It is still not known whether the mucus layer is continuous or discontinuous in human airways in vivo, although it appears likely at least that the layer is not homogeneous but is deeper at some sites than at others. Because they provide, in effect, a combinatorial library of carbohydrate sequences, mucins can bind to virtually all particles that land on airway epithelia and can thus clear them from the lung ( 16). It appears that mucin macromolecules are well adapted to binding and trapping inhaled particles for clearance from the lung, at least in part because of the extraordinary diversity of their carbohydrate side chains. The properties of the mucin gel are determined by this tangled network, which reflects, in part, the water content, monovalent and divalent ion concentrations, and pH of the ASL. The mucus layer consists of high–molecular weight, heavily glycosylated macromolecules, products of at least two distinct genes ( MUC5AC and MUC5B), that behave as a tangled network of polymers ( 15). The ASL consists of at least two layers, a mucus layer and a periciliary liquid layer (PCL Figure 2). Scale bar = 5 μm.Īnalysis of photomicrographs of this preparation, combined with immunocytochemical studies, have revealed several key features of the microanatomy of the ASL compartment ( 13, 14). The keratan sulfate component of the glycocalyx is visualized by Texas red–labeled anti–keratan sulfate (anti-KS) antibodies. Bottom right: Detection of glycocalyx by fluorescence/confocal microscopy. The mucus layer is visualized as green fluorescent beads and the PCL as the “bead-free zone” interposed between the mucus layer and cell surface (black). Top right: Fluorescent “dissection” of mucus layer and PCL in living WD airway epithelia by confocal microscopy. The cells were stained with calcein, AM, (green), and the ASL was visualized with Texas red dextran. ( c) Left: X-Z confocal image of living WD human airway epithelial culture.
Note the high degree of organization of this barrier. ( b) Visualization of glycocalyx on WD human airway epithelia by the freeze substitution technique. Note a distinct mucus layer atop a distinct PCL. ( a) WD human airway epithelial culture exhibiting rotational mucus transport (see Figure 3), fixed with perfluorocarbon/osmium. We will attempt to fill in the gaps in our knowledge regarding important aspects of the mucus clearance system, and, where relevant, point out differences between the two views of innate airway defense. Here, we will focus on the role of mucus clearance in the lung as the more important innate defense mechanism in health and disease, including CF. The predictions of each of these models and the relevant data have been extensively reviewed ( 2, 3, 10, 11). In this hypothesis, the two important functions for epithelia are the production of salt-sensitive defensins that are secreted into airway lumens, and the production of a low-salt (<50 mM NaCl) liquid on airway surfaces that renders defensins active ( 9). This view emphasizes a role for a “chemical shield” in protecting the lung against inhaled bacteria ( 8).
More recently, a second view of innate airway defense has emerged as a result of studies of the pathogenesis of cystic fibrosis (CF) ( 7). In this view, the role of the epithelia lining airway surfaces is to provide the integrated activities required for mucus transport, including ciliary activity and regulation of the proper quantity of salt and water on airway surfaces via transepithelial ion transport. In the more traditional view, mechanical clearance of mucus is considered the primary innate airway defense mechanism ( 4– 6). There is still little agreement on the nature of these innate airway defense mechanisms ( 2, 3) (Figure 1). The chemical shield hypothesis is shown on the right, with the epithelium depicted as having a salt- but not a volume-absorbing function to produce the hypotonic ASL required for defensin activity. The schema depicts discrete mucus and periciliary liquid layers and ascribes to the epithelium a volume-absorbing function. The mechanical-clearance-of-mucus hypothesis is shown on the left. The lung is depicted as an inverted funnel, reflecting the relative surface area of distal versus proximal airways. Pulmonary defense mechanisms preventing chronic bacterial infection.
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