Chest
Translating Basic Research Into Clinical PracticeMucins, Mucus, and Sputum
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).
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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.