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The Respiratory System

The respiratory system consists of a conducting portion and a respiratory portion. The conducting portion provides a passageway for air and functions to condition the incoming air, by warming, moistening and cleaning it. It consists of the nasopharynx, larynx, trachea, bronchi, bronchioles and terminal bronchioles. (We omit the nasopharynx and larynx in this block.) The respiratory portion serves to rid the body of carbon dioxide and pick up oxygen. It consists of respiratory bronchioles, alveolar ducts and alveolar sacs. All of these structures bear alveoli, the tiny air sacs in which the gas exchange takes place.

Conducting Portion:Table of Contents

The conducting portion not only brings the air to the respiratory portion, but also cleanses, moistens and warms the incoming air. Hair and secretions of sebaceous glands in the nasal cavity trap particulate matter, and a countercurrent flow between the incoming air and the blood warms the air. [See pp 530-535 of Ross et al., 3rd edition for more details.] In the trachea and lower portions, secretions of mucous and serous glands moisten the air, which protects the alveoli from desiccation, and trap extraneous matter. These secretions are then directed toward the pharynx by the beating of cilia on epithelial cells. The vasculature in these structures also warms the incoming air.

Trachea: Low power view of human tracheaTable of Contents

The trachea is a flexible tube that extends from the larynx into the thorax. Its main function is to act as a conduit for air, but it also helps condition the inspired air. The trachea consists of four layers: a mucosa (epithelium and lamina propria), a submucosa, a fibrocartilage layer and an adventitia. These four layers are shown in Figure 1Large version of Fig. 1 view of human trachea (human trachea, slide 15 in your collection). Figure 1 is to show illustrate the overall structure of the trachea, you will see the details in other figures.

The mucosa consists of a pseudostratified, ciliated, columnar epithelium, (described below) with a very elastic lamina propria. Without special stains, the elastic fibres in the lamina propria (or anywhere else) are not identifiable. The basement membrane of the epithelium appears unusually thick because a large number of collagen fibres are found underneath the actual basement membrane.

The submucosa consists of loose connective tissue with numerous mixed (serous and mucous) glands. Ducts from these glands open toward the lumen. Particles get entrapped in the mucus which floats on the serous secretions. The beating of cilia of epithelial cells directs the secretions toward the oral cavity, where they can be swallowed or spat out. The boundary between the mucosa and the submucosa is not obvious. Special stains would reveal an abundance of elastic fibres at this boundary.

The fibrocartilage layer consists of a series (16-20) of C-shaped cartilage rings which prevent the trachea from collapsing. As is typical of cartilage, the rings are surrounded by a band of dense connective tissue called a perichondrium. The perichondrium merges with the submucosa and the adventitia (see below). At the back, the open ends of the C are joined by a band of smooth muscle called the trachealis muscle. Contraction of this muscle reduces the tracheal diameter and increases intrathoracic pressure during coughing. The area between the rings is occupied by fibroelastic connective tissue.

The adventitia is a layer of connective tissue that binds the trachea to adjacent structures in the neck and mediastinum. It contains the largest blood vessels, nerves and lymphatics.

Large version of Fig. 2 view of rabbit tracheaLow power view of rabbit tracheaTable of Contents

A low power view of the rabbit trachea (slide 93) is shown in Figure 2. The layers are the same as those of the human trachea, but the rabbit has numerous blood vessels in its submucosa and mucosa rather than glands. The mucosa and submucosa blend indistinguishably into each other.
There is a tear (artifact) that runs along most of the cartilage. The rabbit trachea is in your collection so you can look at the epithelium. (The epithelium on the human trachea slides is in very bad shape.)

High power view of epithelium of rabbit tracheaTable of Contents

Figure 3 Large version of Fig. 3 view of epithelium  rabbit tracheashows a high power view of the epithelium of the rabbit trachea. It is taken from the back of the trachea, and the trachealis muscle replaces the fibrocartilage layer. In this section, the thickness of the lamina propria and submucosa are reduced.

The epithelium is pseudostratified. The base of every cell actually rests on the basement membrane, therefore it is simple, not stratified. However, the epithelial cells are of different heights, there are short basal cells and tall columnar cells, and their nuclei are seen at different levels. This gives the epithelium a stratified appearance. Because it contains tall cells, it is called a pseudostratified, columnar epithelium. There are five types of cells in the tracheal epithelium.

The most abundant cell type is the ciliated columnar cell. These cells have about 300 cilia at their apical surface, and the cilia sweep in a coordinated fashion from the deepest passageways to the pharynx, to protect the lungs from particulate matter. The cilia appear as a fuzzy line along the top surface of the epithelium. The nuclei of ciliated cells are relatively pale and lie in about the middle of the cell.

The next most abundant cell type is the goblet cell, which secretes mucus. Goblet cells are interspersed among the ciliated cells and also extend the full length of the epithelium. The mucinogen granules are found in the cytoplasm at the apical end. The thick mucus extends the apical end, rendering the cell wineglass-shaped (hence its name). The nucleus is flattened at the base of the mucus cup (not generally identifiable). With special preparation, the mucus can be seen; in standard sections it is washed out leaving a clear (white) area where the mucus had been. Your sections are cut thicker than the width of a single cell, therefore (i) you often just see the top (white) part of the goblet cell, and (ii) the cell might look like it is ciliated, as is the case in the goblet cells seen here. The cilia belong to ciliated cells lying below the goblet cell in the plane of focus. The best goblet cell in Figure 3 is about one-third of the way in from the left. (With the fine focus knob of your microscope, you can focus on cells at different levels and see that the section is quite thick. For this reason, it is also hard to make out the boundaries of any individual cell. )

The third most abundant cell type is the basal cell. Basal cells are short, rounded cells with densely staining nuclei which lie in a row close to the basement membrane. These cells are reserve cells that can differentiate into other cell types.

There are two other cell types in the epithelium that you will not be able to distinguish in standard preparations. One is the small granule cell, which resembles the APUD (amine precursor uptake and decarboxylation) cells of the gut. The granules of these cells can only be seen with special techniques such as silver staining. They secrete catecholamines or polypeptide hormones and may function in regulating the caliber of airways or blood vessels, or be involved in regulating mucous and serous secretions. They resemble basal cells and are found in the same region. However, they are much less abundant, therefore most of the basal nuclei you see will belong to basal cells.

The final cell type is the brush cell. Brush cells are columnar cells with short microvilli at their apical surface (hence name), and their basal surface is in contact with afferent nerve fibres. They are thought to be sensory receptors.

Summary of epithelial cell types: You should be able to identify ciliated columnar cells, goblet cells and basal cells, and know about small granule cells and brush cells.

Large version of Fig. 4 epithelium of human bronchusHigh power view of epithelium of human bronchusTable of Contents

Because of the poor condition of the epithelium in slide 15 (human trachea), the cell types of the epithelium shown in Figure 4 are from a human bronchus (slide 83). (Ignore the other layers for now.) The epithelium is similar to that of the trachea, but the columnar cells are not as tall, as the height of the epithelium decreases continuously as you travel down the respiratory tree. Ciliated columnar cells and goblet cells can be seen, as can some (probable) basal cell nuclei. While you can see good examples of the three identifiable cell types, is not possible to attribute every nucleus seen to a particular type of cell.

Large version of Fig. 5 view of submucosal mixed glandsHigh power view of submucosal mixed glandsTable of Contents

Figure 5 shows a high power view of the serous and mucous glands in the submucosa of the trachea. The glands consist of secretory endpieces called acini (sing. acinus). The serous glands secrete a watery proteinaceous product, while the mucous glands secrete a viscous, heavier product called mucus. An ideal cross section of a serous acinus is more or less shaped like a pie cut into wedges. The rounded nuclei are located at the base of the cells (outer edge of pie), and the secretory product toward the apex of the cells. The secretory product empties into a central lumen, which is not identifiable in every cross-section. Serous cells stain purple-red. The mucous acini stain poorly because their mucinogen granules are lost in standard preparations. Their cells tend to have flattened nuclei (due to heavier mucus) and the acini are of more irregular shape than serous glands. Quite often, a mucous gland will bear a crescent-shaped band of serous cells, called a serous demilune.

Large version of Fig. 6 Duct of submucosal glandDuct of submucosal glandTable of Contents

The ducts of the glands pass through the lamina propria and epithelium to empty into the lumen. Figure 6 shows the duct of a gland. The lumen is obscured as it approaches the epithelium. (This is a frequent phenomenon of sectioning.) It is not worth trying to identify the different epithelial cells in the figure (from slide 15, human trachea). However, you can note the abundance of lymphocytes (appear as purple dots) in the connective tissue of the lamina propria.

Large version of Fig. 7 High power view of cartilageHigh power view of cartilageTable of Contents

A high power view of the cartilage in the fibrocartilage layer in the human trachea is shown in Figure 7. The matrix of cartilage typically stains a purplish color. Staining is most intense around the cartilage cells, which are called chondrocytes and sit in spaces called lacunae. Chondrocytes are often found in clusters (called isogenous groups). During life, the cells occupy the whole lacuna, but they frequently shrink during preparation, and the lacunae appear as spaces around cells (or as empty spaces if a cell is lost). The cells at the periphery of the cartilage are smaller and more elongated than centrally located cells. Cartilage is surrounded by a perichondrium, a band of dense connective tissue. The perichondrium blends with the connective tissue of surrounding structures (here the adventitia; the extensive spaces in the CT are artifacts of preparation). The details of the histology of cartilage are described in the Musculoskeletal Block. For the purposes of this block, you are only expected to recognize it.

Large version of Fig. 8 trachealis muscle and glandsLower power view of trachealis muscle and glandsTable of Contents

A lower power view of the human trachea at the area of the trachealis muscle is shown. The trachealis muscle consists of bands of smooth muscle whose fibres insert into the perichondrium of the cartilage and connect the two ends of the C. Contraction of this muscle reduces the tracheal diameter and raises intrathoracic pressure during coughing. Mixed glands are found interspersed within and around this muscle.

Bronchi:Table of Contents

The end of the trachea divides into two primary bronchi that enter the lungs. Histologically, the trachea and primary bronchi are very similar and you will not be expected to distinguish between them. Within the lung, the primary bronchi almost immediately divide into secondary (or lobar) bronchi that supply each lobe. Secondary bronchi divide into tertiary (or segmental) bronchi that supply the segments of each lobe. These bronchi continue to divide to give rise to many generations of bronchi, each smaller than the preceding one.

You are not expected to distinguish different generations of bronchi, you are only expected to tell a bronchus from the trachea and from bronchioles (see below).
In bronchi, the C-shaped cartilage of the trachea is replaced by separate plates of cartilage. These plates become smaller and farther apart the more distal the bronchus. (When no more cartilage is present, you have a bronchiole, not a bronchus). At the same time, the lamina propria becomes surrounded by a band of smooth muscle. The muscle fibres that appear in the bronchi are arranged spirally and criss-cross one another, so they do not appear as a continuous band in a cross-section. This band of smooth muscle becomes a more conspicuous feature as the cartilage diminishes. The smooth muscle can be considered as a separate layer, the muscularis, lying between the mucosa on the one side and the submucosa, fibrocartilage layer (with plates) and adventitia on the other. Going distally down the bronchial tree, the lamina propria becomes reduced and the smooth muscle of the muscularis comes to lie closer to the epithelium. Serous and mucous glands are present in the submucosa of bronchi, their numbers also decrease with each division into smaller orders of bronchi. (Like the cartilage, all glands are gone when bronchi branch into bronchioles.) The epithelium is similar to that of the trachea, but its height becomes reduced and goblet cells become less frequent.

Large version of Fig. 9 bronchus and artery in lungLow power view of bronchus and artery in lungTable of Contents

Figure 9 is a low power view of a bronchus next to a (pulmonary) artery in the perfused monkey lung (slide 60). The lung itself is airy-looking because of all the air sacs (alveoli) which are expanded. Here the bronchus is on the right and the artery on the left.

In the bronchus, you can see the cartilage plates quite clearly. It is much more difficult at this magnification to distinguish the smooth muscle of the muscularis and the epithelium, which conveniently has come detached at the upper leader. (Sometimes even at low magnifications, it is possible to make out the general fuzziness of the ciliated epithelium to help distinguish components of the respiratory tree from blood vessels.)

The tunica media of the artery next to the bronchus can be seen. Like all blood vessels, it would be lined by endothelial cells (which could not be seen at this magnification).

About blood vessels in the lungs: Table of Contents

Blood vessels are frequently seen next to components of the respiratory tree. That is because branches of the pulmonary artery travel along the respiratory tree to become distributed in a capillary network over the alveoli, where gas exchange occurs. In addition to branches of the pulmonary arteries, whose purpose is to bring deoxygenated blood to the lungs for oxygenation, bronchial arteries arising from the aorta are present. Bronchial arteries are nutrient vessels that supply the tissue of the lung with oxygen. They also accompany the respiratory tree, and at the level of respiratory bronchioles (described below), anastomose with pulmonary arteries.

Veins arising from the capillary network around the alveoli can also be seen, they are extremely thin-walled. These veins travel independently of arteries, that is they will not follow the respiratory tree but are heading toward the intersegmental connective tissue where they will join to form the pulmonary veins. Most of the blood reaching the lungs via the bronchial arteries is drained by the pulmonary veins. Bronchial veins drain only the the connective tissue in the hilar region.

Because the right side of the heart operates at a much lower pressure than the left, pulmonary arteries tend to have much less muscular walls than do typical arteries. However, they contain a great deal of elastic tissue and are considered elastic arteries. Bronchial arteries are smaller, but their structure is more typical of regular arteries, that is they have a relatively thicker tunica media. The branches of the pulmonary veins will have extremely thin walls. You will not be asked to distinguish different types of vessels in the lung, but you should be aware of the functions of the pulmonary and bronchial circulation. There are excellent illustrations of the branching of the respiratory tree, and its blood supply in Netter, 9th edition, 1997, Plates 192, 193 and 194.

Large version of Fig. 10  view of wall of bronchusHigher power view of wall of bronchusTable of Contents

Figure 10 shows the structure of the bronchial wall at a higher power. The mucosa appears folded (probably as a result of contraction of the muscularis. Details of the epithelium cannot be seen, but the lamina propria is quite prominent with abundant lymphocytes (little purple dots). Smooth muscle bundles of the muscularis, which criss-cross along the respiratory tree, surround the lamina propria. In the submucosa, mixed glands can be seen. Part of a large cartilage plate is in the field of view.

Large version of Fig. 11 Mucosa and muscularisMucosa and muscularis of a large bronchusTable of Contents

Figure 11, a rerun of Figure 4, shows a higher power view of the mucosa and muscularis of a large (=early) bronchus. Note that the lamina propria is quite prominent, that is the muscularis is some distance away from the epithelium (compare with next figure). As the bronchi branch and become smaller, the muscularis will become ever closer to the epithelium. Beyond the muscularis, you can see a hint of the submucosa. Neither the submucosa nor the cartilage plates of this bronchus are in the field of view.

Large version of Fig. 12 wall of a more distal bronchusWall of a more distal bronchusTable of Contents

A higher magnification of a smaller, more distal bronchus can be seen in Figure 12. The epithelium is has become shorter (it is still pseudostratified, columnar ciliated) and goblet cells are less abundant. The muscularis has come to lie very close to the epithelium and the lamina propria is reduced to a thin band underneath the epithelium. The submucosa is also very scanty. A large cartilage plate lies almost directly under the muscularis. In this bronchus, there would be fewer cartilage plates and fewer glands in the submucosa.

Bronchioles:Table of Contents

As the bronchi branch and become smaller, the cartilage plates become smaller and farther apart and the mixed glands become fewer. When the cartilage and glands have disappeared, you have entered the bronchioles. At this point, the muscularis is very close to the epithelium. The epithelium is still pseudostratified, ciliated columnar, although it becomes progressively less tall. Goblet cells are still quite common in large bronchioles, their numbers also progressively decrease.

Large version of Fig. 13 section of wall of bronchioleSection of wall of bronchioleTable of Contents

Figure 13 shows the wall of a fairly large (regular) bronchiole. You can still recognize the cell types of the epithelium, especially the ciliated and goblet cells. The lamina propria has become a thin band, with abundant elastic fibres (no special stain here, therefore they aren’t obvious). The muscularis, which appears as discontinuous bundles of smooth muscle, is relatively thick. Bronchiolar smooth muscle effectively controls the resistance to air flow in the lungs. Parasympathetic stimulation reduces the diameter of the bronchioles, while sympathetic stimulation increases it by relaxing the smooth muscle. Hence epinethrine and sympathomimetic drugs are used during asthma attacks. The adventitia blends in with the connective tissue of surrounding structures.

Large version of Fig. 14 view of bronchiole between two vesselsLow power view of bronchiole between two vesselsTable of Contents

Figure 14 shows a bronchiole such as it might appear when you scan your slide at low power. The folded mucosa is typical and is a result of the contraction of the muscularis during preparation. A particularly prominent bundle of smooth muscle, easily identifiable even at this magnification, is indicated by an asterisk. The bronchiole is lying between two arteries. Their most prominent feature is their tunica media.

Terminal bronchiolesTable of Contents

As the (regular) bronchioles branch into smaller and smaller bronchioles, they eventually give rise to terminal bronchioles. As their name implies, terminal bronchioles represent the last part of the conducting portion of the respiratory tree. In terminal bronchioles, the ciliated pseudostratified epithelium abruptly gives way to simple cuboidal epithelium consisting of Clara cells. Clara cells are secretory: the lipoprotein they secrete prevents luminal adhesion during expiration and inactivates harmful substances.

[Details on the epithelium: In late regular bronchioles, the epithelium may appear simple low columnar (with cilia). It is considered pseudostratified because the odd basal cell is still present. In the terminal bronchioles, an occasional ciliated cell (or brush cell or granule cell) may be seen with the electron microscope (eg., see Fig 18.10 in Ross et al., third edition). For practical purposes though, terminal bronchioles are totally lined with Clara cells. The best way to recognize terminals is to look for the transition from the (usually at this point) low columnar-appearing ciliated epithelium of the late regular bronchiole to the cuboidal unciliated Clara cells.]

Longitudinal section of bronchiole from regular to terminal to respiratoryTable of ContentsLarge version of Fig. 15 bronchiole from regular to terminal

Figure 15 shows a longitudinal section of a regular bronchiole with ciliated pseudostratified epithelium giving rise to a terminal bronchiole with non-ciliated Clara cells. The arrow is pointing at the last of the ciliated cells of the regular bronchiole. The terminal bronchiole shown here is very long, in many of the sections you will see, terminal bronchioles will only be the length of a few Clara cells.

The section also shows the terminal bronchiole giving rise to a respiratory bronchiole, marking the beginning of the respiratory portion of the respiratory tree (discussed below). The dip in the respiratory bronchiole is an alveolus, one of the air sacs in which gas exchange occurs. Notice how the smooth muscle is also progressively reduced during the transition from regular bronchiole to terminal bronchiole to respiratory bronchiole.

Respiratory bronchioles:Table of Contents

The purpose of the conducting part of the respiratory tree is to get the air to the millions of tiny air sacs, or alveoli (sing. alveolus) of the lungs, where the gas exchange occurs. The respiratory portion of the tree begins in the respiratory bronchioles when these alveoli first arise. Look again at Figure 15. The respiratory portion begins when an air sac appears as an outpocketing of the bronchiole. At this point, the terminal bronchiole has become a respiratory bronchiole.

Large version of Fig. 16 view of respiratory bronchioleHigh power view of respiratory bronchioleTable of Contents

Figure 16 shows a higher power view of a respiratory bronchiole. Its wall is very similar to that of a terminal bronchiole, in that it has Clara cells lying almost directly over smooth muscle bundles. The arrow shows where these Clara cells can be seen most clearly. The alveoli which form outpocketings from the wall are lined by very squamous cells called alveolar type I cells (more on them below), not identifiable here. Other alveoli are seen at the right of the field of view.

Alveolar ducts, alveolar sacs and alveoliTable of Contents

As the respiratory bronchioles continue and branch, the alveoli forming outpocketings from their walls become progressively more frequent and closer together. Eventually alveoli are so frequent that they are side by side separated only by their walls (alveolar septa). This marks the beginning of the alveolar ducts. At first, the ends of the septa facing into the lumen of the alveolar duct have prominent knobs of smooth muscle. These become progressively less prominent and eventually disappear.

Large version of Fig. 17 view of alveolar ductHigh power view of alveolar ductTable of Contents

Figure 17 shows a high power view of an alveolar duct with prominent smooth muscle knobs at the luminal ends of the alveolar septa. To the left of the figure, other alveoli from the surrounding lung tissue can be seen.

The alveolar ducts will branch and terminate in blind-ended alveolar sacs. Alveolar sacs consists of spaces (sometimes called atria) surrounded by alveoli.

Low power view of alveolar duct and alveolar sacsTable of ContentsLarge version of Fig. 18 view of alveolar duct and sacs

Figure 18 shows a low-power view of an alveolar duct progressing into two alveolar sacs. Other alveolar sacs can be seen in the surrounding tissue, one (at left) is labelled as such. A few of the numerous, individual alveoli are indicated by asterisks.

Because many of the later passageways of the respiratory tree branch into the next section shortly after arising (eg., terminal branching into respiratory bronchioles), sections that are cut even slightly obliquely can show different passageways in one cross-section. For example, the top might be a respiratory bronchiole, while the bottom could be an alveolar duct. Also you will see the alveoli sectioned in various ways. Sometimes alveoli are sectioned such that they look free-standing, that is you can’t see whether they arise from a respiratory bronchiole, alveolar duct or aleolar sac (see for example the alveoli at the left in Figure 17). The abundance of alveoli give the lungs a spongy appearance.

Large version of Fig. 19 longitudinal section of respiratory treeLow power view of longitudinal section of the respiratory treeTable of Contents

Sometimes you will get a longitudinal section that nicely shows the progression and branching of the passageways. Figure 19 (not labelled) shows a low power view of such a longitudinal section. Remember that the branching occurs in three dimensions, therefore not all of the branches can be seen in one field of view. An artery is seen under the bronchus in Figure 19.

Septa of the alveoli:Table of Contents

The septa between alveoli are specialized for the diffusion of gases. The surfaces facing the air are lined by an epithelium made of two types of cells, type I and type II alveolar cells. Most of the surface (about 95%) is lined by type I alveolar cells (or type I pneumocytes). These cells are extremely squamous. The other type of epithelial cell is the type II alveolar cell (or type II pneumocyte, or great septal cell). Type II cells are found interspersed among the type I cells, singly or in clusters. They are often found in the angles of the alveolar walls. Type II cells secrete surfactant, a phospholipid that spreads over the alveolar surfaces to reduce surface tension. This prevents the alveoli from collapsing upon expiration. (Premature babies with insufficient surfactant suffer from hyaline membrane disease.) Surfactant also has a bacteriacidal effect. Type II cells are fairly large cuboidal cells that have a large nucleus and vacuolated cytoplasm. They are about as abundant as type I cells even though they cover only 5% of the surface area of the alveoli.

Within the septal wall are found capillaries (the alveoli contain the richest capillary network of the body), elastic and collagen fibres, fibroblasts and macrophages called dust cells. The septal walls have thick portions and thin portions. The thick portions could contain any of the components listed above.

The exchange of gases occurs in the thin portions of the septa, which contain only the following three components:

(1) the cytoplasm of the type I cell, (2) the fused basement membranes of the type I cell and the endothelial cell, and (3) the cytoplasm of the endothelial cell of a capillary.

When you look at the alveolar septa, you will be able to identify (some of the) type II cells, capillaries if well-sectioned, and (if they are filled with carbon particles or some other material) dust cells. You will not be able to tell the nuclei of type I cells from those of fibroblasts. There is no point in trying to identify every cell in the septal walls.

Alveolar walls with septal cellsTable of ContentsLarge version of Fig. 20 Alveolar walls with septal cells

Figure 20 shows two clusters of type II or septal cells in the alveolar walls. Note that one can see their nuclei, and that there is an identifiable amount of pale cytoplasm around the nuclei. A number of alveoli are seen at the left of the figure, part of an alveolar sac is seen at the right. Capillaries can be seen within the walls.

Large version of Fig. 21 Capillaries in alveolar wallsCapillaries in alveolar walls Table of Contents

Capillaries within the septal walls can be seen a bit more clearly in Figure 21. Note that nice endothelial cell nuclei can be seen in a few of them (especially the one near the centre of the field of view). Where the capillaries are located, the septal wall is very thin. A septal cell is also seen.

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