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COMMENTARY COMMENTARY

What it takes for a to expel mucus from the airway Burton F. Dickeya,1

Cough is one of the most common symptoms for beating of cilia on epithelial cells that are interspersed seeking medical care (1, 2). If cough is going to cause among secretory cells in a mosaic pattern (Fig. 1, that much trouble, it better be worth it, and the clinical Lower Right). Inhaled particles and land evidence is that indeed it is. Patients with impaired on the mucus layer and are moved by cilia up the cough due to neuromuscular disease or postoperative , through the vocal cords, and then swallowed sedation suffer high rates of and pneumo- and cleared by the (Fig. 1, Upper nia due to the failure to clear secretions from the air- Right). Topologically, the is a blind sac, so with- ways, and there is evidence that a heightened cough out the clearance of particles and pathogens by a mo- reflex improves health (3, 4). Chief among airway se- mucus layer, these materials would accumulate. cretions is mucus, and, in PNAS, Button et al. (5) ana- In contrast, the gastrointestinal tract is an open tube lyze the biophysical requirements for a cough to through which particles and pathogens pass readily. separate adherent mucus from an airway wall. Before The mucus layer is generated by the secretion of mu- diving into the details, it is worth reviewing what is cins from surface epithelial cells (Fig. 1, Lower Right) known about the biochemistry of mucus and the and submucosal (not illustrated). Ciliary beat- forces generated by a cough. ing is the primary mechanism for clearance of mucus, Mucus is an important defense against perturba- with cough being a backup mechanism when mucus tions from the outside world at wet epithelial surfaces accumulates in the airways or adheres to airway walls throughout the body, including the eyes, airways, (3, 11). gastrointestinal tract, and genitourinary tract. Its im- Cough has been studied extensively, so its mech- portance is revealed when the mucus barrier malfunc- anism and the forces it generates are well known (12). tions in disorders such as dry eyes or inflammatory A cough begins with a rapid inspiration to fill the bowel disease. Mucus is a remarkable and protean with air, followed by closure of the glottis, contraction substance, with properties on the border between a of the expiratory muscles of the chest and abdomen to viscous fluid and a soft elastic solid. Its properties generate a high intrathoracic pressure, and the sud- primarily reflect the interactions of glycopro- den opening of the glottis to forcefully expel air from teins (∼0.5% of mass) with water (∼98%) and salts the mouth. During coughing, intrathoracic pressure

(∼1%). Globular proteins are also present in normal can reach 200 cmH2O, which both provides the mo- mucus (∼0.5% of mass) but do not have a major impact tive force for airflow (up to 8 L/s) and narrows the on the physical properties of mucus unless they and central airways by compression (Fig. 1, Middle Right) DNA are present in abnormal amounts during patho- to maximize velocity (up to 28,000 cm/s or 626 mi/h). logic processes (3). are very large highly gly- This expels secretions from the airways and into the cosylated molecules, accounting for their avid throat () (Fig. 1, Left), where they can be either interactions with water. Secreted mucins polymerize swallowed or expectorated. What has been almost into chains and networks that confer on mucus its entirely unknown until now is how the shear force gen- semisolid consistency. However, the physical proper- erated by cough interacts with adherent mucus in ties of mucus are highly dependent on mucin concen- the airways. tration, with dilute mucus acting like a fluid, and To address this issue, Button et al. (5) first devel- concentrated mucus like a solid (6). Furthermore, di- oped a conceptual model whereby adherent mucus lute mucus is an excellent lubricant, whereas concen- could be separated from the airway wall either by co- trated mucus is adhesive (7–10). hesive or adhesive failure. Cohesive failure involves In the lungs, a layer of mucus is continuously fracture of the adherent mucus by physically breaking propelled from peripheral to central airways by the mucins and other polymers within the mucus, whereas

aDepartment of Pulmonary Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030 Author contributions: B.F.D. wrote the paper. The author declares no conflict of interest. Published under the PNAS license. See companion article on page 12501. 1Email: [email protected]. Published online November 20, 2018.

12340–12342 | PNAS | December 4, 2018 | vol. 115 | no. 49 www.pnas.org/cgi/doi/10.1073/pnas.1817484115 Downloaded by guest on September 30, 2021 Fig. 1. The pulmonary mucus clearance system. Mucins are synthesized by secretory cells in the airway surface (Lower Right)andin submucosal glands (not shown). Secreted mucins rise through the periciliary layer and combine with water and salts to form an overlying layer of mucus that is propelled from peripheral to central airways by the beating of cilia. Normally, cilia propel a thin layer of mucus up the trachea and through the larynx at the posterior commissure (Upper Right), which is covered by mucociliary epithelium (unlike the vocal cords, which are covered by squamous epithelium), and then into the pharynx where it mixes with from the mouth and is swallowed into the (Left). During a cough, central airways narrow (Middle Right), and globs of mucus are propelled forcefully by a column of air moving at high velocity directly into the pharynx where they are either swallowed or expectorated, while some small fragments of mucus break off to travel as droplets with the expired air (20). Image courtesy of The University of Texas MD Anderson Cancer Center.

adhesive failure involves separating the adherent mucus from the protection comes at a price because the MUC5B-overexpressing glycocalyx of the underlying cell surfaces (see figure 1 of ref. 5). allele is the major risk factor for idiopathic pulmonary fibrosis late Next, they set up a peel-testing device to measure the force re- in life, probably as a result of epithelial progenitor depletion quired to peel an adherent mucus layer off a layer of airway epi- caused by the proteostasis stress of producing high levels of thelial cells to test their model. This system was also used to assess this large and complex molecule (14, 15). the roles of mucin concentration and pH in determining the Far more common than the problems that MUC5B hyper- strength of mucus cohesion and adhesion, finding that the effects expression causes in pulmonary fibrosis are the central roles that of mucin concentration dominated over pH within physiologic mucus dysfunction plays in obstructive diseases of the airways ranges of these two parameters. Last, they assessed the effects such as asthma, chronic obstructive pulmonary disease (COPD), of therapeutic modalities such as mucus hydration with so- and (CF). In asthma, mucus dysfunction is mostly lution, mucin polymer lysis with a reducing agent to break disul- due to hyperproduction of the other secreted airway mucin, fide bonds, and decreasing cohesion and adhesion with a MUC5AC, together with the abnormal presence of plasma surfactant. Each of these modalities provided benefit when used proteins, both resulting from inflammation as part of aberrant alone, and the combination of hydration and mucin lysis was defenses (16). In CF, mucus dysfunction is due to in- particularly effective. sufficient chloride and bicarbonate transport into the airway lu- The mobile mucus layer is an essential defense of mammalian men to allow adequate mucin hydration and expansion (17). In lungs, as shown by the death of mice from infection, inflammation, COPD, mucus dysfunction is due to a combination of the mech- and obstruction when the major secreted airway mucin, Muc5b, is anisms operating in asthma and CF, as well as to ciliary dysfunc- deleted (13). The importance of this defense to human health is tion, all induced by cigarette smoke (3). In these disorders, mucus highlighted by the fact that an overexpressing allele of MUC5B both accumulates in large central airways and plugs small periph- has been so strongly selected that it is present in 20% of whites eral airways. Accumulated mucus in central airways is cleared rel- (14), similar to the allele frequency of sickle in areas atively effectively by cough because, at that level, airflow is high of hyperendemic malaria. Also similar to sickle hemoglobin, and mucus is not as concentrated as in peripheral airway plugs.

Dickey PNAS | December 4, 2018 | vol. 115 | no. 49 | 12341 Downloaded by guest on September 30, 2021 However, in small airways, airflow during coughing tapers off pe- the benefits of the complex biological defense mechanism that is ripherally, and concentrated mucus becomes impacted. A radio- mucus clearance, while minimizing the adverse effects of mucus graphic imaging study in subjects with asthma has shown that dysfunction (19). peripheral airway mucus plugs persist for years (18). Airways of intermediate size and distance from the trachea are where work Acknowledgments like that of Button et al. (5) is likely to have the biggest impact. The I thank David M. Aten, MA, CMI, for the artwork. This research is supported by careful definition of forces involved in clearing mucus adherent to the NIH National Heart Lung and Blood Institute Grant R01 HL129795, the NIH airway walls by cough, combined with analysis of the interactions National Institute of and Infectious Diseases Grant R21 AI137319, and of new mucus therapies with these forces, will allow us to derive the Cystic Fibrosis Foundation Grant DICKEY18G0.

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12342 | www.pnas.org/cgi/doi/10.1073/pnas.1817484115 Dickey Downloaded by guest on September 30, 2021