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CHAPTER 11. The Respiratory System

The microscopic study of animal tissues and cells

Overview – Respiratory System
Plate 11-1. The Trachea 
Plate 11-2. The Bronchiole 
Plate 11-3. The Terminal Bronchiole 
Plate 11-4. The Respiratory Bronchiole And Alveolus

The primary function of the respiratory system is to provide oxygen to, and remove carbon dioxide from, the circulating blood. To accomplish this task, the respiratory system must take in oxygen from the atmosphere and deliver it directly to the red blood cells. The red blood cells, or erythrocytes, course through the general circulation and exchange oxygen for carbon dioxide with each of the body’s many trillions of cells.

The microanatomic architecture of the respiratory system is highly complex. Despite its structural complexity, the respiratory system can be easily understood if you remember that it is constructed to perform one major function: to exchange gases between blood and air. Gas exchange between blood and air occurs across the thin walls of tiny hollow sacs called alveoli, which lie within the lung at the distal end of the respiratory tree. When inhaled air arrives at an Alveolus, it can go no further; it remains there until it is moved out by exhalation to make room for fresh, oxygen-rich air taken in with the next breath.

Much of the respiratory system is designed to deliver air to the alveoli. The major parts of the respiratory system through which air passes are the nasal cavity, the pharynx, the larynx, the trachea, the bronchi, the bronchioles, the terminal bronchioles, the respiratory bronchioles, the alveolar ducts, the alveolar sacs, and finally the alveoli. All of the airways from the nasal cavity through the terminal bronchioles are called conductive airways, since no gas exchange occurs across their walls. The respiratory bronchioles, alveolar ducts, alveolar sacs, and alveoli are called respiratory airways, since gas exchange does occur across their walls.

When one breathes in, air is drawn into the nasal cavity, in which a number of processes prepare the air for passage into the delicate alveoli. First, the air is warmed by blood that flows through a rich capillary bed that underlies the nasal Mucosa. Next, the air is moistened by the blanket of watery Mucus that lines the nasal epithelium. Secreted by both goblet cells and a well-developed system of submucosal glands, the Mucus that covers the epithelial lining of the nasal cavity and other conductive airways also serves to purify the air by surface adsorption of potentially harmful substances including airborne particles such as asbestos and water-soluble gases such as sulfur dioxide. Toxic materials unsuitable for inhalation will in all likelihood be detected by a battery of exquisitely sensitive olfactory receptors located deep within the nasal cavity that will alert the individual to their presence.

Having passed through the nasal cavity, pharynx, and larynx, air enters the trachea, a short tube roughly the width of a garden hose with walls that are reinforced by cartilage. The trachea then bifurcates to form two smaller bronchi that enter the lungs. The bronchi branch repeatedly into smaller subunits – the bronchioles, terminal bronchioles, and respiratory bronchioles. The respiratory bronchioles give rise to alveolar ducts; these, in turn, lead to alveolar sacs, which are lined with alveoli.

The microanatomy of five of these airways – the trachea, bronchioles, terminal bronchioles, respiratory bronchioles, and alveoli – will be described in this chapter. The histologic organization of the nasal Mucosa and the olfactory Mucosa will be described in Chapter 20.

After inhaled air has passed through the nose, pharynx, and larynx, it enters the trachea. The trachea is a thick-walled tube, some 12 cm in length, that directs air down toward the pair of primary bronchi that enter the lung. The entire wall of the trachea of the mouse, which was selected because its small size permits inclusion in a single photographic field, is shown in cross section by the light microscope in Figure A. The trachea’s inner surface, facing the lumen (L), is lined by a pseudostratified Columnar Epithelium that contains ciliated cells, goblet cells, and Basal Cells. Even at this relatively low magnification, motile cilia (arrow) are evident at the epithelial surface, as are Mucus droplets (arrowhead) atop the goblet cells.

The tracheal epithelium (E) lies atop a highly elastic Lamina Propria (LP), which grades into the Submucosa (S). The well-developed Submucosa contains conspicuous rings of Hyaline Cartilage (C) that keep the trachea open when the neck is bent or turned. The cartilage is covered by a tough Perichondrium (P), which, in the outer region of the wall, is covered by the Adventitia (A), a sheath of loose connective tissue that envelops the outer surface of the trachea. This spatial arrangement of component tissues – epithelium, lamina propria, subcosa, and Adventitia – is common to many of the body’s interior tubular systems.

The epithelium, Lamina Propria, and part of the Submucosa are shown in greater detail in Figure B and C, a matched pair of light and electron micrographs of serial cross sections through the trachea of the monkey. The pseudostratified columnar ciliated epithelium of the monkey trachea is much thicker than that of the mouse depicted in Figure A. The goblet cells (G), as the name suggests, have a goblet-shaped Cytoplasm filled with Mucus droplets that displace the Nucleus and biosynthetic machinery toward the basal pole of the cell. The ciliated cells (Ci) appear much darker and have numerous motile cilia projecting from the cell surface. Taken together, these two cell types generate the mucociliary blanket that protects the inner tracheal surface. The goblet cells, along with large submucosal glands, produce and secrete the Mucus; the cilia move Mucus toward the mouth. In this way, foreign materials that enter the respiratory system are entrapped by the sticky Mucus and are rapidly moved toward the throat to be swallowed or expectorated. At the bottom of the epithelium are the Basal Cells (B), stem cells that replace worn-out ciliated and goblet cells.

The epithelium rests upon a well-developed basement membrane (BM), readily visible by light and electron microscopy. The Basement Membrane, in turn, rests upon the Lamina Propria (LP), a network of loose connective tissue that, in the trachea, is rich in elastic fibers. Because the tracheal epithelium, like all epithelia, is avascular, it must receive nutrients and oxygen from the rich bed of capillaries (Ca) that flow through the Lamina Propria. Cells of the immune series, such as Plasma cells (*), are common in the Lamina Propria, as are the flattened profiles of Elastin-producing and Collagen-producing fibroblasts (F).

Beneath the lamina propia lies the Submucosa (S), which here contains Hyaline Cartilage (C). Deeper in the respiratory system, the cartilage becomes less and less prominent until it is absent from the bronchioles, as depicted in Plate 11-2.

Figure A. Light micrograph of cross section through mouse trachea. A, Adventitia; C, cartilage; E, epithelium; L, lumen; LP, lamina propria; P, Perichondrium; S, Submucosa; arrow, motile cilia; arrowhead, Mucus droplet. 610 X

Figures B and C. Matched pair of light and electron micrographs of serial sections through the trachea of the macaque. B, basal cell; BM, Basement Membrane; Ca, capillary; Ci, ciliated cell; C, cartilage; I, Fibroblast; G, Goblet Cell; L, lumen; LP, Lamina Propria; S, Submucosa; SG, submucosal gland; *, Plasma cell. 740 X

Respiratory System

Plate 11-1
Plate 11-1, Figures B and C. Matched pair of light and electron micrographs of serial sections through the trachea of the macaque. B, basal cell; BM, Basement Membrane; Ca, capillary; Ci, ciliated cell; C, cartilage; I, Fibroblast; G, Goblet Cell; L, lumen; LP, Lamina Propria; S, Submucosa; SG, submucosal gland; *, Plasma cell. 740 X

The trachea, described in Plate 11-1, forks at its base to form two primary bronchi. Although the bronchi are histologically similar to the trachea, the arrangement of cartilage in their walls is markedly different. Bronchi, for example, do not have the C-shaped rings of cartilage present in the trachea. Instead, they have a series of plates of cartilage in their walls. These cartilage plates become fewer along the length of the bronchial tree as the primary bronchi divide and produce generations of smaller bronchi. Small bronchi continue to divide, thus giving rise to a series of airways of smaller and smaller caliber. When the airways are reduced to a diameter of 1 mm or less, they are called bronchioles.

Bronchioles differ from bronchi in two very important ways. First, they usually lack the cartilage plates that support the walls of the bronchi. Second, the bronchioles have a relatively greater amount of Smooth Muscle in their walls than bronchi. These two distinct microanatomic features allow the bronchiole’s walls to constrict, thereby providing a mechanism for controlling the flow of air to the more distal portion of the lung, in which gas exchange occurs. When the parasympathetic nerves that innervate the Smooth Muscle bundles are stimulated, the muscles contract and the bronchioles constrict. Conversely, under conditions of sympathetic nervous stimulation, bronchioles dilate. In this fashion, the amount of ventilation of the alveoli can be brought to a level that matches the perfusion (circulation) of blood in a specific region of the lung at a particular time.

The microanatomy of the bronchiole of the squirrel monkey is illustrated in Figures A and B. The bronchiolar epithelium, like that of the trachea, is a pseudostratified columnar ciliated epithelium consisting of goblet cells (G), ciliated cells (Ci), and Basal Cells (B). As one looks distally along the branches of the respiratory tree, the epithelium changes in several ways. First, the epithelium decreases in height. Second, the ratio of the number of goblet cells to ciliated cells decreases (compare, for example, the epithelium of the bronchiole shown at left with that of the trachea on Plate 11-1). In Figures A and B, the lumen (L) of the bronchiole is at the top of the field of view. Many motile cilia (arrow), emerging from a row of basal bodies (BB) near the surface of the ciliated epithelial cells (Ci), project into the lumen. Mitochondria, which provide the ATP necessary for ciliary motility, are abundant at the apical pole of the ciliated cells. Goblet cells are scarce and in this preparation were rarely caught in longitudinal section, appearing instead as islands of Mucus droplets (arrowhead). Consequently, the plane of section can give the incorrect impression that Mucus droplets arise from cells other than the goblet cells themselves.

The Cytoplasm of the goblet cells appears darker than that of the ciliated epithelial cells. Darker still are the Basal Cells – small, pyramidal cells whose nuclei lie close to the Basement Membrane. As in the trachea, the basal cells serve as stem cells that undergo periodic mitotic division. The daughter cells then differentiate to form new ciliated or goblet cells as needed.

Beneath the Basement Membrane lies the Lamina Propria (LP), which rests atop the Submucosa (S). The Submucosa contains connective tissue fibers (CT) and the fibroblasts (F) that make them, Antibody-producing Plasma cells (P-Fig. A), and capillaries (C). In addition, bundles of Smooth Muscle cells (SM) are present. The Smooth Muscle bundles are wrapped spirally within the bronchiole’s wall like the coils of a spring. Consequently, in a longitudinal section through a bronchiole, such as that depicted at left, the smooth muscle fibers appear in nearly cross-sectional image.


Plate 11-3
Plate 11-3, Figures A and B. Low-magnification electron micrographs of a cross section through the bronchiole of the squirrel monkey. B, basal cell; BB, basal bodies; BM, Basement Membrane; C, capillary; Ci, ciliated epithelial cell; CT, connective tissue fibers; F, Fibroblast; G, Goblet Cell; L, lumen; LP, Lamina Propria; P, Plasma cell (Fig. A); S, Submucosa; SM, Smooth Muscle; arrow, motile cilia; arrowhead, Mucus droplets. Figure A, 2,000 X; Figure B, 2,800 X

As described in the preceding sections on the respiratory system, the respiratory tree branches repeatedly, giving rise to successive generations of smaller and smaller airways. The final, and smallest, element in the conductive portion of the respiratory system is the terminal bronchiole. Having a diameter less than 0.5 mm, the terminal bronchiole is a tiny tube that, like the bronchiole from which it stems, has a Submucosa lacking both cartilage and submucosal glands.

The microanatomy of a typical primate terminal bronchiole is shown at right. Figure A, a survey electron micrograph, depicts a longitudinal section through a terminal bronchiole at low magnification. Figure B shows a small part of the same field at higher magnification. In Figure A, the lumen (L) of the terminal bronchiole is at the upper right; the lumen of an adjacent pulmonary vein (V) is at the lower left. The image of the tissue that transects the field, then, consists of the wall of a terminal bronchiole and the wall of a vein that both run parallel through the lung. At the left side of the micrograph (arrow), the airway and the vessel split apart, revealing the terminal bronchiole itself, apart from the vein.

The key to visual recognition of the terminal bronchiole lies in the structure of its epithelium, which differs from that of the bronchiole in two important respects. First, the epithelium has experienced a significant decrease in height and is now a ciliated simple Cuboidal Epithelium. Second, no goblet cells are present. Instead, a new type of cell, the Clara Cell (C), is encountered. The ciliated epithelial cells (Ci), much shorter than those of the trachea or bronchiole, are cuboidal cells with large, round, centrally located nuclei. Each Nucleus is euchromatic and possesses a prominent Nucleolus. The Cytoplasm, relatively pale in appearance, contains a dense population of free ribosomes. Slender Mitochondria are uniformly distributed throughout the cell; motile cilia project from basal bodies at its free surface. In addition, many Microvilli, interspersed among the cilia, cover the apex of the cell and substantially increase its surface area. Comparative examination of Plates 11-1, 11-2, and 11-3 gives the distinct impression that, as the airways become smaller, not only does the number of goblet cells decrease, but the number of cilia per ciliated cell is reduced. These two microanatomic features may be related; as one proceeds along the respiratory tree, less Mucus is secreted, requiring fewer cilia for its transport along the epithelial surface.

Perhaps the most distinctive morphologic feature of the terminal bronchiole is the Clara Cell. Clara cells are dark, slender cells that are taller than the ciliated epithelial cells. They are readily identified in light and electron micrographs by their conspicuous vesicle-rich, domed cell surface – a dome that projects into the lumen well above the surface of the ciliated epithelial cells. Clara cells are believed to be secretory cells that, elaborate a substance that, when liberated by Exocytosis from the cell, flows along the lumenal surface of the epithelium. This substance, apparently similar to pulmonary Surfactant (see Plate 11-4), is thought to reduce surface tension, thereby preventing the inner surfaces of the terminal bronchiole from sticking together when the bronchiole is closed during expiration.

Closure of the terminal bronchioles during expiration is accomplished by the Smooth Muscle that is abundant in the Submucosa. As in the bronchiole, the Smooth Muscle, here imaged in cross section, is wrapped spirally around the terminal bronchiole. Contraction of these smooth muscle fibers constricts the lumen, thereby forcing air out of and preventing airflow into the terminal bronchiole itself.

At its distal end, the terminal bronchiole – the last of the conductive airways – gives rise to the respiratory bronchiole, the first of the respiratory airways. The microanatomy of the respiratory bronchiole and alveoli is illustrated in the overleaf in Plate 11-4.

Plate 11-4
Plate 11-4, Figures A and B. Cross sections through the terminal bronchiole of the squirrel monkey. C, Clara Cell; Ci, ciliated epithelial cell; L, lumen of bronchiole; SM, Smooth Muscle; V, vein (Fig. A); arrow, point of separation of venous and bronchiolar walls (Fig. A). Figure A, 2,500 X; Figure B, 5,130 X

The respiratory bronchiole, the first of the airways to participate in true gas exchange, is shown at low magnification by the electron microscope in Figure A. Its wall has a patchy appearance; the epithelium in different patches can vary from simple cuboidal to simple squamous. To see this, follow the respiratory bronchiole in Figure A from left to right. Initially, when the epithelium is cuboidal, Clara cells (C) are evident and the Submucosa contains Smooth Muscle cells (S). Suddenly, the wall becomes extremely thin (arrow); simple Squamous Epithelium takes over, and the respiratory bronchiole’s wall is thin enough to permit gas exchange. Then it thickens again. And so it goes along its length-alternating patches of thick (albeit not very thick) and thin epithelium form the wall of this first of the respiratory airways.

Respiratory bronchioles communicate with alveolar ducts, alveolar sacs, and alveoli (A). The delicate, lacelike structure of the alveolar portion of the lung is readily apparent in Figure A. The structure of the alveoli serves the primary functions of the respiratory system well. The microanatomy of the Alveolus is simple to understand if you remember that air is in the alveolar spaces and blood is in the capillaries. The interalveolar Septum is the ultra-thin “wall” of tissue that separates air from blood. Consequently, the Interalveolar Septum consists of two walls of simple Squamous Epithelium placed back to back: the epithelium of the Alveolus and that of the capillary. The Interalveolar Septum can be so thin (0.1 Â µm) that it can be beneath the limit of resolution of the light microscope.

The fine structure of two alveoli and their associated capillaries is shown at intermediate magnification by electron microscopy in Figure B. This monkey’s lung was fixed by immersion, and so its capillaries contain blood cells. (Organs fixed by intravascular perfusion often have empty capillaries). Red blood cells (R), shaped like biconcave disks, are here cut in a variety of planes of section and display a variety of images. A Lymphocyte (Ly) is present at upper right, as is part of a Platelet. As mentioned above, the Interalveolar Septum that separates the alveolar air space from the capillary lumen can be extremely thin. The ultra-thin interalveolar Septum is something of a bioarchitectural miracle, inasmuch as it consists of four elements sandwiched together: the Cytoplasm of the thin type I alveolar cell; its Basement Membrane; the Basement Membrane of the capillary endothelial cell; and the Cytoplasm of the capillary endothelial cell. In other places, usually near epithelial cell nuclei, the wall thickens and contains connective tissue rich in elastic fibers that facilitate elastic recoil of the lung during the breathing cycle.

Several other types of cells are associated with the Alveolus. One, not shown here, has several names; it is called the Greater Alveolar Cell, the Septal Cell, or the pneumocyte type H. Unlike the thin alveolar epithelial cells, the Greater Alveolar Cell is bulky. Its Cytoplasm contains large inclusions called lamellar bodies that are thought to contain Surfactant. When released from the cell, Surfactant spreads, reducing surface tension across the Alveolus – surface tension that would otherwise collapse the ultra-thin alveolar walls when pressure drops at exhalation. Another type of cell quite commonly encountered in association with the Alveolusis the pulmonary alveolar Macrophage, or “Dust Cell.” A single pulmonary alveolar Macrophage (M) is evident in Figure B. These large cells glide along the interior of the alveolar walls, sweeping them clean by Phagocytosis of foreign matter.

Alveolus and bronchiole

Plate 11-4
Plate 11-4, Figure A. Low-power electron micrograph of a monkey respiratory bronchiole, A, Alveolus; C, Clara Cell; Ca, capillary; L, lumen of respiratory bronchiole; S, Smooth Muscle; arrow, simple Squamous Epithelium. 645 X

Figure B. Portions of two alveoli and associated capillaries from the lung of the macaque. A, Alveolus; Ca, capillary; Ly, Lymphocyte; M, pulmonary alveolar Macrophage; P, Platelet; R, red blood cell. 3,800 X