Rhodin (12) and, more recently, Breeze and Sheldon (13), have described the morphology of the airways. A ciliated pseudo-stratified respiratory tract mucosa extends from the nose down to the terminal bronchioles.
Figure 1 shows a scanning electron micrograph of a cross section of a rat trachea showing the cilia and overlying mucus. The major sources ofmucous glycoproteins are goblet cells and submucosal glands of both serous and mucous types (7). From the comparative volume of goblet cells and submucosal glands in nornal airways, it has been suggested that mucosal glands contribute 40 times the volume of secretions secreted by goblet cells (14,15). As one moves to the periphery of the lung, the percentages of both ciliated and goblet cells decreases (5,16). Epithelial serous cells (7), with a distribution similar to that of goblet cells, are another source of mucus. Clara cells, found primarily in the bronchioles (13), are also possible sources of glycoprotein or lipid or both (7).
Submucosal glands are limited to the trachea and bronchi. There are considerable species differences. Submucosal glands are numerous in humans, cats, pigs, and ferrets, infrequent in rodents, and nonexistent in geese and chickens (7,16,17). Goblet cells are numerous in humans, cats, pigs, and geese and infrequent in rodents (7).
Inhalation of irritant gases and aerosols can cause hypertrophy of mucous glands and hyperplasia of goblet cells (5,18). It is not clear which of these responses is of greater importance; the nature of the response presumably depends at least somewhat on the type of irritant and the species studied. Most of the data available for pollutant responses are from rats that have fewer goblet cells and mucous glands than man.
Control mechanisms of mucus glycoprotein secretions are not entirely clear. There is strong evidence for efferent parasympathetic innervation of the mucous glands (7), and so they are at least partially under the influence of the nervous system. Goblet cells and serous cells are more likely to be influenced by local effects; however, goblet cell numbers are increased by parenteral administration of the sympathomimetic agent isoproteronol (19). Both parasympathetic and sympathetic stimulation have produced increased mucus glycoprotein production and volume of secretions (19). Parasympathetic agonists decreased secretions, whereas sympathetic agonists appeared to have no effect (19).
There is general agreement that the mucous blanket consists of two phases. An approximately 5,m thick layer of low viscosity periciliary fluid bathes the cilia in the trachea. Above this is a gel phase of higher viscosity material about 5 ,um thick (20). Recent observations in our laboratory indicate that the mucus glycoprotein blanket preserved after fixation and drying is ca. 1 to 2 ,m thick in normal rats (Fig. 1). The clawed tips of the cilia touch the upper layer at the top of their stroke (5). The existence of these two layers is supported by the work of Lucas and Douglas (21) and Bang and Bang (22) and Morgan et al. (23). The primary source of the upper layer is undoubtedly goblet cells and mucous glands; however, the source and control of the periciliary fluid has not been clearly demonstrated, although it appears to be related to water transport (7) across the epithelium.
Whether the upper mucous layer is a continuous blanket or consists of discrete "flakes" or "plaques" is a controversial issue. The work of Iravani and Van As (24), reviewed by Van As (25), supports the latter hypothesis. Many other workers have presented data indicating a continuous mucous blanket (20-22,26,27).
From available data it appears most likely that the gel mucous layer is thinner and discontinuous as the airways become smaller (5), where there are fewer ciliated and mucous secreting cells, as noted earlier. Even in the trachea we have observed areas as shown in Figure 2a where there is no overlying mucous glycoprotein and in Figure 2b where it is relatively thin and strands of glycoprotein can be seen. In our observations, these regions represent 20 to 25% of the surface area of the trachea in normal rats. Certainly mucous transport velocities decrease from the trachea to peripheral airways as shown by Iravani and van As (24), Asmundsson and Kilburn (28), and Morrow et al. (29).
Tracheal mucous velocities have been observed to range from 2 to 20 mm/min (1,2,5) in a variety of species measured with a variety of techniques. When consistent methodology is used (30), smaller species have slower velocities than large species. Velocities in the smaller bronchioles have been found to be
It must be recognized that description of mucociliary clearance in terms of velocity has limitations. At best, it represents an average which has a wide standard deviation (31,32), and it represents the fastest movement of material when a leading edge of transported material is measured. The key point is that mucous clearance is not necessarily as relentless and uniform as it is sometimes portrayed. For instance, there are preferential routes of clearance, at least in the trachea (32), and presumably in the lower airways. Therefore, there is the chance for particles to remain in an area of slow clearance for some time. Clearance from the smaller airways is also probably slower than has been generally recognized. Lee (33) has calculated velocities as low as - 5 j.tm/min for terminal bronchioles by fitting a kinetic model to observed lung clearance curves.