Chapter 2: Development and Functional Anatomy of the Lungs and Airways

The respiratory system is classically divided into two parts, based on their structures and functions. The first is the conducting zone, being the organized array of progressively smaller airways through which air moves into and out of the lungs during tidal ventilation. The conducting zone starts at the nares (and/or mouth) and includes the nasal cavities, pharynx, larynx, trachea, bronchi, and bronchioles. The second part is the respiratory parenchyma, being the densely packed collection of membrane walls, thin enough to support molecular diffusion between the inspired air and blood coursing through the microvasculature of the lung (Fig. 2.1). Constituents of the respiratory parenchyma begin where the conducting zone ends and include the respiratory bronchioles, alveolar ducts, alveolar sacs, and alveoli. The gross and microscopic appearances of each component are the primary focus of this chapter, with the principal functions for each presented with more detail in subsequent chapters.

The major histologic features of each constituent of the respiratory tract are broadly summarized in Table 2.1. Within the lungs are blood and lymphatic vessels and nerves. The pulmonary arteries and their branches travel beside similarly sized airways, while pulmonary veins and lymphatics travel in the connective tissue septa that form the boundaries of each lung lobule. Bronchial arteries have narrower diameters and thicker walls than the pulmonary arteries, reflecting the smaller quantity of blood they carry (but under higher pressure). They also travel with airways but are inconspicuous due to their small size. Within the connective tissue surrounding larger airways are afferent and efferent nerve fibers. The external surface of the lung is covered by mesothelium, a simple squamous epithelium which normally is in contact with the mesothelial lining of the hemithoraces. The mesothelial layer that covers the entire outer surface of the lungs is called the visceral pleura, while the mesothelium that lines the hemithoraces is called the parietal pleura.

The Nasal Cavities

The two nasal cavities are separated by a nasal septum composed of cartilage anteriorly and bone posteriorly. Each cavity is subdivided into three segments: the vestibule, the respiratory segment, and the olfactory segment. The vestibule is the short chamber just internal to the naris and is lined by stratified squamous epithelium. Externally, this epithelium is keratinized like skin before gradually transitioning to a nonkeratinizing form as in the oropharynx. Vestibular hairs, called vibrissae, filter large particulate matter. Within the lamina propria of the vestibule, as in the dermis, are hair follicles, eccrine glands, and sebaceous glands (Fig. 2.2).

Internal to each vestibule are the respiratory segments of the nasal cavities. Although they are parts of the conducting zone and not the diffusive respiratory parenchyma, their name reflects their lining of respiratory mucosa. Respiratory mucosa is common within the respiratory system and consists of a ciliated pseudo-stratified columnar respiratory epithelium overlying layers of dense irregular connective tissue, the perichondrium of cartilage and the periosteum of bone. Deeper within the respiratory system, this connective tissue layer consists of loose irregular connective tissue characteristic of lamina propria. The staggered vertical distribution of nuclei within the respiratory epithelium suggests that it is stratified into multiple layers. However, all of its cells touch the basement membrane, and thus the epithelium is pseudo-stratified. Within it are three main types of cells: ciliated cells, goblet cells, and basal cells. Ciliated cells exhibit coordinated motility of their apical cilia to propel a sheet of mucus in retrograde direction over the surface of the epithelium, plus any particulate matter embedded within the mucus. Goblet cells are unicellular glands that produce copious quantities of mucus. Basal cells serve as progenitors that repopulate the epithelium as needed through mitosis and subsequent differentiation. Additional cell types that are less commonly noted within respiratory epithelium include brush cells, which are columnar in appearance and have apical microvilli rather than true cilia. There are also small granular neuroendocrine cells that rest upon the basement membrane (Fig. 2.3).

Extending from the lateral walls of the nasal cavity are three bony projections termed the superior, middle, and inferior conchae. The middle and inferior conchae are part of the vestibule and are lined by respiratory mucosa; the roof and superior concha comprise the olfactory segments of the nasal cavity. An olfactory segment consists of an olfactory epithelium overlying a lamina propria that contains Bowman glands, which are serous. The principal constituents within the olfactory epithelium are olfactory cells (or bipolar neurosensory cells). These are modified neurons with apical nonmotile cilia, which function as chemoreceptors, and basal afferent axons that join to form the olfactory nerves. In addition, the olfactory epithelium contains supporting cells, with apical microvilli that resemble the brush cells of respiratory epithelium, and regenerative basal cells, also similar to those in respiratory epithelium. Histologically, the olfactory epithelium is also termed pseudo-stratified: nuclei situated closest to the lumen belong to supporting cells; nuclei nearest the epithelium’s basement membrane are basal cells; and nuclei located between these two other nuclear layers are those of the chemoreceptive olfactory cells (Fig. 2.4).

The Paranasal Sinuses

The paranasal sinuses are blind-ended cavities within the frontal, maxillary, ethmoid, and sphenoid bones. The sinuses open into the larger and more centrally located nasal cavities. As noted for the respiratory segments of the nasal cavities, the paranasal sinuses are lined by respiratory mucosa with abundant seromucinous glands. The motile cilia on their epithelial surfaces move mucus and any embedded particulate matter into the nasal cavity for subsequent expulsion.

The Pharynx

The pharynx is divided positionally into its nasal and oral portions. The nasopharynx is lined by the same general type of respiratory mucosa as the respiratory segments of the nasal cavities. In contrast, the oropharynx is covered by a nonkeratinizing stratified squamous epithelium, similar in appearance and function to epithelium that lines the internal nasal vestibule and much of the oral cavity (Fig. 2.5).

The Larynx

The larynx connects the pharynx and trachea. Its most notable feature is the epiglottis, a movable boundary separating the respiratory tract from the digestive system. During swallowing, the epiglottis covers the laryngeal lumen to prevent aspiration of oropharyngeal materials and direct those materials into the esophagus. When breathing and/or speaking, the epiglottis is retracted anteriorly, allowing large volumes of air to travel into and out of the trachea. The core of the epiglottis is made of elastic cartilage that provides flexibility and strength. The epiglottal surface is covered by stratified squamous epithelium on its anterosuperior/lingual portion and also on the superior segment of its inferior/laryngeal portion. On the laryngeal side of the epiglottis, the stratified squamous epithelium found apically makes a smooth transition into ciliated pseudo-stratified respiratory epithelium toward the base.

The larynx (Fig. 2.6) is generally arranged as an epithelium overlying sheets of fibrous connective tissue that contain abundant seromucinous glands and cartilage, all of which are surrounded by skeletal muscles. Inferior to the epiglottis are the false vocal chords (or vestibular folds). Inferior to the false chords are the laryngeal ventricles, blind-ended sacs that extend superolaterally from the laryngeal lumen. Beneath these ventricles are the true vocal chords (or vocal folds), a common reference point used to describe the position of masses and other objects within the larynx. In this sense, supraglottic refers to laryngeal locations that are superior to the true vocal chords, and infraglottic refers to laryngeal locations that are inferior to the true vocal chords.

Except for the true vocal chords and part of the epiglottis, the larynx is lined by true respiratory epithelium overlying perichondrium of any regional cartilage and overlying lamina propria in those areas lacking cartilage (Fig. 2.6). The lamina propria of the laryngeal ventricles contains lymphoid tissues that form an airway component of the mucosa-associated lymphoid tissues (MALTs). Unlike most of the larynx, the true vocal chords are covered by nonkeratinizing stratified squamous epithelium that overlies a lamina propria containing the vocalis muscle, a skeletal muscle important in phonation. The shield-shaped thyroid cartilage and the signet ring-shaped cricoid cartilage are both composed of hyaline cartilage, while the epiglottis, corniculate cartilages and cuneiform cartilages are of the elastic form. The arytenoid cartilages that serve as insertions for the vocalis muscles contain both elastic and hyaline cartilage. Although these structures are collectively called the laryngeal cartilages, with age they can undergo ossification and become composites of cartilage and bone.

The Trachea and Bronchi

The trachea extends from the inferior-most cartilage of the larynx (the cricoid cartilage) to the primary bronchi and is lined by the same respiratory mucosa described earlier. In the lamina propria of the tracheal mucosa are abundant seromucinous glands, below which are a series of C-shaped rings of hyaline cartilage (Fig. 2.7). The opening of each C-shaped tracheal ring is directed posteriorly, where the tracheal mucosa overlies smooth muscle that completes the wall of each ring. At the carina, the trachea bifurcates into right and left mainstem or primary bronchi, each of which dichotomously branches 9-12 times. Each generation of these deeper branches becomes successively shorter and narrower. From inside to out, bronchial walls consist of respiratory epithelium, with fewer goblet cells than in trachea, overlying a lamina propria that sits upon crisscrossing bands of smooth muscle comprising the muscularis mucosae. Beneath the muscularis mucosae is a submucosal layer with fewer seromucinous glands than the trachea. The submucosal layer overlies hyaline cartilage, which is itself surrounded by a diffuse adventitia of fibrous connective tissue (Fig. 2.8).

Proximally, bronchial cartilage forms a series of rings; distally, the bronchial cartilage consists of islands and plates. Moving from the proximal to distal bronchi, the relative densities of both goblet cells and seromucinous glands decrease (Fig. 2.8).

The Bronchioles

As these dichotomously branching airways become smaller, they contain less cartilage and fewer submucosal glands. Indeed, a bronchiole is defined as a distal airway devoid of cartilage and submucosal glands. A bronchiole that subtends or abuts a lung acinus is termed a terminal bronchiole. When alveoli are seen histologically to project outward from the lumen of a bronchiole, that airway is called a respiratory bronchiole. Functionally, this is an important distinction because such a respiratory bronchiole signifies the beginning of the respiratory parenchyma, where at least limited diffusive gas exchange occurs (Chaps. 4 and 9). Bronchiolar epithelium changes in thickness over its proximal to distal length, from pseudo-stratified ciliated columnar epithelium (where the airway is widest) to a simple ciliated columnar epithelium, and then to simple ciliated cuboidal epithelium (where the airway is narrowest). While proximal bronchioles contain scattered goblet cells, the terminal and respiratory bronchioles normally contain none. The crisscrossing smooth muscle layers of the muscularis mucosae that are such prominent features of upper bronchi also diminish distally, being nearly absent in respiratory bronchioles (Fig. 2.9).

Alveolar Ducts, Alveolar Sacs, and Alveoli

Alveolar ducts arise from distal respiratory bronchioles but are difficult to recognize histologically due to their narrow lumens and random orientation in a tissue plane. Students should remember to translate the flat images of lung they see on slides into what such a section must look like in three dimensions (Fig. 2.10). Thus, the wall of an alveolar duct often appears to be just two-three rows of openings into adjacent alveoli, separated by pillars of smooth muscle and elastin that function as tiny sphincters and maintain structural integrity.

Alveolar ducts and their surrounding alveoli are lined by a simple squamous epithelium composed of type 1 pneumocytes that account for ~95% of total alveolar surface area. Interspersed among type 1 cells and often situated in alveolar corners are cuboidal type 2 pneumocytes that cover ~5% of alveolar surfaces. As presented in Chap. 9, most diffusive gas exchange occurs from alveolar air spaces through type 1 pneumocytes, whose basement membranes are fused to the basement membrane of capillary endothelial cells (Fig. 2.11). Type 2 pneumocytes secrete surfactant, a mixture of phospholipids and proteins that reduces surface tension and promotes alveolar stability at low lung volumes (Chap. 5). While alveoli are often visualized as blind-ended sacs, their walls contain pores of Kohn to facilitate pressure equilibration and cellular communication among adjacent alveoli (Chap. 10).

A lung lobule is defined as the smallest subunit of respiratory parenchyma bounded by the connective tissue sheath of an interlobular septum (Fig. 2.12). A typical lung lobule is about 2 cm in diameter, and its boundary layer of connective tissue normally is very thin and difficult to see macroscopically. In certain pathologic conditions, these interlobular septa are thickened and more readily seen. In this context, a lung lobule is the smallest anatomical unit of lung that has its own major airway and innervation, and it receives blood from both ventricles. In contrast, the lung acinus is the smallest functional unit of the lung, consisting of all the respiratory parenchyma distal to one terminal bronchiole. Each lung lobule contains 3-10 acini.

Pulmonary arteries travel besides conducting zone airways, often being quite similar in diameters. These pulmonary arteries transport deoxygenated blood from the right ventricle to alveolar capillaries via pulmonary arterioles (Chaps. 7 and 9). In turn, alveolar capillaries drain reoxygenated blood into pulmonary venules, which merge into pulmonary veins and then fill the left atrium. While most arteries seen in lung tissue sections are pulmonary arteries from the right heart, smaller bronchial arteries can sometimes be distinguished. These represent aortic branches and carry oxygenated blood and other nutrients to the respiratory parenchyma. Such blood from bronchial arteries is delivered at higher perfusion pressures than those within pulmonary arteries (Chap. 7). Interestingly, bronchial arterial blood also drains into the pulmonary veins, since there are no distinct bronchial veins. This mixing of venous bloods with potentially very different oxygen contents contributes to physiological shunt (Chap. 9).

The lymphatic vessels of the lung as well as the main pulmonary veins do not travel along the principal airways but rather are found in the interlobular septa that define the lung lobules. Within the connective tissue adventitia that surrounds larger airways are efferent parasympathetic fibers (from the vagus nerve), which cause bronchial constriction, as well as efferent sympathetic nerves, which cause bronchial dilation. Also within this connective tissue zone are the smaller afferent visceral nerves that transmit sensations associated with airway caliber and pain (Chap. 11).

During the third week of gestation, a groove in the primitive foregut originates, and, by week 4, the primordial single lung bud bifurcates. During weeks 5-6, the primary bronchi continue to elongate and divide, so that by the end of week 6 there are usually 10 segmental bronchi on the right and 8-9 segmental bronchi on the left. This entire period of lung development from gestational days 26 through 42 is known as the embryonic stage (Fig. 2.13).

During gestational weeks 6-16, in the pseudoglandular stage of lung development, many additional airways are formed, usually to the level of the terminal bronchioles (Fig. 2.14). During this phase, the first ciliated cells appear in the airways (week 10), followed by the first recognizable goblet cells (weeks 13-14), and then development of the more convoluted seromucinous glands of the submucosal layer (weeks 15-16).

During gestational weeks 17-28, the canalicular stage (or acinar stage) of lung development occurs, forming the fundamental gas-exchanging architecture of the lung acini (Fig. 2.15). During this phase, type 1 and type 2 pneumocytes appear (week 20), and by week 24 cartilage extends to the most distal bronchi.

During gestational weeks 28-34, the saccular stage of lung development occurs in which alveolar saccules form by subdividing existing acinar compartments into smaller spaces, and by elaboration of their associated capillary networks. By gestational week 35 and continuing after birth, the alveolar stage of development has begun in earnest, usually evident as an explosive increase of epithelial surface area and a corresponding thinning of the alveolar septal membranes to the dimensions seen in adult lungs.

Throughout gestation, lung vasculature forms concurrently with airway development and is fundamentally an intrauterine process. Major airways and their associated vessels are formed by week 16, although they continue to expand in length and diameter with subsequent growth. Although alveolar development begins in utero, most alveoli in the adult lung form postnatally. At birth, there are ~50 million alveoli. Within several years and presuming a normal growth pattern for a child, the number of alveoli grows to 300-600 million. Subsequent lung growth is predominantly related to modest increases in the diameters of alveoli (that increase respiratory parenchymal volume to the third power of such a change in diameter) rather than vastly increasing the numbers of alveoli.

All epithelial components of the respiratory system are endodermal in origin, while the cartilaginous and muscular components derive from the splanchnic mesoderm that surrounds the fetal foregut. Laryngeal muscles originate from the fourth and sixth branchial arches and are innervated by branches of the vagus nerve (cranial nerve X). Muscles that are derivatives of the fourth branchial arch, including the cricothyroid, levator palatini, and pharyngeal constrictors, are innervated by the superior laryngeal nerve. Muscles derived from the sixth branchial arch, notably the intrinsic laryngeal muscles, are innervated by the recurrent laryngeal nerve.