0
Translating Basic Research Into Clinical Practice |

Mucins, Mucus, and Sputum FREE TO VIEW

Judith A. Voynow, MD; Bruce K. Rubin, MEngr, MD, MBA, FCCP
Author and Funding Information

*From the Department of Pediatrics (Dr. Voynow), Duke University School of Medicine, Durham; and Department of Pediatrics (Dr. Rubin), Wake Forest University School of Medicine, Winston-Salem, NC.

Correspondence to: Judith A. Voynow, MD, Division of Pediatric Pulmonary Diseases, Box 2994, Duke University Medical Center, Durham, NC 27710; e-mail: voyno001@mc.duke.edu


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.).

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.

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


Chest. 2009;135(2):505-512. doi:10.1378/chest.08-0412
Text Size: A A A
Published online

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.

Figures in this Article

Normal mucus and mucociliary clearance are critical components of lung innate immune function. Airway mucus maintains hydration in the airway and traps particulates, bacteria, and viruses. Mucus also has antioxidant, antiprotease, and antimicrobial activities. While the terms sputum and mucus are commonly used interchangeably by clinicians, these are very different substances. The gel forming mucins are the principal polymeric components of normal mucus, but this is rarely true in chronic airway disease. While mucin is generally cleared by cilia, with chronic inflammation the ciliated epithelium becomes damaged and the increased volume of secretions often requires clearance by cough. These expectorated secretions are called sputum.

The major macromolecular constituents of mucus are the mucin glycoproteins.1 Mucins are large glycoproteins with a signature feature of tandemly repeating amino acids rich in serine and threonine, which are the sites for O-linked glycosylation.2 Secreted mucins form large oligomeric structures that impart viscoelastic properties to mucus.1 Importantly, mucin glycoproteins may also contribute important antimicrobial and anti-inflammatory properties.

For normal function, mucus must be cleared by ciliary motion and this process requires a balance between the volume and composition of the mucus, adequate periciliary liquid volume, and normal ciliary beat frequency.3 This balance may be stressed by inflammatory conditions that induce mucin overproduction and hypersecretion. However, in cystic fibrosis (CF) and other chronic inflammatory airways diseases, other large polymers predominate in the airway secretions; these polymers include DNA, filamentous actin, proteoglycans, and biofilms, which in combination with bacteria and inflammatory cells constitute sputum.4 Excessive sputum overwhelms ciliary clearance and obstructs airways, causing morbidity and mortality in chronic inflammatory lung diseases like asthma, CF, and COPD.

This review will highlight our current understanding of mucin gene regulation and regulation of mucin secretion. We will also discuss how mucus biology is perturbed in disease and how insights regarding the biochemical and biophysical characteristics of mucus and sputum need to be considered to more effectively treat airway obstruction in chronic inflammatory airway diseases.

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, MUC15, MUC20); and a non–gel-forming, secreted mucin (MUC7). Mucins have been very difficult to study because of their large size and because attached sugars mask a large portion of the protein domains. Recently, antibodies have become commercially available to identify the protein backbones of MUC1, MUC2, MUC4, MUC5AC, MUC5B, MUC7 and MUC8. Using MUC-specific antibodies, investigators1 have identified the major secreted mucin glycoproteins in human airway secretions as MUC5AC and MUC5B; this corresponds with in vitro data obtained by analysis of mucin glycoproteins in secretions from primary cultures of human airway cells.5

The localization of mucins is restricted to specific compartments in the normal airway. The membrane-associated mucins, MUC1 and MUC4, are present at the apical surface of ciliated cells. The secreted mucins, mainly MUC5AC and some MUC5B, are expressed in goblet cells, while MUC5B is the predominant mucin expressed in the mucous cells of the submucosal gland.1,6,7 MUC7 is expressed in serous cells of the submucosal glands and expression levels are not altered in CF.8 In chronic inflammatory airway diseases, MUC2 expression is detectable in the goblet cells,9 and MUC5AC and MUC5B expression is increased.6 Of the secreted mucins, MUC2 was the first MUC gene identified in the lung, although MUC5AC and MUC5B appear to be major human airway mucin glycoproteins. In mouse models, Muc5ac is a marker of goblet-cell metaplasia.10 Therefore, MUC2, MUC5AC and MUC5B have been the most intensively studied MUC genes for evaluation of airway mucin gene regulation and mucin glycoprotein secretion. Figure 1 is a summary of known transcriptional signaling pathways regulating MUC5AC.

Figure Jump LinkFigure 1 Regulation of MUC5AC gene transcription. The stimuli regulating MUC5AC in this diagram are limited to those with defined signaling pathways leading to transcriptional regulation. Stimuli are noted by red arrows. Transcription factors are in blue. Arrows denote positive signaling pathways. Both EGFR-dependent and EGFR-independent pathways activate MUC5AC transcription. Mitogen-activated-protein-kinase signaling pathways result in activation of several alternative transcription factors required for MUC5AC upregulation. AP1 = activator protein 1; CREB = cyclic adenosine monophosphate response element binding protein; ERK = extracellular signal-related kinase; IKK = IκB kinase; IRAK1 = IL-1 receptor-associated kinase 1; MEK = mitogen-activated protein/extracellular signal-regulated kinase 1; MKK = mitogen-activated protein kinase kinase; MSK1 = mitogen- and stress-activated protein kinase 1; NE = neutrophil elastase; ROS = reactive oxygen species; RSK = p90 ribosomal S6 kinase; SP1 = specificity protein 1; TACE = TNF-α converting enzyme; TAK1 = transforming growth factor β-activated kinase 1; TRAF6 = TNF receptor-associated factor.Grahic Jump Location

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,9,11Staphylococcus aureus,12Streptococcus pneumoniae,13 nontypeable Haemophilus influenzae,14,15 and Mycoplasma pneumoniae16 activate cell surface receptors resulting in nuclear factor (NF)-κB activation and MUC2 and/or MUC5AC transcriptional up-regulation.2 Respiratory viruses also activate mucin expression in airway cells. Rhinovirus upregulates MUC5AC and MUC5B gene expression in airway epithelial cells,17 while other respiratory viruses including influenza,18 RSV,19 and paramyxoviruses20 induce Muc5ac gene expression associated with mucous cell metaplasia in mice.

Several cytokines including tumor necrosis factor (TNF)-α,21 interleukin (IL)-1β,22 and IL-1323 upregulate MUC5AC expression, and IL-6 and IL-17 upregulate both MUC5AC and MUC5B expression.24 IL-13, a central mediator of airway remodeling in asthma,25 increases MUC5AC expression by several indirect mechanisms including upregulation of transforming growth factor-β226 and Stat6 phosphorylation and suppression of the transcription factor, forkhead box A2 (FoxA2).23 FoxA2 inhibits MUC5AC expression and FoxA2 expression is inversely related to goblet-cell metaplasia.27 Complement C3 upregulates murine Muc5ac in vivo and in vitro.28 Airway proteases including neutrophil elastase,2931 matrix metalloprotease 9,32 tissue kallikrein,33 and human airway trypsin34 upregulate MUC5AC expression. Finally, pollutants and oxidants including prostaglandin (PG) E2,35 hydrogen peroxide,36 dual oxidase 1,37 tobacco smoke,38 acrolein,32 and residual oil fly ash,39 all upregulate MUC5AC messenger RNA expression. These stimuli activate several signaling pathways resulting in the activation of NF-κB, activating protein 1, specificity protein 1, or cyclic adenosine monophosphate response element binding protein promoter elements2,6 (Fig 1). Several stimuli activate epidermal growth factor receptor (EGFR)-mediated and alternative signaling, resulting in redundant pathways for MUC5AC upregulation.38,40 In contrast to the pro-inflammatory stimuli that increase MUC expression, the glucocorticoid dexamethasone is one of the few agents that transcriptionally decreases MUC5AC messenger RNA abundance in airway epithelial cells.41

Transcriptional regulation is likely not the only mechanism of MUC gene expression. Several inflammatory mediators, including neutrophil elastase, TNFα, and IL-8, increase MUC5AC steady state expression by increasing messenger RNA stability in human airway epithelia.2MUC2 and MUC5B are regulated by DNA methylation and histone deacetylase activity in cancer epithelial cells, suggesting that epigenetic mechanisms of MUC regulation may play a role in inflammatory airway diseases.42

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 PGF2α47; (2) proteases48 including neutrophil elastase,49,50 and P aeruginosa proteases51; and (3) cytokines including TNF-α52 and platelet activating factor.53 Common signaling intermediates for many stimuli include G protein–coupled receptor activation, protein kinase C activation, tyrosine phosphorylation, and phospholipase activation.54,55 The molecular components of the mucin granule exocytic machinery are currently being determined.56 The myristoylated alanine-rich C-kinase substrate protein is a component of the secretory complex required for mucin granule exocytosis. A peptide related to myristoylated alanine-rich C-kinase substrate inhibits stimulated exocytosis in vivo, suggesting a novel approach to regulate mucin hypersecretion.57,58 As the secretory machinery of mucin granules is defined, the proteins required for mucin exocytosis will provide new targets for therapies to control mucus hypersecretion.59

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 ligand binding to the MUC1 extracellular domain, the MUC1 cytoplasmic tail interacts with Src family nonreceptor tyrosine kinases, resulting in activation of phospholipase C, protein kinase C, and downstream extracellular signal-related kinase 1/2. MUC1 has been reported to interact with ErbB family members, and components of the Wnt signaling pathway. Another major membrane-associated mucin, MUC4, has been reported to activate ErbB2 in colon cancer cells,63 but this function has not yet been confirmed in the lung.

Functions for the various motifs in the protein domains of secreted mucins have been more difficult to elucidate. Muc2-null mice develop colitis or colon carcinoma, suggesting that secreted mucins play an important role in preventing epithelial inflammation in the colon.64,65 Epidemiologic data associate MUC7 allele length polymorphisms with a propensity for asthma and decreased lung function with age,66 although the functional impact of changes in tandem repeat sequence length is not known. Finally, several investigators6770 have demonstrated that P aeruginosa binds to mucin carbohydrate structures including amino sugars and fucose. This function underlies the importance of normal mucus composition and efficient mucociliary clearance to rid the airways of pathogens and toxins.

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 to mimic the low-stress, high-frequency forces applied by beating cilia; the low-stress, low-frequency extrusion of secretions from glands; or the high-velocity, high-stress forces imposed by cough airflow. Classic rheologic measurements include the following: viscosity or energy loss and deformation; elasticity or energy storage; mechanical impedance or rigidityas the absolute resistance to deformation; shear thickening or thinning; reversible shear thinning (thixotropy); and apparent yield stress, which is a catastrophic decrease in viscosity when polymeric bonds are irreversibly ruptured. Each of these may have a role in the behavior of airway secretions.71

Mucus polymer structure has been characterized as a tangled network. Mucins oligomerize into long linear chains similar to railcars hooking up on a long freight train.1 It is thought that disulfide bond cross linking is inhibited by mucin glycosylation but that these elongated oligomers will tangle to form a low viscosity network. Recognition that in some diseases, such as severe asthma, there is indeed intermolecular cross linking between mucin chains suggests that this tangled network structure may be more physically complex under some circumstances.72 This is also seen in plastic bronchitis (Fig 2, right, C). Although it is assumed that each of the elongated mucin oligomers is made of a single mucin species (primarily MUC5AC or MUC5B), it is possible that these are heteromeric and this would suggest further polymerization after exocytosis.

Figure Jump LinkFigure 2 Laser scanning confocal micrograph of mucus and sputum. Normal mucus (left, A), cystic fibrosis sputum (center, B), and a plastic bronchitis secretion plug (cast) [right, C] are shown (unpublished data). Mucin is stained with Texas red phalloidin conjugated to UEA lectin (red) and DNA with YOYO-1 (green). In plastic bronchitis secretions (right, C), the mucin stain shows a complex cross-linked polymer that is different from the linear polymers seen in normal airway mucus (left, A), and the DNA is only on the outside of the cast in discrete cells or short polymers, suggesting a secondary inflammatory response. In contrast, in CF sputum (center, B), there is a paucity of mucin staining, and DNA polymers are present in long linear bundles. All images are 200 × 200 microns.Grahic Jump Location

The secondary polymer structure consisting of DNA (Fig 2, center, B) and filamentous actin (F-actin) copolymers is more rigid, consisting of thicker polymer bundles that do not coassociate with the mucin network. This secondary network is characteristic of sputum or pus. It tends to have a lower elasticity than pure mucin and is the result of inflammatory cell necrosis. This is the dominant polymeric species in diseases like CF and bronchiectasis, and it changes the rheologic properties of the secretion.73 Therapies that target DNA polymers (deoxyribonuclease) and F-filamentous actin polymers (thymosin β4), may decrease CF sputum viscoelasticity.74

Cough and ciliary clearance are also highly dependent on the interaction between the epithelial or ciliary surface and the surface of the secretion. Surface interactions are nearly independent of polymeric structure. Surface forces are dominated by surface tension and surfactant interactions that are characterized by wettability and interfacial tension (Fig 3). Assuming a sessile drop, Young's equation allows the calculation of adhesive work determined as γ(1 + cos θ), where γ is the interfacial tension and θ is the contact angle at the solid-liquid-air interface. Combined with the intermolecular attractive force of cohesivity, this yields a measurement called tenacity; the greatest determinant of the cough clearability of secretions. Although the viscoelasticity of CF sputum is lower than that of either asthma or chronic bronchitis secretions, tenacity is greatly increased due to very high adhesivity.75 Interfacial and adhesion tension is markedly increased by hydrolysis of the normal surfactant layer, which permits transfer of energy from the cilia to the mucus while preventing ciliary entanglement.7678 Finally, in vitro studies79 suggest that CF airway surface liquid is diminished when adenosine triphosphate is decreased in the airway surface liquid (ASL) and purinergic receptor P2Y activation of alternative chloride is silenced. The loss of sufficient ASL may impede ciliary motion and results in mucus stasis.80

Figure Jump LinkFigure 3 Model demonstrating the epithelial and mucus surface forces in health and disease. Source of mucus is from both goblet cells and submucousal glands. Left, A: The proposed effect of surface forces on mucus transport in the healthy airway. A surfactant layer may facilitate the mucus wetting (spreading over) the underlying epithelium after goblet-cell exocytosis or extrusion from submucosal glands. Increased wettability is measured by a small contact angle, θ, and decreased surface mechanical impedance G*s. Interfacial tension γ1,2 is measured at the air (1)-mucus (2) interface, and the contact angle θ is measured at the mucus (2)-periciliary/solid (3) interface. Right, B: The effect of surface forces on sputum cough transport in the diseased airway. Surfactant hydrolysis to lysophospholipids may decrease wettability and increase interfacial tension. Coupled with stimulated mucus hypersecretion, this leads to a buildup of mucus on the top of the epithelium.Grahic Jump Location

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 further exacerbates obstruction. It is likely that infection and irritants initially increase both the production and the clearance of secretions to augment airway defenses. However, when clearance is disturbed, as in patients with life-threatening asthma, there can be profound consequences with airway obstruction and gas trapping.

The rheologic properties that favor mucociliary clearance appear to hinder cough clearance and vice versa.81 The ciliary interaction requires that the cilia efficiently transmit energy to the mucus layer by elastic interaction, and that the cilia can effectively sweep through the mucus unhindered by high viscosity or by low-volume ASL. For airflow-dependent clearance, secretion viscosity and cohesivity allow the secretions to remain intact in the high-velocity airflow, a low elasticity prevents recoil, and apparent yield stress augments the bolus transport of secretions. It follows that medications that decrease viscosity, such as mucolytics, may benefit ciliary clearance but hamper cough clearance, while medications that decrease the adhesion of secretions to the epithelial surface are likely to improve airflow-dependent clearance. Alternatively, in CF, augmenting ASL volume and/or decreasing ASL viscosity by using hypertonic saline solution increases mucus clearance.82

Although it has long been assumed that patients with CF have mucus hypersecretion and there appears to be stimulation of mucin gene expression in the CF airway, CF sputum contains almost no intact mucin.73 This may be due to proteolytic degradation of mucins and accumulation of other biopolymers such as proteoglycans, DNA, lipids, and F-actin, which dilute the relative concentration of secreted mucins.4 During an acute exacerbation of CF when expectorated sputum volume increases, the mucin concentration in sputum also increases, suggesting that the cellular mechanisms for mucin protein production and exocytosis remain intact.83 Regardless of the mechanism leading to decreased mucins in CF sputum, this reduction alone strongly suggests that we must be cautious in using medications meant to decrease mucin secretion in CF.

The critical protective role of mucins in preventing airway disease, the relationship between secreted mucins, mucus, and sputum polymers, and the optimization of sputum clearance all require further exploration in order to develop appropriate therapy for specific airway diseases.

ASL

airway surface liquid

CF

cystic fibrosis

EGFR

epidermal growth factor receptor

F-actin

filamentous actin

FoxA2

forkhead box A2

IL

interleukin

NF

nuclear factor

PG

prostaglandin

TLR

Toll-like receptor

TNF

tumor necrosis factor

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

Thornton DJ, Rousseau K, McGuckin MA. Structure and function of the polymeric mucins in airways mucus. Annu Rev Physiol. 2008;70:459-486. [PubMed] [CrossRef]
 
Rose MC, Voynow JA. Respiratory tract mucin genes and mucin glycoproteins in health and disease. Physiol Rev. 2006;86:245-278. [PubMed]
 
Tarran R, Button B, Boucher RC. Regulation of normal and cystic fibrosis airway surface liquid volume by phasic shear stress. Annu Rev Physiol. 2006;68:543-561. [PubMed]
 
Matthews LW, Spector S, Lemm J, et al. Studies on pulmonary secretions: I. The over-all chemical composition of pulmonary secretions from patients with cystic fibrosis, bronchiectasis, and laryngectomy. Am Rev Respir Dis. 1963;88:199-204. [PubMed]
 
Holmen JM, Karlsson NG, Abdullah LH, et al. Mucins and their O-glycans from human bronchial epithelial cell cultures. Am J Physiol Lung Cell Mol Physiol. 2004;287:L824-L834. [PubMed]
 
Thai P, Loukoianov A, Wachi S, et al. Regulation of airway mucin gene expression. Annu Rev Physiol. 2008;70:405-429. [PubMed]
 
Schulz BL, Sloane AJ, Robinson LJ, et al. Mucin glycosylation changes in cystic fibrosis lung disease are not manifest in submucosal gland secretions. Biochem J. 2005;387:911-919. [PubMed]
 
Sharma P, Dudus L, Nielsen PA, et al. MUC5B and MUC7 are differentially expressed in mucous and serous cells of submucosal glands in human bronchial airways. Am J Respir Cell Mol Biol. 1998;19:30-37. [PubMed]
 
Li J-D, Dohrman AF, Gallup M, et al. Transcriptional activation of mucin byPseudomonas aeruginosalipopolysaccharide in the pathogenesis of cystic fibrosis lung disease. Proc Natl Acad Sci U S A. 1997;94:967-972. [PubMed]
 
Zuhdi Alimam M, Piazza FM, Selby DM, et al. Muc-5/5ac mucin messenger RNA and protein expression is a marker of goblet cell metaplasia in murine airways. Am J Respir Cell Mol Biol. 2000;22:253-260. [PubMed]
 
Li D, Gallup M, Fan N, et al. Cloning of the amino-terminal and 5′-flanking region of the human MUC5AC mucin gene and transcriptional up-regulation by bacterial exoproducts. J Biol Chem. 1998;273:6812-6820. [PubMed]
 
Lemjabbar H, Basbaum C. Platelet-activating factor receptor and ADAM10 mediate responses toStaphylococcus aureusin epithelial cells. Nature Med. 2002;8:41-46. [PubMed]
 
Ha U, Lim JH, Jono H, et al. A novel role for IkappaB kinase (IKK) alpha and IKKbeta in ERK-dependent up-regulation of MUC5AC mucin transcription byStreptococcus pneumoniaeJ Immunol. 2007;178:1736-1747. [PubMed]
 
Wang B, Lim DJ, Han J, et al. Novel cytoplasmic proteins of nontypeableHaemophilus influenzaeup-regulate human MUC5AC mucin transcription via a positive p38 mitogen-activated protein kinase pathway and a negative phosphoinositide 3-kinase-Akt pathway. J Biol Chem. 2002;277:949-957. [PubMed]
 
Chen R, Lim JH, Jono H, et al. NontypeableHaemophilus influenzaelipoprotein P6 induces MUC5AC mucin transcription via TLR2-TAK1-dependent p38 MAPK-AP1 and IKKbeta-IkappaBalpha-NF-kappaB signaling pathways. Biochem Biophys Res Commun. 2004;324:1087-1094. [PubMed]
 
Kraft M, Adler KB, Ingram JL, et al. Mycoplasma pneumoniaeinduces airway epithelial cell expression of MUC5AC in asthma. Eur Respir J. 2008;31:43-46. [PubMed]
 
Inoue D, Yamaya M, Kubo H, et al. Mechanisms of mucin production by rhinovirus infection in cultured human airway epithelial cells. Respir Physiol Neurobiol. 2006;154:484-499. [PubMed]
 
Buchweitz JP, Karmaus PW, Harkema JR, et al. Modulation of airway responses to influenza A/PR/8/34 by Delta9-tetrahydrocannabinol in C57BL/6 mice. J Pharmacol Exp Ther. 2007;323:675-683. [PubMed]
 
Hashimoto K, Graham BS, Ho SB, et al. Respiratory syncytial virus in allergic lung inflammation increases Muc5ac and gob-5. Am J Respir Crit Care Med. 2004;170:306-312. [PubMed]
 
Tyner JW, Kim EY, Ide K, et al. Blocking airway mucous cell metaplasia by inhibiting EGFR antiapoptosis and IL-13 transdifferentiation signals. J Clin Invest. 2006;116:309-321. [PubMed]
 
Lora JM, Zhang DM, Liao SM, et al. Tumor necrosis factor-α triggers mucus production in airway epithelium through an IκB kinase β-dependent mechanism. J Biol Chem. 2005;280:36510-36517. [PubMed]
 
Song K, Lee WJ, Chung KC, et al. Interleukin-1β and tumor necrosis factor-α induce MUC5AC overexpression through a mechanism involving ERK/p38 mitogen-activated protein kinases-MSK1-CREB activation in human airway epithelial cells. J Biol Chem. 2003;278:23243-23250. [PubMed]
 
Zhen G, Park SW, Nguyenvu LT, et al. IL-13 and epidermal growth factor receptor have critical but distinct roles in epithelial cell mucin production. Am J Respir Cell Mol Biol. 2007;36:244-253. [PubMed]
 
Chen Y, Thai P, Zhao YH, et al. Stimulation of airway mucin gene expression by interleukin (IL)-17 through IL-6 paracrine/autocrine loop. J Biol Chem. 2003;278:17036-17043. [PubMed]
 
Wills-Karp M, Luyimbazi J, Xu X, et al. Interleukin-13: central mediator of allergic asthma. Science. 1998;282:2258-2263. [PubMed]
 
Chu HW, Balzar S, Seedorf GJ, et al. Transforming growth factor-β2 induces bronchial epithelial mucin expression in asthma. Am J Pathol. 2004;165:1097-1106. [PubMed]
 
Wan H, Kaestner KH, Ang SL, et al. Foxa2 regulates alveolarization and goblet cell hyperplasia. Development. 2004;131:953-964. [PubMed]
 
Dillard P, Wetsel RA, Drouin SM. Complement C3a regulates Muc5ac expression by airway Clara cells independently of Th2 responses. Am J Respir Crit Care Med. 2007;175:1250-1258. [PubMed]
 
Voynow JA, Young LR, Wang Y, et al. Neutrophil elastase increasesMUC5ACmRNA and protein expression in respiratory epithelial cells. Am J Physiol. 1999;276:L835-L843. [PubMed]
 
Voynow JA, Fischer BM, Malarkey DE, et al. Neutrophil elastase induces mucus cell metaplasia in mouse lung. Am J Physiol Lung Cell Mol Physiol. 2004;287:L1293-L1302. [PubMed]
 
Shao MX, Nadel JA. Neutrophil elastase induces MUC5AC mucin production in human airway epithelial cells via a cascade involving protein kinase C, reactive oxygen species, and TNF-α-converting enzyme. J Immunol. 2005;175:4009-4016. [PubMed]
 
Deshmukh HS, Case LM, Wesselkamper SC, et al. Metalloproteinases mediate mucin 5AC expression by epidermal growth factor receptor activation. Am J Respir Crit Care Med. 2005;171:305-314. [PubMed]
 
Casalino-Matsuda S, Monzon ME, Conner GE, et al. Role of hyaluronan and reactive oxygen species in tissue kallikrein-mediated epidermal growth factor receptor activation in human airways. J Biol Chem. 2004;279:21606-21616. [PubMed]
 
Chokki M, Yamamura S, Eguchi H, et al. Human airway trypsin-like protease increases mucin gene expression in airway epithelial cells. Am J Respir Cell Mol Biol. 2004;30:470-478. [PubMed]
 
Gray T, Nettesheim P, Loftin C, et al. Interleukin-1β-induced mucin production in human airway epithelium is mediated by cyclooxygenase-2, prostaglandin E2 receptors, and cyclic AMP-protein kinase A signaling. Mol Pharmacol. 2004;66:337-346. [PubMed]
 
Takeyama K, Dabbagh K, Jeong Shim J, et al. Oxidative stress causes mucin synthesis via transactivation of epidermal growth factor receptor: role of neutrophils. J Immunol. 2000;164:1546-1552. [PubMed]
 
Shao MX, Nadel JA. Dual oxidase 1-dependent MUC5AC mucin expression in cultured human airway epithelial cells. Proc Natl Acad Sci U S A. 2005;102:767-772. [PubMed]
 
Gensch E, Gallup M, Sucher A, et al. Tobacco smoke control of mucin production in lung cells requires oxygen radicals AP-1 and JNK. J Biol Chem. 2004;279:39085-39093. [PubMed]
 
Longphre M, Li D, Li J, et al. Lung mucin production is stimulated by the air pollutant residual oil fly ash. Tox Appl Pharmacol. 2000;162:86-92
 
Yuan-Chen Wu D, Wu R, Reddy SP, et al. Distinctive epidermal growth factor receptor/extracellular regulated kinase-independent and -dependent signaling pathways in the induction of airway mucin 5B and mucin 5AC expression by phorbol 12-myristate 13-acetate. Am J Pathol. 2007;170:20-32. [PubMed]
 
Chen Y, Nickola TJ, DiFronzo NL, et al. Dexamethasone-mediated repression of MUC5AC gene expression in human lung epithelial cells. Am J Respir Cell Mol Biol. 2006;34:338-347. [PubMed]
 
Vincent A, Perrais M, Desseyn JL, et al. Epigenetic regulation (DNA methylation, histone modifications) of the 11p15 mucin genes (MUC2, MUC5AC, MUC5B, MUC6) in epithelial cancer cells. Oncogene. 2007;26:6566-6576. [PubMed]
 
Rogers DF. The airway goblet cell. Int J Biochem Cell Biol. 2003;35:1-6. [PubMed]
 
Peatfield AC, Davies JR, Richardson PS. The effect of tobacco smoke upon airway secretion in the cat. Clin Sci (Lond). 1986;71:179-187. [PubMed]
 
Jiang N, Dreher KL, Dye JA, et al. Residual oil fly ash induces cytotoxicity and mucin secretion by guinea pig tracheal epithelial cells via an oxidant-mediated mechanism. Toxicol Appl Pharmacol. 2000;163:221-230. [PubMed]
 
Wright D, Fischer BM, Li C, et al. Oxidant stress stimulates mucin secretion and PLC in airway epithelium via a nitric oxide-dependent mechanism. Am J Physiol. 1996;271:L854-L861. [PubMed]
 
Adler K, Holden-Stauffer WJ, Repine JE. Oxygen metabolites stimulate release of high-molecular weight glycoconjugates by cell and organ cultures of rodent respiratory epithelium via an arachidonic acid-dependent mechanism. J Clin Invest. 1990;85:75-85. [PubMed]
 
Nadel J. Role of mast cell and neutrophil proteases in airway secretion. Am Rev Respir Dis. 1991;144:S48-S51. [PubMed]
 
Niles R, Christensen TG, Breuer R, et al. Serine proteases stimulate mucous glycoprotein release from hamster tracheal ring organ culture. J Lab Clin Med. 1986;108:489-497. [PubMed]
 
Park JA, He F, Martin LD, et al. Human neutrophil elastase induces hypersecretion of mucin from well-differentiated human bronchial epithelial cellsin vitrovia a protein kinase C{delta}-mediated mechanism. Am J Pathol. 2005;167:651-661. [PubMed]
 
Klinger J, Tandler B, Liedtke CM, et al. Proteinases ofPseudomonas aeruginosaevoke mucin release by tracheal epithelium. J Clin Invest. 1984;74:1669-1678. [PubMed]
 
Fischer BM, Rochelle LG, Voynow JA, et al. Tumor necrosis factor-α stimulates mucin secretion and cyclic GMP production by guinea pig tracheal epithelial cellsin vitroAm J Respir Cell Mol Biol. 1999;20:413-422. [PubMed]
 
Adler KB, Schwarz JE, Anderson WH, et al. Platelet activating factor stimulates secretion of mucin by explants of rodent airways in organ culture. Exp Lung Res. 1987;13:25-43. [PubMed]
 
Kim KC, McCracken K, Lee BC, et al. Airway goblet cell mucin: its structure and regulation of secretion. Eur Respir J. 1997;10:2644-2649. [PubMed]
 
Abdullah LH, Davis CW. Regulation of airway goblet cell mucin secretion by tyrosine phosphorylation signaling pathways. Am J Physiol Lung Cell Mol Physiol. 2007;293:L591-L599. [PubMed]
 
Davis CW, Dickey BF. Regulated airway goblet cell mucin secretion. Annu Rev Physiol. 2008;70:487-512. [PubMed]
 
Li Y, Martin LD, Spizz G, et al. MARCKS protein is a key molecule regulating mucin secretion by human airway epithelial cellsin vitroJ Biol Chem. 2001;276:40982-40990. [PubMed]
 
Singer M, Martin LD, Vargaftig BB, et al. A MARCKS-related peptide blocks mucus hypersecretion in a mouse model of asthma. Nature Med. 2004;10:193-196. [PubMed]
 
Rogers DF, Barnes PJ. Treatment of airway mucus hypersecretion. Ann Med. 2006;38:116-125. [PubMed]
 
Lillehoj EP, Kim BT, Kim KC. Identification ofPseudomonas aeruginosaflagellin as an adhesin for Muc1 mucin. Am J Physiol Lung Cell Mol Physiol. 2002;282:L751-L756. [PubMed]
 
Lu W, Hisatsune A, Koga T, et al. Cutting edge: enhanced pulmonary clearance ofPseudomonas aeruginosaby Muc1 knockout mice. J Immunol. 2006;176:3890-3894. [PubMed]
 
Singh PK, Hollingsworth MA. Cell surface-associated mucins in signal transduction. Trends Cell Biol. 2006;16:467-476. [PubMed]
 
Ramsauer VP, Pino V, Farooq A, et al. Muc4-ErbB2 complex formation and signaling in polarized CACO-2 epithelial cells indicate that Muc4 acts as an unorthodox ligand for ErbB2. Mol Biol Cell. 2006;17:2931-2941. [PubMed]
 
Van der Sluis M, De Koning BA, De Bruijn AC, et al. Muc2-deficient mice spontaneously develop colitis, indicating that MUC2 is critical for colonic protection. Gastroenterology. 2006;131:117-129. [PubMed]
 
Velcich A, Yang W, Heyer J, et al. Colorectal cancer in mice genetically deficient in the mucin Muc2. Science. 2002;295:1726-1729. [PubMed]
 
Rousseau K, Vinall LE, Butterworth SL, et al. MUC7 haplotype analysis: results from a longitudinal birth cohort support protective effect of the MUC7*5 allele on respiratory function. Ann Hum Genet. 2006;70:417-427. [PubMed]
 
Scharfman A, Arora SK, Delmotte P, et al. Recognition of Lewis x derivatives present on mucins by flagellar components ofPseudomonas aeruginosaInfect Immun. 2001;69:5243-5248. [PubMed]
 
Carnoy C, Scharfman A, Van Brussel E, et al. Pseudomonas aeruginosaouter membrane adhesins for human respiratory mucus glycoproteins. Infect Immun. 1994;62:1896-1900. [PubMed]
 
Vishwanath S, Ramphal R. Tracheobronchial mucin receptor forPseudomonas aeruginosa: predominance of amino sugars in binding sites. Infect Immun. 1985;48:331-335. [PubMed]
 
Mitchell E, Houles C, Sudakevitz D, et al. Structural basis for oligosaccharide-mediated adhesion ofPseudomonas aeruginosain the lungs of cystic fibrosis patients. Nat Struct Biol. 2002;9:918-921. [PubMed]
 
King M, Rubin BK.Takishima T. Mucus rheology, relationship with transport. Airway secretion: physiologic bases for the control mucus hypersecretion. 1994; New York. NY Marcel Dekker:283-314
 
Sheehan JK, Richardson PS, Fung DC, et al. Analysis of respiratory mucus glycoproteins in asthma: a detailed study from a patient who died in status asthmaticus. Am J Respir Cell Mol Biol. 1995;13:748-756. [PubMed]
 
Henke M, Renner A, Huber RM, et al. MUC5AC and MUC5B mucins are decreased in cystic fibrosis airway secretions: am. J Respir Cell Mol Biol. 2004;31:86-91
 
Kater A, Henke MO, Rubin BK. The role of DNA and actin polymers on the polymer structure and rheology of cystic fibrosis sputum and depolymerization by gelsolin or thymosin beta 4. Ann N Y Acad Sci. 2007;1112:140-153. [PubMed]
 
Albers GM, Tomkiewicz RP, May MK, et al. Ring distraction technique for measuring surface tension of sputum: relationship to sputum clearability. J Appl Physiol. 1996;81:2690-2695. [PubMed]
 
Puchelle E, de Bentzmann S, Zahm JM. Physical and functional properties of airway secretions in cystic fibrosis-therapeutic approaches. Respiration. 1995;62Suppl:2-12. [PubMed]
 
Girod S, Galabert C, Lecuire A, et al. Phospholipid composition and surface-active properties of tracheobronchial secretions from patients with cystic fibrosis and chronic obstructive pulmonary diseases. Pediatr Pulmonol. 1992;13:22-27. [PubMed]
 
Girod de Bentzmann S, Pierrot D, Fuchey C, et al. Distearoyl phosphatidylglycerol liposomes improve surface and transport properties of CF mucus. Eur Respir J. 1993;6:1156-1161. [PubMed]
 
Tarran R, Button B, Picher M, et al. Normal and cystic fibrosis airway surface liquid homeostasis: the effects of phasic shear stress and viral infections. J Biol Chem. 2005;280:35751-35759. [PubMed]
 
Matsui H, Randell SH, Peretti SW, et al. Coordinated clearance of periciliary liquid and mucus from airway surfaces. J Clin Invest. 1998;102:1125-1131. [PubMed]
 
Rogers DF, Rubin BK.Stockley RA, Rennard S, Rabe K, et al. Mucolytics for COPD. Chronic obstructive lung disease. 2006; Oxford, UK Blackwell Publishing:756-768
 
Donaldson SH, Bennett WD, Zeman KL, et al. Mucus clearance and lung function in cystic fibrosis with hypertonic saline. N Engl J Med. 2006;354:241-250. [PubMed]
 
Henke MO, John G, Germann M, et al. MUC5AC and MUC5B mucins increase in cystic fibrosis airway secretions during pulmonary exacerbation. Am J Respir Crit Care Med. 2007;175:816-821. [PubMed]
 

Figures

Figure Jump LinkFigure 1 Regulation of MUC5AC gene transcription. The stimuli regulating MUC5AC in this diagram are limited to those with defined signaling pathways leading to transcriptional regulation. Stimuli are noted by red arrows. Transcription factors are in blue. Arrows denote positive signaling pathways. Both EGFR-dependent and EGFR-independent pathways activate MUC5AC transcription. Mitogen-activated-protein-kinase signaling pathways result in activation of several alternative transcription factors required for MUC5AC upregulation. AP1 = activator protein 1; CREB = cyclic adenosine monophosphate response element binding protein; ERK = extracellular signal-related kinase; IKK = IκB kinase; IRAK1 = IL-1 receptor-associated kinase 1; MEK = mitogen-activated protein/extracellular signal-regulated kinase 1; MKK = mitogen-activated protein kinase kinase; MSK1 = mitogen- and stress-activated protein kinase 1; NE = neutrophil elastase; ROS = reactive oxygen species; RSK = p90 ribosomal S6 kinase; SP1 = specificity protein 1; TACE = TNF-α converting enzyme; TAK1 = transforming growth factor β-activated kinase 1; TRAF6 = TNF receptor-associated factor.Grahic Jump Location
Figure Jump LinkFigure 2 Laser scanning confocal micrograph of mucus and sputum. Normal mucus (left, A), cystic fibrosis sputum (center, B), and a plastic bronchitis secretion plug (cast) [right, C] are shown (unpublished data). Mucin is stained with Texas red phalloidin conjugated to UEA lectin (red) and DNA with YOYO-1 (green). In plastic bronchitis secretions (right, C), the mucin stain shows a complex cross-linked polymer that is different from the linear polymers seen in normal airway mucus (left, A), and the DNA is only on the outside of the cast in discrete cells or short polymers, suggesting a secondary inflammatory response. In contrast, in CF sputum (center, B), there is a paucity of mucin staining, and DNA polymers are present in long linear bundles. All images are 200 × 200 microns.Grahic Jump Location
Figure Jump LinkFigure 3 Model demonstrating the epithelial and mucus surface forces in health and disease. Source of mucus is from both goblet cells and submucousal glands. Left, A: The proposed effect of surface forces on mucus transport in the healthy airway. A surfactant layer may facilitate the mucus wetting (spreading over) the underlying epithelium after goblet-cell exocytosis or extrusion from submucosal glands. Increased wettability is measured by a small contact angle, θ, and decreased surface mechanical impedance G*s. Interfacial tension γ1,2 is measured at the air (1)-mucus (2) interface, and the contact angle θ is measured at the mucus (2)-periciliary/solid (3) interface. Right, B: The effect of surface forces on sputum cough transport in the diseased airway. Surfactant hydrolysis to lysophospholipids may decrease wettability and increase interfacial tension. Coupled with stimulated mucus hypersecretion, this leads to a buildup of mucus on the top of the epithelium.Grahic Jump Location

Tables

References

Thornton DJ, Rousseau K, McGuckin MA. Structure and function of the polymeric mucins in airways mucus. Annu Rev Physiol. 2008;70:459-486. [PubMed] [CrossRef]
 
Rose MC, Voynow JA. Respiratory tract mucin genes and mucin glycoproteins in health and disease. Physiol Rev. 2006;86:245-278. [PubMed]
 
Tarran R, Button B, Boucher RC. Regulation of normal and cystic fibrosis airway surface liquid volume by phasic shear stress. Annu Rev Physiol. 2006;68:543-561. [PubMed]
 
Matthews LW, Spector S, Lemm J, et al. Studies on pulmonary secretions: I. The over-all chemical composition of pulmonary secretions from patients with cystic fibrosis, bronchiectasis, and laryngectomy. Am Rev Respir Dis. 1963;88:199-204. [PubMed]
 
Holmen JM, Karlsson NG, Abdullah LH, et al. Mucins and their O-glycans from human bronchial epithelial cell cultures. Am J Physiol Lung Cell Mol Physiol. 2004;287:L824-L834. [PubMed]
 
Thai P, Loukoianov A, Wachi S, et al. Regulation of airway mucin gene expression. Annu Rev Physiol. 2008;70:405-429. [PubMed]
 
Schulz BL, Sloane AJ, Robinson LJ, et al. Mucin glycosylation changes in cystic fibrosis lung disease are not manifest in submucosal gland secretions. Biochem J. 2005;387:911-919. [PubMed]
 
Sharma P, Dudus L, Nielsen PA, et al. MUC5B and MUC7 are differentially expressed in mucous and serous cells of submucosal glands in human bronchial airways. Am J Respir Cell Mol Biol. 1998;19:30-37. [PubMed]
 
Li J-D, Dohrman AF, Gallup M, et al. Transcriptional activation of mucin byPseudomonas aeruginosalipopolysaccharide in the pathogenesis of cystic fibrosis lung disease. Proc Natl Acad Sci U S A. 1997;94:967-972. [PubMed]
 
Zuhdi Alimam M, Piazza FM, Selby DM, et al. Muc-5/5ac mucin messenger RNA and protein expression is a marker of goblet cell metaplasia in murine airways. Am J Respir Cell Mol Biol. 2000;22:253-260. [PubMed]
 
Li D, Gallup M, Fan N, et al. Cloning of the amino-terminal and 5′-flanking region of the human MUC5AC mucin gene and transcriptional up-regulation by bacterial exoproducts. J Biol Chem. 1998;273:6812-6820. [PubMed]
 
Lemjabbar H, Basbaum C. Platelet-activating factor receptor and ADAM10 mediate responses toStaphylococcus aureusin epithelial cells. Nature Med. 2002;8:41-46. [PubMed]
 
Ha U, Lim JH, Jono H, et al. A novel role for IkappaB kinase (IKK) alpha and IKKbeta in ERK-dependent up-regulation of MUC5AC mucin transcription byStreptococcus pneumoniaeJ Immunol. 2007;178:1736-1747. [PubMed]
 
Wang B, Lim DJ, Han J, et al. Novel cytoplasmic proteins of nontypeableHaemophilus influenzaeup-regulate human MUC5AC mucin transcription via a positive p38 mitogen-activated protein kinase pathway and a negative phosphoinositide 3-kinase-Akt pathway. J Biol Chem. 2002;277:949-957. [PubMed]
 
Chen R, Lim JH, Jono H, et al. NontypeableHaemophilus influenzaelipoprotein P6 induces MUC5AC mucin transcription via TLR2-TAK1-dependent p38 MAPK-AP1 and IKKbeta-IkappaBalpha-NF-kappaB signaling pathways. Biochem Biophys Res Commun. 2004;324:1087-1094. [PubMed]
 
Kraft M, Adler KB, Ingram JL, et al. Mycoplasma pneumoniaeinduces airway epithelial cell expression of MUC5AC in asthma. Eur Respir J. 2008;31:43-46. [PubMed]
 
Inoue D, Yamaya M, Kubo H, et al. Mechanisms of mucin production by rhinovirus infection in cultured human airway epithelial cells. Respir Physiol Neurobiol. 2006;154:484-499. [PubMed]
 
Buchweitz JP, Karmaus PW, Harkema JR, et al. Modulation of airway responses to influenza A/PR/8/34 by Delta9-tetrahydrocannabinol in C57BL/6 mice. J Pharmacol Exp Ther. 2007;323:675-683. [PubMed]
 
Hashimoto K, Graham BS, Ho SB, et al. Respiratory syncytial virus in allergic lung inflammation increases Muc5ac and gob-5. Am J Respir Crit Care Med. 2004;170:306-312. [PubMed]
 
Tyner JW, Kim EY, Ide K, et al. Blocking airway mucous cell metaplasia by inhibiting EGFR antiapoptosis and IL-13 transdifferentiation signals. J Clin Invest. 2006;116:309-321. [PubMed]
 
Lora JM, Zhang DM, Liao SM, et al. Tumor necrosis factor-α triggers mucus production in airway epithelium through an IκB kinase β-dependent mechanism. J Biol Chem. 2005;280:36510-36517. [PubMed]
 
Song K, Lee WJ, Chung KC, et al. Interleukin-1β and tumor necrosis factor-α induce MUC5AC overexpression through a mechanism involving ERK/p38 mitogen-activated protein kinases-MSK1-CREB activation in human airway epithelial cells. J Biol Chem. 2003;278:23243-23250. [PubMed]
 
Zhen G, Park SW, Nguyenvu LT, et al. IL-13 and epidermal growth factor receptor have critical but distinct roles in epithelial cell mucin production. Am J Respir Cell Mol Biol. 2007;36:244-253. [PubMed]
 
Chen Y, Thai P, Zhao YH, et al. Stimulation of airway mucin gene expression by interleukin (IL)-17 through IL-6 paracrine/autocrine loop. J Biol Chem. 2003;278:17036-17043. [PubMed]
 
Wills-Karp M, Luyimbazi J, Xu X, et al. Interleukin-13: central mediator of allergic asthma. Science. 1998;282:2258-2263. [PubMed]
 
Chu HW, Balzar S, Seedorf GJ, et al. Transforming growth factor-β2 induces bronchial epithelial mucin expression in asthma. Am J Pathol. 2004;165:1097-1106. [PubMed]
 
Wan H, Kaestner KH, Ang SL, et al. Foxa2 regulates alveolarization and goblet cell hyperplasia. Development. 2004;131:953-964. [PubMed]
 
Dillard P, Wetsel RA, Drouin SM. Complement C3a regulates Muc5ac expression by airway Clara cells independently of Th2 responses. Am J Respir Crit Care Med. 2007;175:1250-1258. [PubMed]
 
Voynow JA, Young LR, Wang Y, et al. Neutrophil elastase increasesMUC5ACmRNA and protein expression in respiratory epithelial cells. Am J Physiol. 1999;276:L835-L843. [PubMed]
 
Voynow JA, Fischer BM, Malarkey DE, et al. Neutrophil elastase induces mucus cell metaplasia in mouse lung. Am J Physiol Lung Cell Mol Physiol. 2004;287:L1293-L1302. [PubMed]
 
Shao MX, Nadel JA. Neutrophil elastase induces MUC5AC mucin production in human airway epithelial cells via a cascade involving protein kinase C, reactive oxygen species, and TNF-α-converting enzyme. J Immunol. 2005;175:4009-4016. [PubMed]
 
Deshmukh HS, Case LM, Wesselkamper SC, et al. Metalloproteinases mediate mucin 5AC expression by epidermal growth factor receptor activation. Am J Respir Crit Care Med. 2005;171:305-314. [PubMed]
 
Casalino-Matsuda S, Monzon ME, Conner GE, et al. Role of hyaluronan and reactive oxygen species in tissue kallikrein-mediated epidermal growth factor receptor activation in human airways. J Biol Chem. 2004;279:21606-21616. [PubMed]
 
Chokki M, Yamamura S, Eguchi H, et al. Human airway trypsin-like protease increases mucin gene expression in airway epithelial cells. Am J Respir Cell Mol Biol. 2004;30:470-478. [PubMed]
 
Gray T, Nettesheim P, Loftin C, et al. Interleukin-1β-induced mucin production in human airway epithelium is mediated by cyclooxygenase-2, prostaglandin E2 receptors, and cyclic AMP-protein kinase A signaling. Mol Pharmacol. 2004;66:337-346. [PubMed]
 
Takeyama K, Dabbagh K, Jeong Shim J, et al. Oxidative stress causes mucin synthesis via transactivation of epidermal growth factor receptor: role of neutrophils. J Immunol. 2000;164:1546-1552. [PubMed]
 
Shao MX, Nadel JA. Dual oxidase 1-dependent MUC5AC mucin expression in cultured human airway epithelial cells. Proc Natl Acad Sci U S A. 2005;102:767-772. [PubMed]
 
Gensch E, Gallup M, Sucher A, et al. Tobacco smoke control of mucin production in lung cells requires oxygen radicals AP-1 and JNK. J Biol Chem. 2004;279:39085-39093. [PubMed]
 
Longphre M, Li D, Li J, et al. Lung mucin production is stimulated by the air pollutant residual oil fly ash. Tox Appl Pharmacol. 2000;162:86-92
 
Yuan-Chen Wu D, Wu R, Reddy SP, et al. Distinctive epidermal growth factor receptor/extracellular regulated kinase-independent and -dependent signaling pathways in the induction of airway mucin 5B and mucin 5AC expression by phorbol 12-myristate 13-acetate. Am J Pathol. 2007;170:20-32. [PubMed]
 
Chen Y, Nickola TJ, DiFronzo NL, et al. Dexamethasone-mediated repression of MUC5AC gene expression in human lung epithelial cells. Am J Respir Cell Mol Biol. 2006;34:338-347. [PubMed]
 
Vincent A, Perrais M, Desseyn JL, et al. Epigenetic regulation (DNA methylation, histone modifications) of the 11p15 mucin genes (MUC2, MUC5AC, MUC5B, MUC6) in epithelial cancer cells. Oncogene. 2007;26:6566-6576. [PubMed]
 
Rogers DF. The airway goblet cell. Int J Biochem Cell Biol. 2003;35:1-6. [PubMed]
 
Peatfield AC, Davies JR, Richardson PS. The effect of tobacco smoke upon airway secretion in the cat. Clin Sci (Lond). 1986;71:179-187. [PubMed]
 
Jiang N, Dreher KL, Dye JA, et al. Residual oil fly ash induces cytotoxicity and mucin secretion by guinea pig tracheal epithelial cells via an oxidant-mediated mechanism. Toxicol Appl Pharmacol. 2000;163:221-230. [PubMed]
 
Wright D, Fischer BM, Li C, et al. Oxidant stress stimulates mucin secretion and PLC in airway epithelium via a nitric oxide-dependent mechanism. Am J Physiol. 1996;271:L854-L861. [PubMed]
 
Adler K, Holden-Stauffer WJ, Repine JE. Oxygen metabolites stimulate release of high-molecular weight glycoconjugates by cell and organ cultures of rodent respiratory epithelium via an arachidonic acid-dependent mechanism. J Clin Invest. 1990;85:75-85. [PubMed]
 
Nadel J. Role of mast cell and neutrophil proteases in airway secretion. Am Rev Respir Dis. 1991;144:S48-S51. [PubMed]
 
Niles R, Christensen TG, Breuer R, et al. Serine proteases stimulate mucous glycoprotein release from hamster tracheal ring organ culture. J Lab Clin Med. 1986;108:489-497. [PubMed]
 
Park JA, He F, Martin LD, et al. Human neutrophil elastase induces hypersecretion of mucin from well-differentiated human bronchial epithelial cellsin vitrovia a protein kinase C{delta}-mediated mechanism. Am J Pathol. 2005;167:651-661. [PubMed]
 
Klinger J, Tandler B, Liedtke CM, et al. Proteinases ofPseudomonas aeruginosaevoke mucin release by tracheal epithelium. J Clin Invest. 1984;74:1669-1678. [PubMed]
 
Fischer BM, Rochelle LG, Voynow JA, et al. Tumor necrosis factor-α stimulates mucin secretion and cyclic GMP production by guinea pig tracheal epithelial cellsin vitroAm J Respir Cell Mol Biol. 1999;20:413-422. [PubMed]
 
Adler KB, Schwarz JE, Anderson WH, et al. Platelet activating factor stimulates secretion of mucin by explants of rodent airways in organ culture. Exp Lung Res. 1987;13:25-43. [PubMed]
 
Kim KC, McCracken K, Lee BC, et al. Airway goblet cell mucin: its structure and regulation of secretion. Eur Respir J. 1997;10:2644-2649. [PubMed]
 
Abdullah LH, Davis CW. Regulation of airway goblet cell mucin secretion by tyrosine phosphorylation signaling pathways. Am J Physiol Lung Cell Mol Physiol. 2007;293:L591-L599. [PubMed]
 
Davis CW, Dickey BF. Regulated airway goblet cell mucin secretion. Annu Rev Physiol. 2008;70:487-512. [PubMed]
 
Li Y, Martin LD, Spizz G, et al. MARCKS protein is a key molecule regulating mucin secretion by human airway epithelial cellsin vitroJ Biol Chem. 2001;276:40982-40990. [PubMed]
 
Singer M, Martin LD, Vargaftig BB, et al. A MARCKS-related peptide blocks mucus hypersecretion in a mouse model of asthma. Nature Med. 2004;10:193-196. [PubMed]
 
Rogers DF, Barnes PJ. Treatment of airway mucus hypersecretion. Ann Med. 2006;38:116-125. [PubMed]
 
Lillehoj EP, Kim BT, Kim KC. Identification ofPseudomonas aeruginosaflagellin as an adhesin for Muc1 mucin. Am J Physiol Lung Cell Mol Physiol. 2002;282:L751-L756. [PubMed]
 
Lu W, Hisatsune A, Koga T, et al. Cutting edge: enhanced pulmonary clearance ofPseudomonas aeruginosaby Muc1 knockout mice. J Immunol. 2006;176:3890-3894. [PubMed]
 
Singh PK, Hollingsworth MA. Cell surface-associated mucins in signal transduction. Trends Cell Biol. 2006;16:467-476. [PubMed]
 
Ramsauer VP, Pino V, Farooq A, et al. Muc4-ErbB2 complex formation and signaling in polarized CACO-2 epithelial cells indicate that Muc4 acts as an unorthodox ligand for ErbB2. Mol Biol Cell. 2006;17:2931-2941. [PubMed]
 
Van der Sluis M, De Koning BA, De Bruijn AC, et al. Muc2-deficient mice spontaneously develop colitis, indicating that MUC2 is critical for colonic protection. Gastroenterology. 2006;131:117-129. [PubMed]
 
Velcich A, Yang W, Heyer J, et al. Colorectal cancer in mice genetically deficient in the mucin Muc2. Science. 2002;295:1726-1729. [PubMed]
 
Rousseau K, Vinall LE, Butterworth SL, et al. MUC7 haplotype analysis: results from a longitudinal birth cohort support protective effect of the MUC7*5 allele on respiratory function. Ann Hum Genet. 2006;70:417-427. [PubMed]
 
Scharfman A, Arora SK, Delmotte P, et al. Recognition of Lewis x derivatives present on mucins by flagellar components ofPseudomonas aeruginosaInfect Immun. 2001;69:5243-5248. [PubMed]
 
Carnoy C, Scharfman A, Van Brussel E, et al. Pseudomonas aeruginosaouter membrane adhesins for human respiratory mucus glycoproteins. Infect Immun. 1994;62:1896-1900. [PubMed]
 
Vishwanath S, Ramphal R. Tracheobronchial mucin receptor forPseudomonas aeruginosa: predominance of amino sugars in binding sites. Infect Immun. 1985;48:331-335. [PubMed]
 
Mitchell E, Houles C, Sudakevitz D, et al. Structural basis for oligosaccharide-mediated adhesion ofPseudomonas aeruginosain the lungs of cystic fibrosis patients. Nat Struct Biol. 2002;9:918-921. [PubMed]
 
King M, Rubin BK.Takishima T. Mucus rheology, relationship with transport. Airway secretion: physiologic bases for the control mucus hypersecretion. 1994; New York. NY Marcel Dekker:283-314
 
Sheehan JK, Richardson PS, Fung DC, et al. Analysis of respiratory mucus glycoproteins in asthma: a detailed study from a patient who died in status asthmaticus. Am J Respir Cell Mol Biol. 1995;13:748-756. [PubMed]
 
Henke M, Renner A, Huber RM, et al. MUC5AC and MUC5B mucins are decreased in cystic fibrosis airway secretions: am. J Respir Cell Mol Biol. 2004;31:86-91
 
Kater A, Henke MO, Rubin BK. The role of DNA and actin polymers on the polymer structure and rheology of cystic fibrosis sputum and depolymerization by gelsolin or thymosin beta 4. Ann N Y Acad Sci. 2007;1112:140-153. [PubMed]
 
Albers GM, Tomkiewicz RP, May MK, et al. Ring distraction technique for measuring surface tension of sputum: relationship to sputum clearability. J Appl Physiol. 1996;81:2690-2695. [PubMed]
 
Puchelle E, de Bentzmann S, Zahm JM. Physical and functional properties of airway secretions in cystic fibrosis-therapeutic approaches. Respiration. 1995;62Suppl:2-12. [PubMed]
 
Girod S, Galabert C, Lecuire A, et al. Phospholipid composition and surface-active properties of tracheobronchial secretions from patients with cystic fibrosis and chronic obstructive pulmonary diseases. Pediatr Pulmonol. 1992;13:22-27. [PubMed]
 
Girod de Bentzmann S, Pierrot D, Fuchey C, et al. Distearoyl phosphatidylglycerol liposomes improve surface and transport properties of CF mucus. Eur Respir J. 1993;6:1156-1161. [PubMed]
 
Tarran R, Button B, Picher M, et al. Normal and cystic fibrosis airway surface liquid homeostasis: the effects of phasic shear stress and viral infections. J Biol Chem. 2005;280:35751-35759. [PubMed]
 
Matsui H, Randell SH, Peretti SW, et al. Coordinated clearance of periciliary liquid and mucus from airway surfaces. J Clin Invest. 1998;102:1125-1131. [PubMed]
 
Rogers DF, Rubin BK.Stockley RA, Rennard S, Rabe K, et al. Mucolytics for COPD. Chronic obstructive lung disease. 2006; Oxford, UK Blackwell Publishing:756-768
 
Donaldson SH, Bennett WD, Zeman KL, et al. Mucus clearance and lung function in cystic fibrosis with hypertonic saline. N Engl J Med. 2006;354:241-250. [PubMed]
 
Henke MO, John G, Germann M, et al. MUC5AC and MUC5B mucins increase in cystic fibrosis airway secretions during pulmonary exacerbation. Am J Respir Crit Care Med. 2007;175:816-821. [PubMed]
 
NOTE:
Citing articles are presented as examples only. In non-demo SCM6 implementation, integration with CrossRef’s "Cited By" API will populate this tab (http://www.crossref.org/citedby.html).

Some tools below are only available to our subscribers or users with an online account.

Related Content

Customize your page view by dragging & repositioning the boxes below.

Find Similar Articles
CHEST Journal Articles
PubMed Articles
  • CHEST Journal
    Print ISSN: 0012-3692
    Online ISSN: 1931-3543