Effective Mucus Clearance Is Essential for Respiratory Health

Abstract

A coordinated system of epithelial water and ion transport, mucin secretion, cilia action, and cough, collectively termed “mucus clearance,” results in the continuous flow of fluid and mucus over airway surfaces. The study of mucus clearance has a fascinating history, and was investigated using “classical” particle clearance physiologic techniques 25–30 yr ago (reviewed in Ref. 1). Despite advances made by pioneering scientists, it was clear that “the factors which normally control [airway surface liquid] secretion in such a manner as to prevent flooding or drying of the airways and facilitate mucociliary transport are still largely unknown” (2). Subsequently, mucus clearance per se has received less attention, as greater emphasis was placed on cellular and molecular aspects of pulmonary pathophysiology. Furthermore, the pathogenic importance of mucus transport was questioned due to minimal impact of mucolytic therapy on airway diseases. From her early work on the lungs' secretory apparatus (3), to her generation of valuable tools to study mucous cells (4, 5), through her landmark cloning of the MUC5AC promoter (6), and recent studies of detailed signal transduction mechanisms in bacterial infection (7) and after smoke exposure (8), it is clear that Carol B. Basbaum recognized the importance of mucus clearance for respiratory health. We consider it an honor and privilege to summarize recent advances in the field of mucus clearance as a tribute to her in the American Journal of Respiratory Cell and Molecular Biology. Rather than a comprehensive review of the entire field and its literature, we present eight topics that build on recent observations and also point toward future studies needed to advance this field. As background, it is important to understand that water transport across the apical plasma membrane of airway epithelial cells, and thus the hydration status of airway surface liquid (ASL), is principally regulated by Cl− ion export through both the cystic fibrosis transmembrane conductance regulator (CFTR) and Ca++ activated chloride channels (CaCC), and by Na+ influx through the epithelial Na+ channel (ENaC) (Figure 1). Open in a separate window Figure 1. A depiction of ion transport across the apical plasma membrane of airway epithelial cells. Schema describing extracellular nucleotide/nucleoside biochemical networks, sensors (receptors), and regulatory paths controlling effectors (ion channels). Cl− can egress through CFTR after adenosine stimulation of A2b-R or through CaCC after stimulation of P2Y2-R by ATP. Na+ transport is facilitated by ENaC. CF cells will not be able to mount a Cl− response after adenosine due to the absence of functional CFTR. Finally, adenosine (ADO) and inosine (INO) are removed from the airway surface by concentrative nucleoside transporters (CNTs) (63).