Innate immunity and mucus structure and function

Cystic Fibrosis Center, Campus Box 7248, 4019a Thurston Bowles, University of North Carolina at Chapel Hill, NC 27599, USA.
Novartis Foundation symposium 02/2006; 279:155-66; discussion 167-9, 216-9. DOI: 10.1002/9780470035399.ch13
Source: PubMed


Many of the proteins associated with innate immunity in the upper respiratory tract are to be found localized into mucus gels and the mucin-rich surface layers of the epithelium and the cilia. Mucus is a relatively dilute suspension of such macromolecules being around 2-4% solids in normal induced sputum. These proteins scavenge, immobilise and/or kill pathogens and at the same time immobilize them into the mucus. Mucus is moved from the lung by the mucociliary clearance mechanisms or by cough. Some 190 proteins are readily detectable in sputum by proteomics methods and about 100 in bronchial air-liquid interface culture secretions. This cell culture system mimics the surface ciliated phenotype of the large airways very well and about 85 secreted proteins are common to both culture and sputum secretions. The major single protein by weight in cell culture secretions is MUC5B and in sputum a mixture of MUC5B and MUC5AC. The three epithelial mucins MUC1, 4 and 16 are also detectable in both secretions. In this paper the roles that these molecules play in protecting and stabilising the ciliated surface and building the gel will be discussed. The role of water and ion homeostasis is particularly crucial in mucus gel formation and evidence is gathering that it is perturbation of hydration mechanisms that may play into defective mucus leading subsequently to stasis and mechanical problems.

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Available from: Mehmet Kesimer, Nov 16, 2015
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    • "The mucus layer is a tangled macromolecular mesh comprising 90% gel-forming mucins such as MUC5AC and MUC5B secreted by goblet surface epithelia and cells from the gland mucous tubule (Button et al., 2012). The other 10% of the mesh consists primarily of tethered mucins MUC1, MUC4 and MUC16 that are attached to surface cells, and therefore densely pack the negatively charged PCL fluid (Sheehan et al., 2007). CF is a mutation in the gene for the protein cystic fibrosis transmembrane conductance regulator (CFTR). "
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    ABSTRACT: The genetic disease cystic fibrosis (CF) is a mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, and results in viscous mucus and impaired mucociliary clearance leading to chronic recurring pulmonary infections. Although extensive experimental research has been conducted over the last few decades, CF lung pathophysiology remains controversial. There are two competing explanations for the observed depletion of periciliary liquid (PCL) in CF lungs. The low volume hypothesis assumes fluid hyperabsorption through surface epithelia due to an over-active Epithelial Na(+) Channel (ENaC), and the low secretion hypothesis assumes inspissated mucins secreted from glands due to lack of serous fluid secreted from gland acini. We present a spatial mathematical model that reflects in vivo fluid recycling via submucosal gland (SMG) secretion, and absorption through surface epithelia. We then test the model in CF conditions by increasing ENaC open probability and decreasing SMG flux while simultaneously reducing CFTR open probability. Increasing ENaC activity only results in increased fluid absorption across surface epithelia, as seen in in vitro experiments. However, combining potential CF mechanisms results in markedly less fluid absorbed while providing the largest reduction in PCL volume, suggesting that a compromise in gland fluid secretion dominates over increased ENaC activity to decrease the amount of fluid transported transcellularly in CF lungs in vivo. Model results also indicate that a spatial model is necessary for an accurate calculation of total fluid transport, as the effects of spatial gradients can be severe, particularly in close proximity to the SMGs. Copyright © 2015. Published by Elsevier Ltd.
    Journal of Theoretical Biology 07/2015; 382. DOI:10.1016/j.jtbi.2015.06.050 · 2.12 Impact Factor
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    • "The rate of mucociliary clearance depends on the composition of the airway surface liquid (ASL) lining the airway surface. ASL is made up of two layers, an upper viscoelastic layer of mucins secreted by the goblet cells and submucosal glands,50 which floats on a lower periciliary layer containing large membrane-bound glyocproteins, as well as tethered mucins (muc-1, muc-4 and muc-16).51,52 The periciliary layer is relatively less viscous, approximately 7 µM in height which corresponds to a length of outstretched cilia and acts as a lubricating layer for cilia to beat.32,52,53 "
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    ABSTRACT: Airway epithelium contributes significantly to the barrier function of airway tract. Mucociliary escalator, intercellular apical junctional complexes which regulate paracellular permeability and antimicrobial peptides secreted by the airway epithelial cells are the three primary components of barrier function of airway tract. These three components act cooperatively to clear inhaled pathogens, allergens and particulate matter without inducing inflammation and maintain tissue homeostasis. Therefore impairment of one or more of these essential components of barrier function may increase susceptibility to infection and promote exaggerated and prolonged innate immune responses to environmental factors including allergens and pathogens resulting in chronic inflammation. Here we review the regulation of components of barrier function with respect to chronic airways diseases.
    10/2013; 1(4):e24997. DOI:10.4161/tisb.24997
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    • "The fact that the solMUC5B had a slightly higher density compared to the gelMUC5B fits nicely with the findings that the surface layer of stomach mucus displayed a lower density than the superficial layer. In the airways, it has been suggested that the two mucins MUC5B and MUC5AC form spatially distinct mucus gels, one tuned to flow and the other to coughing (Sheehan et al., 2006). In the oral situation, one could postulate that gelMUC5B would act primarily on a surface constituting the mucus barrier, while solMUC5B would constitute a more solubilized lubricating mucus interacting with oral bacteria not yet attached to a surface. "
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    ABSTRACT: Salivary mucin, MUC5B, is an oligomeric glycoprotein, heterogeneous in size and with a diverse repertoire of oligosaccharides, which differ in composition and charge. Since complex salivary glycoproteins are considered to be the major source of nutrients for the oral supragingival microbiota, the major aim of the current study was to determine whether different preparations of non-denatured MUC5B could be isolated exhibiting different biological properties in relation to the microflora associated with the surfaces of the oral cavity. Two preparations, solMUC5B and gelMUC5B, were isolated by density-gradient centrifugation and were shown to have different buoyant densities, carbohydrate content and surface-adsorbing characteristics. To ascertain differences in biological activity, the two mucin preparations, both in solution and adsorbed to a model surface, were incubated with freshly isolated dental plaque and assayed for metabolic (dehydrogenase) activity with the fluoresecent substrate CTC (5-cyano-2,3-ditolyl tetrazolium chloride). The plaque bacteria exhibited higher metabolism with the solMUC5B preparation in solution, with 79.4 % active plaque cells compared to the controls without mucin (9.6 %), while gelMUC5B showed 48.2 % active cells with the same plaque population. In contrast, the same mucins adhered to a surface elicited a significantly lower metabolic response, with surface-associated plaque cells showing only 12.1 % active cells with solMUC5B and 29.2 % with gelMUC5B. These results suggested that the metabolism by the plaque cells adsorbed to surface-associated mucins was downregulated compared to the same cells suspended in mucin solution. This was confirmed in an experiment where active dispersed plaque/solMUC5B suspensions were shown to lose significant metabolic activity (e.g. 74.9 to 19.3 %) when allowed to interact with gelMUC5B adsorbed to a surface. Clearly, the solMUC5B and gelMUC5B preparations exhibited different biological activity when assayed with freshly plaque bacteria in suspension and in a biofilm.
    Microbiology 02/2009; 155(Pt 1):53-60. DOI:10.1099/mic.0.022111-0 · 2.56 Impact Factor
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