTR provides a major HCO₃⁻ conductance that is lost in CF. Other sources of HCO₃⁻ transport across the apical membrane of airway epithelial cells include Ca²⁺-mediated HCO₃⁻ secretion (CaCC) and pendrin, a Cl⁻/HCO₃⁻ exchanger. H⁺ channels, V-ATPase, and H⁺/K⁺ ATPase are three apical membrane proteins that contribute to the acidification of ASL. We note that basolateral transport mechanisms and the paracellular pathway are also important to these processes (not shown).

Figure 3. A scheme for how changes in ASL pH may influence CF pathogenesis

CF is caused by loss of CFTR function, an anion channel that conducts Cl⁻ and HCO₃⁻. Loss of CFTR function results in decreased HCO₃⁻ conductance across airway epithelial cells leading to decreased ASL pH. Many antimicrobials have reduced activity at a low pH. Cilia beat frequency is also reduced at lower pH values and mucins increase in viscosity as pH falls, leading to decreased mucociliary clearance. Phagocytic cell function may also be reduced in environments with lower pH. This decrease in antimicrobial activity subsequently contributes to respiratory infections in the CF airway, caused by both viral and bacterial pathogens.