Mucus clearance as a primary innate defense mechanism for mammalian airways.

The conducting airways branch 20–25 times between the trachea and the alveoli as inhaled air passes from the relatively constricted nasal/tracheal passages to the large surface area of alveoli (70 m2), where gas exchange occurs. This branching anatomy leads to a surface area that expands greatly from proximal airways (e.g., third generation; ∼50 cm2) to distal airways (20th to 25th generation; ∼2 m2). The regional differences in airway surface area (or airway perimeters; ref. 1), which is often depicted by showing the airways as an inverted funnel (Figure 1), pose interesting challenges for lung defense. Because many of the particles that settle on airway surfaces are infectious, airways have evolved innate defense mechanisms that constantly protect airways against bacterial and other types of infection. There is still little agreement on the nature of these innate airway defense mechanisms (2, 3) (Figure 1). In the more traditional view, mechanical clearance of mucus is considered the primary innate airway defense mechanism (4–6). 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. More recently, a second view of innate airway defense has emerged as a result of studies of the pathogenesis of cystic fibrosis (CF) (7). This view emphasizes a role for a “chemical shield” in protecting the lung against inhaled bacteria (8). 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). The predictions of each of these models and the relevant data have been extensively reviewed (2, 3, 10, 11). 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. 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. Microanatomy of the airway surface With the advent of the capacity to fix airway surface liquid (ASL) in vivo, using the perfluorocarbon/osmium technique pioneered by Sims et al. (12), and the development of well-differentiated (WD) human airway epithelial cultures that exhibit mucus transport in vitro (13), it is now possible to investigate the microanatomy of mucus transport on airway surfaces at high resolution. Representative images depicting the range of morphologic techniques that can be applied to this culture system are shown in Figure 2. Analysis of photomicrographs of this preparation, combined with immunocytochemical studies, have revealed several key features of the microanatomy of the ASL compartment (13, 14). The ASL consists of at least two layers, a mucus layer and a periciliary liquid layer (PCL; Figure 2). 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 Mucus clearance as a primary innate defense mechanism for mammalian airways