PerspectiveBiochemistry

Walking on Solid Ground

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Science  24 Aug 2012:
Vol. 337, Issue 6097, pp. 924-925
DOI: 10.1126/science.1227091

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Mucosal surfaces throughout the human body—including those of the respiratory, gastrointestinal, and genitourinary tracts—are wet tissues that include some form of mucus gel among their defenses (1). In the airways, the mucus gel layer is propelled out of the lungs by ciliary beating and continually renewed by secretion of polymeric mucins (see the figure, panels A and B). This process enables the rapid removal of inhaled pathogens and toxicants (2). The conventional model has been that the mucus gel layer is suspended above a fluid periciliary layer by the beating of cilia. However, as Button et al. report on page 937 of this issue (3), this model is fundamentally wrong. The authors show that the periciliary layer has a macromolecular glycoconjugate structure with a higher density than the mobile gel layer. This dense network is grafted to the epithelial surface.

The incorrect impression of a fluid periciliary layer seems to have arisen because microscopy using older fixation techniques did not show any structure and because intuition suggests that motile cilia should move best in a fluid. However, more recent studies have revealed a dense network of macromolecules in the periciliary layer, emanating from the surface of cilia, microvilli, and apical cell membranes (3, 4). This network is mainly composed of mucin proteins tethered to the cell surface by transmembrane domains, and tethered mucopolysaccharides closer to the cell surface (5). Mucins are large, heavily glycosylated proteins. Because the charged sugar moieties repel each other, membrane-tethered mucins adopt a partially extended configuration protruding from the cell surface (see the figure, panels C and D).

Airway mucus layers.

(A) A mobile mucus gel is continually swept out of the lungs and swallowed (blue). (B) The mucus layer moves over an immobile periciliary layer. Secretory cells synthesize polymeric mucins that form the mobile gel; ciliated cells propel the gel. (C) Secretory cells release mucin polymers that travel upwards to be incorporated into the mobile gel layer. Button et al. now show that glycoconjugates (membrane-tethered mucins and mucopolysaccharides) are present in the periciliary layer at greater density than glycoconjugates (polymeric mucins) in the gel layer. (D) Densely packed sugar side chains cause membrane-tethered mucins to assume a partially extended configuration, whereas mucins in the gel layer are random entangled coils.

CREDIT: ADAPTED BY P. HUEY/SCIENCE

These observations led Button et al. to propose a gel-on-brush model, in which the mucus gel overlies a brush with mucin and mucopolysaccharide bristles. The model has several important implications. First, it helps to explain how distinct mucus and periciliary layers form in the liquid overlying the epithelium. The dense packing of grafted mucins in the periciliary layer will tend to exclude unattached polymeric mucins, which form the mobile gel layer.

The model may also help to explain the coordination of the rhythmic beating of the cilia, which are physically coupled by the spatial impingement of grafted mucins on neighboring cilia.

Furthermore, charged polymers are highly effective lubricants in an aqueous environment (6). This lubrication could enable low-friction ciliary beating despite the density of macromolecules in the periciliary layer, as well as low friction between the periciliary and mobile gel layers.

Button et al. show that mucins and tethered mucopolysaccharides are grafted with increasing density from the top of the periciliary layer (in contact with the gel layer) to its bottom (in contact with the epithelial surface). This arrangement should propel exogenous particles out of the periciliary layer, minimizing contact between the epithelium and infectious microbes with diameters above 40 nm (including bacteria, fungi, and large viruses) (4, 7).

Finally and most importantly, this model offers a quantitative explanation of the movement of liquid between layers in health and disease. The higher density of glycoconjugates in the periciliary layer than in the gel layer and their grafting to the cell surface result in a nearly constant amount of liquid in the periciliary layer, except under conditions of severe underhydration. Because they are grafted, periciliary glycoconjugates have little ability to absorb more liquid and swell with increasing hydration. Instead, increased liquid causes swelling of the mobile gel layer; such swelling is generally well tolerated (8). With decreasing hydration, the periciliary layer draws liquid from the gel layer because of the higher osmotic modulus of the periciliary layer, attenuating dehydration of the periciliary layer until the gel layer becomes too dehydrated to resist further liquid transfer. At this point, mucus clearance fails catastrophically because compression of cilia prevents their propulsive action (3) and probably also as a result of adhesion between the two layers (9).

Underhydration may be caused by a primary defect in the volume of liquid within the airway lumen in cystic fibrosis or by acquired defects in chronic obstructive pulmonary disease (COPD) and airway infections (2). Indirect underhydration of the gel layer may occur when polymeric mucins are produced, stockpiled, and then suddenly released in asthma, overwhelming the normal liquid volume (10). Another cause of underhydration in cystic fibrosis is the failure of polymeric mucins to fully expand after exocytosis due to defective bicarbonate secretion, resulting in inadequate calcium ion sequestration and excessive mucin cross-linking (1113).

One issue not addressed by Button et al. is that the absence of cilia and their grafted mucins would seem to leave gaps in the periciliary macromolecular network overlying secretory cells (see the figure, panels B and C). Some space may be needed for mucin polymers to flow from secretory granules to the mobile gel layer (14). The gap is partially filled by the outward bulging of secretory cells (see the figure, panel C). In addition, one of the largest proteins in the mammalian genome, the mucin MUC16, is tethered to the surface of secretory cells (4), where it may form an effective glycoconjugate brush together with tethered mucopolysaccharides.

The gel-on-brush model proposed by Button et al. has the capacity to provide a common underlying mechanism to explain the progression of human airway diseases that have mucus stasis, inflammation, and infection in common. It has immediate implications for understanding how contact between pathogens and the underlying epithelial cells is prevented and how airway surface liquid is allocated between the two layers. The gel-on-brush model and the pioneering measurement methods of Button et al. should be used in the future to see how factors such as mesh size, osmotic modulus, rate of mucus clearance, and degree of microbial colonization change in mutant animals (for example, tethered mucin or ion channel deletants) or in conditions of challenge (for example, asthma or infection models). Eventually, these insights should help to yield novel therapeutic strategies for airway diseases.

References and Notes

  1. A gel is a dilute macromolecular network that does not flow. In mucus, the solvent is water and the network is composed of mucin glycoproteins.
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