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Many other stimuli that increase MUC5AC and Muc5ac expression, such as viruses,31 the smoke component acrolein,40and the cytokines interleukin-4, 9, 17, 23, and 25,52-54 do so, at least in part, through interleukin-13. Overexpression of proinflammatory cytokine interleukin-1β or interleukin-17 increases Muc5ac expression,32,54 whereas interleukin-6 and tumor necrosis factor α do not themselves increase Muc5ac expression but do so indirectly by augmenting the intensity of allergic inflammation.55,56 The control of MUC5B and Muc5b expression is less well understood.57

Mucin Secretion

The secretion of polymeric mucins is regulated separately from mucin production.50,58 The most important secretagogue for surface epithelium appears to be ATP, which acts on apical membrane P2Y₂ receptors.59-61 It is not yet clear whether other agonists such as acetylcholine or histamine directly activate receptors on airway epithelial cells or induce airway smooth-muscle contraction leading to ATP release.59,62-64 The continuous presence of low levels of ATP in airway-surface liquid (see below) causes continuous low activity of the secretory machinery, resulting in the steady release of mucins that provide a normal barrier. When mucin production is increased so that mucins accumulate intracellularly (Figure 3B), and secretion of a large number of granules is then triggered (mucus hypersecretion) (Figure 3C), airway luminal occlusion can occur.13,65-67 It might seem that the secretion of a mucin granule would result in no net change in the volume of luminal air space if epithelial-cell volume decreased by the same amount as the volume of secreted mucin. However, mucins are stored in dehydrated form within secretory granules, and they swell to several hundred times their dehydrated volume after secretion as a result of hydration and the exchange of each calcium counterion within the granule for two sodium ions in the extracellular space.9,68 Rapid secretion can deplete airway-surface liquid, resulting in the formation of concentrated, rubbery mucus that is resistant to dilution once the mucin network is formed.1,5,17 Submucosal glands continuously secrete polymeric mucins at a low level and can be further stimulated by adrenergic, cholinergic, and nonadrenergic, noncholinergic nerves.17

Periciliary Layer

The airway mucus gel lies atop a periciliary layer approximately 7 μm deep (Figure 2A). The depth of this layer is critically important for mucociliary clearance (see below). Since the airway epithelium is highly permeable to water, liquid volume is determined by the amount of sodium chloride in the airway lumen.63 In turn, the amount of sodium chloride is regulated primarily by sodium absorption through the epithelial sodium channel and chloride extrusion through the cystic fibrosis transmembrane conductance regulator (CFTR) and calcium-activated chloride channels.63,69 As mucus is propelled proximally, there is net salt and water absorption (>90%) commensurate with the decreasing total cross-sectional area of the airways.2 Locally, the depth of the periciliary layer is fine-tuned by the concentrations of adenine and uridine nucleotides and the metabolite adenosine. Adenine nucleotides are released through channels from ciliated cells that sense mechanical stress during ventilation63,70 and by exocytosis along with uridine nucleotides from secretory cells.60,61 These nucleotides activate P2Y₂ receptors and adenosine activates A2b receptors on the apical membrane of ciliated cells, causing changes in intracellular second messengers that promote chloride release and inhibit sodium absorption; as a result, water moves into the airway lumen.60,61

Membrane-bound mucins contribute to the physical properties of liquid near the cell surface, conferring features of a “grafted gel” rather than a fluid on the periciliary layer (Boucher RC, University of North Carolina: personal communication). MUC4 is densely expressed on cilia, configured like parallel bottle brushes, where it prevents penetration by the mucus gel layer and provides lubrication through bound water.4,6 MUC1 is much smaller than MUC4 and is present on the cell surface and microvilli of both ciliated and secretory cells. It has a cytoplasmic tail capable of intracellular signaling, and it modulates pathogen defense and inflammation.6,71 MUC16, the largest mucin, is expressed by both ciliated and secretory cells, and it can be cleaved and incorporated into the mobile gel layer.6,72

Clearance Mechanisms

The mucus gel is propelled in a proximal direction by ciliary beating, clearing inhaled particles, pathogens, and dissolved chemicals that might damage the lungs.2 Polymeric mucins are continuously synthesized and secreted to replenish the gel layer. Normal cilia beat 12 to 15 times per second, resulting in a velocity of the gel layer of approximately 1 mm per minute.73 The rate of mucociliary clearance increases with greater hydration,2,73 and the rate of ciliary beating can be increased by purinergic, adrenergic, cholinergic, and adenosine-receptor agonists,60,73 as well as irritant chemicals.74

A second mechanism for the expulsion of mucus from the airways is cough clearance. This may help explain why lung diseases caused by impaired ciliary function are less severe than those caused by dehydration, which impedes both clearance mechanisms.2 Although cough contributes beneficially to the clearance of mucus in diseases of excessive production or impaired ciliary function, it can also be a troublesome symptom.75,76

Cystic Fibrosis

Cystic fibrosis is caused by mutations in the gene encoding CFTR, which result in reduced chloride secretion and increased sodium absorption. Together, these result in insufficient airway luminal liquid.78,79 In addition, reduced bicarbonate secretion may result in excessive mucin cross-linking by calcium.80 In transgenic mice with overexpression of a subunit of the epithelial sodium channel in airway epithelial cells, airway luminal liquid is insufficient and a cystic fibrosis–like phenotype develops.81 This finding, coupled with a large amount of supportive data from in vitro studies of human airway epithelial-cell function, has led to a broad consensus that the major consequences of CFTR dysfunction in the airway are dehydration of mucus and reduction in the height of the periciliary layer, particularly in response to infectious or toxic insults.63,69,78,79 These changes result in poor mucus clearance, which sets up a vicious cycle of infection, inflammation, and injury. In patients with cystic fibrosis, mucus has the following characteristics: infiltration with neutrophils and high concentrations of neutrophil-derived DNA and filamentous actin22,82,83; infection with organisms such as Pseudomonas aeruginosa, Staphylococcus aureus, and aspergillus species, often in biofilms at the epithelial-cell surface; and dehydrated, highly entangled polymeric macromolecules that form a gel matrix with a pore size reduced from the normal size of approximately 500 nm to approximately 150 nm.5 Decreased pore size is postulated to immobilize microbes within the mucus gel, thereby promoting biofilm formation, and to inhibit the movement of neutrophils that might otherwise clear the infection.5,69 The net effects of these processes are manifested radiographically as bronchiectasis; pathologically as neutrophilic inflammation, airway fibrosis, and increased numbers of mucin-secreting cells, especially in the submucosal glands; and clinically as cough, purulent sputum, hemoptysis, dyspnea, recurrent lung infections, and rapid loss of lung function.78,79,84

Asthma

The central role of diffuse mucus plugging of the airways in the pathophysiology of asthma has been recognized by pathologists for more than 100 years.65,66,85 However, mucus dysfunction in asthma is often underappreciated by clinicians, possibly because cough in asthma infrequently results in expectoration or because the unavailability of therapies to clear mucus plugs has diverted attention exclusively toward reversing bronchoconstriction and inflammation.86 Mucous metaplasia (i.e., increased surface epithelial mucin production) and an increased number of bronchial microvessels are important components of the airway remodeling in asthma that confers a predisposition to mucus dysfunction.86 These changes occur in patients with airway inflammation characterized by infiltration of the airway wall and luminal mucus with CD4+ T cells, eosinophils, and innate immune cells that secrete Th2 cytokines,85,87 although neutrophil infiltration may also be prominent in acute exacerbations.84 Airway occlusion by mucus plugs can cause localized atelectasis that is evident radiographically in patients with acute asthma exacerbations, and widespread mucus plugging is consistently detected at autopsy in patients with fatal asthma.65,66Diffuse airway narrowing from a combination of concentric smooth-muscle contraction and luminal obstruction with mucus makes asthma uniquely dangerous among airway diseases in its propensity for sudden exacerbations.

Airway mucus in severe asthma has a rubbery quality that contributes to impaired clearance and plug formation. Biochemical analysis of these plugs shows high concentrations of mucins and plasma proteins,84,88 and biophysical analysis shows high entanglement density and elastic modulus.89 Another important pathologic role of plasma proteins in forming these highly elastic mucus plugs is shielding mucins from protease digestion.89 Since neutrophil elastase activity is increased in the airways of patients with asthma in the recovery phase of near-fatal exacerbations, it may help to digest mucus plugs in these patients.90 A history of persistent symptoms related to sputum is associated with more severe disease phenotypes in chronic asthma,91 and mucus hypersecretion is especially problematic in allergic bronchopulmonary aspergillosis.85

Chronic Obstructive Pulmonary Disease

Small-airway mucus obstruction is characteristic of COPD, even in patients who do not expectorate sputum or who have an emphysematous phenotype.92,93 Conversely, patients with COPD who have copious expectoration may have little airflow obstruction, probably because the mucus comes from large airways and causes minimal occlusion. Despite this weak correlation with sputum production, airflow obstruction does correlate with changes in mucin gene expression,38 increases in goblet-cell number and size,38 the occlusion of small airways with mucus,88 and expansion of the submucosal glands.21,92 Mucus dysfunction induced by cigarette smoke is complex and incompletely understood, but it involves adverse effects on the structure and function of cilia,94-96– activation of ErbB receptors,41 decreased function of CFTR,97 and proinflammatory effects that increase mucin production while decreasing mucus hydration and clearance. Cigarette smoke contains multiple toxins, including particulate matter, oxidative chemicals, and organic compounds, among which acrolein is important because it potently induces mucin production. 40

Increased mucin production and decreased luminal liquid in COPD have deleterious consequences for airway health, as they do in asthma and cystic fibrosis, including mucus stasis and airway infection. Haemophilus influenzae, P. aeruginosa, Streptococcus pneumoniae, and Moraxella catarrhalis are detected in sputum in 25 to 50% of adults with COPD. The infection rate increases with increasing disease severity, and the acquisition of new bacterial strains is associated with COPD exacerbations.98 On the basis of studies in a mouse model in which H. influenzae lysate elicited airway inflammation and fibrosis but not mucous metaplasia,56 one may speculate that in COPD, a reduction in mucus clearance that is related to cigarette smoke leads to airway infection, which, in turn, leads to inflammation and fibrosis.

Other Airway Diseases Associated with Mucus Dysfunction

Mucus dysfunction occurs in virtually all inflammatory airway diseases. Acute viral and bacterial infections and chronic diseases such as primary ciliary dyskinesia, non–cystic fibrosis bronchiectasis (which is often caused by atypical mycobacterial infection), panbronchiolitis, and immunodeficiency states (e.g., hypogammaglobulinemia, human immunodeficiency virus infection, organ transplantation, and hematologic malignant conditions) all have a component of mucus dysfunction. In addition, retained mucus is a problem in intubated patients and those in whom lung mechanics are disrupted as a result of paralysis, immobilization, or surgery; atelectasis and pneumonia are common complications in such patients. Genomic markers in chromosomal region 11p15.5 (which encompasses MUC5AC and MUC5B) have been reported to be associated with asthma severity,99 and panbronchiolitis,100 although mechanisms leading to disease susceptibility have not yet been defined.

Recent insights into the formation of pathologic mucus in disease have led to the introduction of tailored therapies such as hydration by means of aerosolized hypertonic saline solutions or the reduction of mucus viscosity and elasticity by aerosolized dornase alfa. Targeted treatment of pathologic airway mucus not only improves symptoms of cough and dyspnea but also decreases the frequency of disease-related exacerbations and slows disease progression. Elucidation of how mucin production is controlled is still needed, since that might allow the development of additional therapies to prevent overproduction.