Chest
Volume 135, Issue 2, February 2009, Pages 505-512
Journal home page for Chest

Translating Basic Research Into Clinical Practice
Mucins, Mucus, and Sputum

https://doi.org/10.1378/chest.08-0412Get rights and content

Normal airway mucus lines the epithelial surface and provides an important innate immune function by detoxifying noxious molecules and by trapping and removing pathogens and particulates from the airway via mucociliary clearance. The major macromolecular constituents of normal mucus, the mucin glycoproteins, are large, heavily glycosylated proteins with a defining feature of tandemly repeating sequences of amino acids rich in serine and threonine, the linkage sites for large carbohydrate structures. The mucins are composed of two major families: secreted mucins and membrane-associated mucins. Membrane-associated mucins have been reported to function as cell surface receptors for pathogens and to activate intracellular signaling pathways. The biochemical and cellular functions for secreted mucin glycoproteins have not been definitively assigned. In contrast to normal mucus, sputum production is the hallmark of chronic inflammatory airway diseases such as asthma, chronic bronchitis, and cystic fibrosis (CF). Sputum has altered macromolecular composition and biophysical properties which vary with disease, but unifying features are failure of mucociliary clearance, resulting in airway obstruction, and failure of innate immune properties. Mucin glycoprotein overproduction and hypersecretion are common features of chronic inflammatory airway disease, and this has been the underlying rationale to investigate the mechanisms of mucin gene regulation and mucin secretion. However, in some pathologic conditions such as CF, airway sputum contains little intact mucin and has increased content of several macromolecules including DNA, filamentous actin, lipids, and proteoglycans. This review will highlight the most recent insights on mucus biology in health and disease.

Section snippets

Mucin Biology

The mucin protein backbones are encoded by genes called MUCs. Many MUC genes are expressed in the airway including MUC1, MUC2, MUC4, MUC5AC, MUC5B, MUC7, MUC8, MUC11, MUC13, MUC15, MUC19, and MUC20.2 The protein structures encoded by these genes segregate into three major families: secreted, gel-forming mucins (predominantly MUC5AC and MUC5B, with smaller contributions from MUC2, MUC8, and MUC19); membrane-associated mucins that may function as cellular receptors (MUC1, MUC4, MUC11, MUC13,

Mucin Gene Regulation

Consistent with their role in airway innate immunity, mucins are upregulated by pathogens, inflammatory mediators, and toxins that exacerbate chronic inflammatory lung diseases such as CF, COPD, and asthma.2, 6 This field was pioneered by Dr. Carol Basbaum, who cloned the promoters for MUC2 and MUC5AC and was the first to show that bacteria upregulated mucin gene expression.9 Her laboratory and others went on to show that many bacteria including Pseudomonas aeruginosa,9, 11 Staphylococcus aureus

Regulation of Mucin Secretion

In the healthy individual, circadian rhythms regulate normal submucosal gland mucus secretion, principally through the vagal nerve. However, in patients with inflammatory airway diseases, mucus hypersecretion from metaplastic and hyperplastic goblet cells likely contributes to mucus obstruction of airways.43 Mucus secretion is stimulated by several inflammatory stimuli such as the following: (1) oxidants including tobacco smoke,44 residual oil fly ash,45 nitric oxide,46 and superoxide via PGF2α

Mucin Function

The precise functions of specific mucin protein domains are not well understood. Most work has focused on the role of membrane-associated mucins as receptors and signaling molecules. MUC1 is a receptor for P aeruginosa flagellin.60 Flagellin binding to MUC1 competes with flagellin binding to Toll-like receptor (TLR) 5, and therefore MUC1 inhibits flagellin-activated TLR-5-mediated signaling and IL-8 release.61 The MUC1 cytoplasmic tail participates in outside-inside signaling.62 Following

Mucus and Sputum Structure and Biophysical Properties

Rheology is the study of the response of material to an applied deforming force. The rheology of airway secretions is determined by their polymer composition and structure and their interaction with cilia and airflow as deforming forces. Rheology is a dynamic rather than a static measurement; thus, rheologic testing of viscoelastic substances like mucous gels yields different results with different applied stresses. In the studies of the rheology of airway secretions, forces are usually chosen

Mucus and Sputum Clearance

There must be an essential balance between adequate mucus production and mucus clearance for optimal airway defense. Airway mucus clearance can be modeled using equations common to fluid dynamics. Putting these mathematical models into common English, we can say that when inflow (mucus production) is high (hypersecretion) there can be overflow (expectoration) even with normal outflow (mucociliary clearance) and when outflow is impaired, even with normal or low inflow, there can be sludging that

Acknowledgment

The authors thank Dr. Bernard Fischer for assistance with Figure 1 and critical review of the manuscript.

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    This work was supported by National Institutes of Health grants HL65611 (J.A.V.), the Duke Children's Miracle Network (J.A.V.), and the Cystic Fibrosis Foundation (J.A.V.).

    Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal.org/misc/reprints.shtml).

    1

    Dr. Voynow is a consultant for BioMarcks. Dr. Rubin holds patents on the use of aerosol surfactant for airway clearance and increasing mucin secretion to protect the CF airway; he also has grant support from GlaxoSmithKline/PLIVA, Hill-Rom, and Bayer for mucus clearance therapies and consults for Boehringer and GlaxoSmithKline.

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