The upper respiratory tract plays a critical role in conditioning air entering the lungs. Most of the air moving through the nasal cavity has turbulent flow characteristics. In addition, air moving downward into the trachea encounters a right-angle turn at the posterior nasopharynx (Fig. 3). Because of these characteristics of nasopharyngeal anatomy and air flow dynamics, most airborne particulate matter and highly reactive gases impact or are absorbed along the mucosal surfaces and so are removed in the upper airways. Aggregates of lymphoid tissue in the posterior pharynx (pharyngeal tonsils) also play a role in clearing the large amounts of airborne material deposited in the nose and other regions of the upper respiratory tract. Most airborne materials deposited in the upper airway tract are moved posteriorly along the nasal mucous coat to the posterior pharynx, where the secretions are eventually swallowed. The upper respiratory tract also plays a role in warming and humidifying the air. This process is continued in the large airways. For gases of low reactivity and particles of 1 µm in size, upper respiratory tract clearance is less efficient. A significant fraction of these airborne pollutants is deposited in the small airways and alveolar regions.
FIG. 3. Anatomy of the upper and lower respiratory tracts
Trachea and Bronchi
The trachea and main bronchi contain U-shaped rings of hyaline cartilage. The dorsal wall of the trachea is made up of a smooth muscle coat (the trachealis muscle). The main bronchi are fully encircled with cartilage for only four to six generations. Thereafter, the cartilaginous rings of intrapulmonary bronchi contain islands of cartilage that are not contiguous. The number and size of these cartilaginous islands diminish as the airways become smaller and more peripheral. This organizational pattern of cartilage has the advantage of assisting in an effective cough mechanism. The cough is initiated when intrapulmonary pressure is raised against a closed glottis, causing the smaller bronchi to narrow in size. The abrupt opening of the glottis with the onset of cough leads to high pressure and rapid flow through narrow airways, which can facilitate removal of obstructing secretions. Under normal breathing conditions, the intrapulmonary bronchi do not collapse because they are tethered to surrounding alveolar tissue with elastic and cartilaginous interconnections. The incomplete cartilage rings provide support for the intrapulmonary airways while still permitting them to narrow.
Intrapulmonary bronchi contain a subepithelial elastic layer. Outside this, smooth muscle bundles form a narrow spiral around the airways, with the smooth muscle extending to the level of the respiratory bronchiole. The tight spiral organization of the smooth muscle causes airway narrowing when the smooth muscle contracts. A loose connective tissue layer surrounds the muscular coat, and bronchial glands and cartilage plates lie in this space.
The bronchial epithelium is a stratified epithelium that includes a number of cell types. Predominant among these are secretory cells, which in the large airways are primarily mucus-secreting cells. Ciliated epithelial cells and nonciliated basal cells make up the other two major airway epithelial cell types. The bronchial epithelium also contains neurosecretory cells, termed Kultschitsky cells or K cells. They are similar to the Kultschitsky cells found in the gastrointestinal tract. These cells, which occur singly or in clusters of four to 10 cells termed neuroepithelial bodies, are thought to have a neuroendocrine secretory function. These endocrine cells are found in both bronchi and bronchioles. Kultschitsky cells are most distinctively recognized by their large numbers of fine, dense core granules aggregated in the basal part of the cells. The granules are secreted basally into the peribronchial connective tissue and surrounding smooth muscle. Various products identified with the neuroendocrine cells influence smooth muscle contraction, secretion of mucus, and ciliary beat.
Cilia are the principal means for clearing inhaled toxicants deposited in the mucous lining layers of the nasal passages and airways. Dysfunction in cilia is known to predispose individuals to respiratory infections and bronchiectasis. Ciliated cells are densely distributed in the airways, and the cilia greatly increase their apical surface area. The plasma membrane surface of the cilia accounts for approximately 80% of the plasma membrane surface in airways. Thus, the cilia themselves are a primary filter and/or target for inhaled toxicants that react with cell membranes. In the serous fluid layer in which they beat, the cilia make up 40%–50% of the volume. Each ciliated cell contains approximately 200 cilia; these beat in a biphasic stroke consisting of a fast forward flick and a slower recovery motion. Coordinated strokes by adjacent ciliated cells produce a proximally directed wave of motion in the mucous lining layer. The beating cilia produce mucociliary transport rates that vary from approximately 20 mm/min in the large bronchi to a distinctly slower rate of approximately 1 mm/min in the bronchioles. This gradient in transport rates has been assumed to be the result of a corresponding gradient in ciliary density, with fewer cilia in the small airways and greater numbers in the larger airways, to prevent piling up of mucus on the relatively small surface area of the larger airways. However, direct measurements of the density of ciliated cells and their cilia do not support this hypothesis. The mechanism or mechanisms responsible for the higher transport rate of mucus in larger airways remain to be determined.
Ciliated cells not only mechanically move mucus but also have a secretory function. These epithelial cells contain ion pumps that move sodium away from the bronchial lumen and chloride toward it. This allows water to follow the resulting osmotic gradient and thereby control the thickness and viscosity of the serous fluid layer. Proteins controlling this ion flux are encoded by the cystic fibrosis transmembrane conductance regulator (CFTR) gene. This gene is a highly regulated chloride channel in the apical membrane of ciliated epithelial cells. Mutations in this gene cause cystic fibrosis.
Mucous cells (goblet cells) and mucous glands both produce mucus, but the volume coming from glands is substantially greater than that derived from mucous cells under normal conditions. The mucous glands are compound tubular glands lining the submucosa of the bronchi between cartilage plates. The glands are connected by a secretory tubule to the airway lumen. Plasma cells are often found around these secretory tubules. The plasma cells contain both IgA and IgG, although the primary immunoglobulin in mucus is 11S secretory IgA. Two IgA molecules, both of which are produced by plasma cells, are joined by the J protein. These molecules are then complexed with a secretory piece by epithelial cells lining the secretory tubules, and the complex is transported into the tubular lumen and into the mucous layer.
Examples of airway epithelium and mucous layer architecture from human bronchi are shown in the electron micrographs of Fig. 4. Characteristic profiles of ciliated and goblet cells are illustrated in Fig. 4A. In Fig. 4B, a goblet cell is in the process of secreting into the mucous lining layer. The mucous lining layer in this micrograph has a well-defined electron-dense surface film at the top of the sol layer. Examples of other secretory and basal cells in human airways are shown in Fig. 5. Secretory cells other than goblet cells are typically found in highly clustered groups, as illustrated in Fig. 5A, showing a group of secretory cells containing electron-dense granules. A basal cell with numerous desmosomes (d) and keratin filaments (f) appears in Fig. 5B. An intermediate cell (I) with the same features as a basal cell (i.e., desmosomes, keratin filaments, and a high nucleus-to-cytoplasm ratio) but no basement membrane contact is shown in Fig. 5C. The layered arrangement of cells in human bronchi is principally attributable to the basal cell layer, which accounts for approximately 90% of the cell surfaces making contact with the basement membrane. In the pseudostratified epithelium of human bronchi, the average basement membrane contact of a ciliated, goblet, or other secretory cell is significantly smaller than that of basal cells. The large concentration of keratin filaments and hemidesmosomes found in basal cells suggests that these cells play a primary role in the attachment of columnar cells to the basal lamina.
FIG. 4. Electron micrographs of the airway epithelium and mucous lining layers from human bronchi. A: Ciliated cells showing mitochondria concentrated in the apical portion of the cell and cilia extending into the mucous lining layer. One goblet cell is shown with its secretory granules distributed across the upper half of the cell. B: Two goblet cells in the process of releasing electron-lucent secretory granules from their apical surface into the mucous lining (arrow). This micrograph also illustrates a region in which the gel (or electron-dense) layer above the cilia is absent.
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