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CHAPTER 1

HISTOLOGY AND GROSS ANATOMY OF THE RESPIRATORY TRACT


Richard S. Fraser

he lower respiratory tract extends from the larynx to the most distal portions of the lung parenchyma. Its airways can be considered in two groups: conducting and transitional.1,2 The former comprises those whose walls do not contain alveoli and are thick enough to prevent gas diffusing into the adjacent lung parenchyma. They include the trachea, bronchi, and membranous (nonalveolated) bronchioles; the latter are defined structurally by the absence of cartilage in their walls. These airways, along with their accompanying arteries and veins, lymphatic vessels, nerves, interlobular septa, and pleura, constitute the nonparenchymal portion of the lung. As the name suggests, transitional airways have both conductive and respiratory functions. They consist of respiratory bronchioles and alveolar ducts; in addition to conducting gas to and from the most peripheral portion of the lung, each has alveoli on its wall that serve in gas exchange. Alveoli associated with the transitional airways and with the more distal alveolar sacs constitute the lung parenchyma. It has been estimated that approximately 87% of the total lung volume is alveolar, 6% of which is composed of tissue, and the remainder of which is gas.3 Both the right and the left lung are enveloped by a thin layer of connective tissue (the visceral pleura), which focally extends into the parenchyma, dividing it into several lobes (upper, middle, and lower on the right side and upper and lower on the left). A potential space (the pleural cavity) separates the visceral pleura from the parietal pleura, which lines the chest wall, mediastinum, and diaphragm.

common usage, the designation main bronchi is applied to the bronchi arising at the bifurcation of the trachea and extending to the origin of the upper lobe bronchus on each side; the terms upper, middle, and lower lobe bronchi are used for the corresponding bronchi supplying individual lobes, and the term intermediate bronchus is applied to the airway segment between the right upper lobe bronchus and the origins of the right middle and lower lobe bronchi. The basic morphology of the conducting airways is similar and consists of a surface epithelium composed largely of ciliated and secretory cells overlying subepithelial tissue that consists predominantly of connective tissues and glands (Figure 1-1). The proportion and type of these elements vary at different levels of the conducting system.

EPITHELIUM
The tracheal and proximal bronchial epithelium are composed predominantly of tall, columnar ciliated and goblet cells, and smaller, somewhat triangular, basal cells (Figure 1-2).4 Ciliated cells are about five times more numerous than goblet cells in the central airways, and the ratio is even greater peripherally.5 They have thin, tapering bases that are attached firmly to the underlying basal lamina. The cells are also attached to one another at their apical surfaces by tight junctions,6 forming a barrier physically impermeable to most substances,7 and laterally to one another and to basal cells by desmosomes. Intercellular spaces containing numerous microvilli are present between the cells, especially at their basal aspects.8 Emanating from the surface of each ciliated cell are approximately 200 to 250 cilia, as well as numerous shorter microvilli (Figure 1-3), which, in addition to microvilli located in the intercellular space, are important in the transepithelial movement of fluid and electrolytes.9 Goblet cells account for about 20 to 30% of cells in the more proximal airways5 and decrease in number distally, so that only occasional cells are present in normal membranous bronchioles.10 Ultrastructurally, the apical portion of the cytoplasm is distended by numerous membrane-bound, electron-lucent secretory granules. Histochemical studies

CONDUCTING AIRWAYS
The basic branching pattern of the conducting zone is dichotomous (that is, the parent branch divides into two parts). As a general rule, the angles made by daughter branches with their parent vary with their diameter1: when the branches are of equal size, the angles tend to be equal; when the branches are of different size, the smaller branch usually makes a larger angle with the parent. Through

Anatomy

FIGURE 1-2 Conducting airway epithelium and lamina propria (electron micrograph). Ciliated cell (short straight arrow), goblet cell (long straight arrow), basal cell (black curved arrow), and subepithelial fibroblast (empty curved arrow).

FIGURE 1-1 Conducting airway (hematoxylin-eosin stain). Subsegmental bronchus showing cartilage (c), mucous glands (short arrows), bronchial artery (long arrow), and muscle (m). Reproduced with permission from Fraser RS, Mller NL, Colman N, Par PD, Diagnosis of Diseases of the Chest, IV edition. Philadelphia: WB Saunders; 1999.

have shown these to contain predominantly neutral mucin and sulfomucins.11 However, variation in both ultrastructural and histochemical features has been demonstrated in different airways, and cells with a large proportion of nonsulfated sialomucins have also been identified.12 Basal cells are relatively small, somewhat triangular cells whose bases are attached to the basement membrane and whose apices normally do not reach the airway lumen. They are more abundant in the proximal airways, where they form a more or less continuous layer, and gradually diminish in number distally, so that they are difficult to identify in bronchioles.13,14 They function as a reserve from which the epithelium is repopulated, both normally and after airway injury,14 and are involved in the attachment of columnar epithelial cells to the basement membrane.15 Clara cells (nonciliated bronchiolar secretory cells) are found primarily in membranous bronchioles, in which they constitute the majority of the epithelium along with ciliated cells.16 They are columnar or (in the more distal airways) cuboidal in shape and bulge somewhat into the airway lumen, slightly projecting above the surrounding ciliated cells. The cytoplasm contains a prominent Golgi apparatus, abundant granular endoplasmic reticulum and mitochondria, and numerous membrane-bound, electron-dense granules. The latter contain a number of lipids and proteins,17 including a 10 kDa protein known as Clara cell-specific

FIGURE 1-3 Ciliated cell (electron micrograph). Apical portion of cell showing cilia (long arrow) and microvilli (short arrow). Secretory granules (g) of a goblet cell can be seen in the adjacent cell. Reproduced with permission Fraser RS, Mller NL, Colman N, Par PD, Diagnosis of Diseases of the Chest, IV edition. Philadelphia: WB Saunders; 1999.

Histology and Gross Anatomy of the Respiratory Tract

protein (CC10, CC16, Protein 1) that may have a role in the regulation of local inflammatory and immune reactions,18 several surfactant apoproteins,19 and a leukocyte protease inhibitor.20 In addition to these secretory functions, there is evidence that Clara cells act as progenitor cells in the regeneration of damaged bronchiolar epithelium.21 Neuroendocrine cells constitute about 1 to 2% of bronchial epithelial cells in neonates22 and 0.5% in adults.23 They are attached at their bases to the basement membrane and have tapering apices that extend toward and may or may not reach the airway surface. Ultrastructurally, the cytoplasm contains numerous membrane-bound, electron-dense neurosecretory granules (Figure 1-4) that contain a variety of peptides, including gastrin-releasing peptide (bombesin), calcitonin, calcitonin generelated peptide, somatostatin, substance P, endothelin, and enkephalin.24 These peptides appear to be secreted mostly at the basal aspect of the cell, although some may also be released via lateral cytoplasmic processes to affect adjacent epithelial cells, or into the airway lumen itself. The principal functions of the cells are believed to be related to the local effects of these secreted peptides. The cells appear as early as 8 weeks in the human fetus and increase in number thereafter,25 suggesting a role in the control of lung development. Cells of the immune system are present within the epithelium of all conducting airways. Dendritic and Langerhans cells are structurally similar cells that possess elongated cytoplasmic extensions and an organelle-rich cytoplasm; Langerhans

cells have characteristic pentalaminar cytoplasmic structures termed Birbeck granules.26 Dendritic cells are found throughout the lung, including the alveolar septa, peribronchiolar connective tissue, and bronchus-associated lymphoid tissue26; Langerhans cells appear to be present only within airway epithelium. In this location, their number is considerably greater in proximal than in distal branches.27 Langerhans cells express cell surface receptors for immunoglobulins,26 and it is believed that they act as antigen-processing and antigen-presenting cells and as stimulators of T-cell proliferation.28 Lymphocytes (predominantly T cells) are present throughout the conducting airway epithelium, usually singly.29 Although they are undoubtedly involved in processing and reacting to inhaled antigens, it is also possible that they have a role in modifying airway epithelial cell function. Greater numbers of lymphocytes can be seen as lymphoid aggregates in the lamina propria and submucosa (bronchusassociated lymphoid tissue), usually in the setting of acute or chronic airway injury. Mast cells are also found in small numbers within the airway epithelium.30 A basement membrane underlies the epithelium over its entire basal aspect. Its primary function is to provide an attachment for the epithelium to the underlying connective tissue. On the epithelial side, this attachment is mediated by adhesion molecules and by hemidesmosomal junctions with basal cells31; on the opposite side, anchoring fibrils emanate from the basement membrane and intertwine with collagen fibers in the upper lamina propria.

SUBMUCOSA

AND

LAMINA PROPRIA

FIGURE 1-4 Neuroendocrine cell (electron micrograph). Basal portion of two cells, one of which is adjacent to the basement membrane (straight arrows). The cytoplasm contains numerous electron-dense neurosecretory granules (curved arrows). Reproduced with permission from Fraser RS, Mller NL, Colman N, Par PD, Diagnosis of Diseases of the Chest, IV edition. Philadelphia: WB Saunders; 1999.

The subepithelial tissue can be subdivided into a lamina propria, situated between the basement membrane and the muscularis mucosa, and a submucosa, consisting of all the remaining airway tissue. The lamina propria consists principally of a network of capillaries, a meshwork of reticulin fibers continuous with the basement membrane, and bundles of elastic and nerve fibers. Ultrastructural examination shows the presence of a population of fibroblasts located immediately beneath the basement membrane (the attenuated fibroblast sheath) that have been speculated to be capable of interaction with adjacent epithelial cells and to be involved with the regulation of local inflammatory and reparative processes.32 The submucosa contains cartilage, muscle, and other supportive connective tissue elements, as well as the major portion of the tracheobronchial glands. The airway wall can also be considered as being composed of inner and outer layers, the former extending from the lumen to the outermost layer of smooth muscle and the latter from the smooth muscle to the airway adventitialparenchymal boundary.33 Tracheal cartilage plates consist of about 16 to 20 U-shaped structures oriented in a horizontal plane with their open ends directed posteriorly.34 The posterior (membranous) portion of the wall is free of cartilage. The spaces between the plates contain smooth muscle, tracheal glands, and collagenous and elastic tissue. The U-shape of the cartilage plates is maintained in the main bronchi; however, they become smaller and irregular in shape in lobar and segmental bronchi and disappear altogether in membranous bronchioles.

Anatomy

Elastic tissue in the lamina propria tends to be clustered in bundles oriented in a longitudinal direction. These bundles are especially well developed in the posterior portion of the trachea and main bronchi, where they form well-defined ridges.35 Prominent elastic thickening is also present in the lamina propria at bronchial branch points. The cartilage plates are connected by bundles of fibroelastic tissue arranged predominantly in a longitudinal direction. At numerous sites, particularly in smaller airways, elastic fibers emanating from these longitudinally arranged bundles intermingle with the elastic tissue of the lamina propria.1 These fibers are believed to help transmit to the more rigid and stronger cartilaginous fibrous tissue the tension that arises in the airway epithelium and lung parenchyma during breathing. Tracheal muscle is found predominantly in the membranous portion, where it is organized in both longitudinal and transverse bundles (Figure 1-5); the latter are attached to the inner perichondrium close to the tip of the cartilaginous rings (the bundles joining each ring posteriorly).36 Although somewhat less prominent, transverse fibers can also be found between the cartilage rings in the anterior portion. In the bronchi, muscle is organized in bundles close to the epithelium adjacent to the lamina propria. In the larger airways, the orientation is mainly circumferential, as in the trachea. In the more distal branches, the muscle is obliquely oriented and arranged in branching and anastomosing bundles that form irregular spirals in the airway wall. The proportion of muscle relative to airway diameter is greater in smaller airways.37 Loose connective tissue consisting of proteoglycans and mature collagen occupies much of the remainder of the submucosa. This tissue is continuous with connective tissue in the adjacent pulmonary arteries as well as that in the perivenous tissue near the hilum and in the interlobular and pleural interstitium. This interdependence of connective tissue is important in maintaining the overall structure of the lung and in providing a scaffold for the more delicate connective tissue of the parenchyma.

Tracheobronchial glands are specialized extensions of the airway surface epithelium into the submucosa. Both the number and size of the glands are greater in the more proximal airways,38 and they are absent altogether in the smallest bronchi and bronchioles. The secretory portion of the gland is connected to the surface by a duct of variable length whose lining is similar to that of the surface airway epithelium (Figure 1-6). Multiple branched secretory tubules arise from the collecting duct. They are lined proximally by mucus-secreting cells that contain several histochemically different types of mucin and distally by serous cells.39 The latter have been shown to contain a variety of substances that are potentially important in local airway defense, including lysozyme, lactoferrin, transferrin, and a protease inhibitor. Myoepithelial cells are present between the basement membrane and both types of epithelial cell40 and are presumably responsible in part for expulsion of glandular secretions. Many cells concerned with airway defense are found in the airway lamina propria and submucosa. Lymphocytes can be identified either singly or in clusters, the latter being variously termed lymphoid nodules, lymphoid aggregates, or bronchus-associated lymphoid tissue (BALT).41 Lymphoid aggregates are composed of well-defined but unencapsulated

FIGURE 1-5 Posterior tracheal wall (hematoxylin-eosin stain). Lamina propria (p), transverse muscle bundle (T), longitudinal muscle bundle (L), and mucous glands (m).

FIGURE 1-6 Bronchial gland (hematoxylin-eosin stain). Collecting duct (D), mucous cells (m), and serous cells (arrows).

Histology and Gross Anatomy of the Respiratory Tract

clusters of mature lymphocytes, with smaller numbers of dendritic cells and lymphoblasts. The cells extend into the overlying epithelium, which is often flattened and lacks mucus or ciliary differentiation. Small, thin-walled blood vessels are present within the aggregates, possibly serving as a site for cell migration to and from the circulation. Plasma cells, primarily IgA and IgG in type, are common in the tracheobronchial wall, particularly in proximal bronchi in association with tracheobronchial glands, and in the lamina propria close to the basement membrane.42 Isolated macrophages can be found throughout the lamina propria and submucosa and tend to be more numerous in individuals exposed to noxious materials such as cigarette smoke and inorganic dust. Mast cells can be found throughout the lung in airway, alveolar, pleural, and interlobular interstitial tissue, as well as in airway epithelium.43 Although the cells are structurally similar, there appear to be differences in mediator content between them, suggesting variable functions.44

however, muscle and elastic tissue continue in a spiral fashion surrounding the alveolar mouths.47 Bronchiolar-type epithelium and lamina propria are absent in alveolar ducts. The contribution of transitional airways to gas exchange is probably substantial; in one investigation, approximately 35% to 40% of all alveoli in three acini were found to be located in these structures.45

RESPIRATORY TISSUE
Alveoli are demarcated by septa composed of a continuous layer of epithelial cells overlying a thin interstitium (Figure 1-8). The former consists principally of two morphologically distinct cells, type I and type II; alveolar macrophages are also present on the epithelial surface. The interstitium contains capillaries involved in gas exchange, as well as connective tissue and a variety of cells responsible for maintaining alveolar shape and defense. Type I alveolar cells cover approximately 95% of the alveolar septal surface.48 The nucleus of this cell type is small and covered by a thin rim of cytoplasm containing few organelles. The rest of the cytoplasm extends as a broad

TRANSITIONAL AIRWAYS
The number and length of airways from the terminal membranous bronchiole to the alveolar sac as well as the pattern of their branching are quite variable.45,46 Some of this irregularity may be related to spatial constraints imposed by pleura, interlobular septa, and larger airways and vessels. On average, however, there are probably about two to three respiratory bronchioles and four to six alveolar ducts between the terminal bronchiole and the alveolar sacs. The surface of respiratory bronchioles is lined by a low columnar to cuboidal epithelium that gradually decreases in extent as the number of alveoli increases. In first- and second-order bronchioles, it is usually complete on one side, where it overlies a lamina propria and muscle continuous with that of the terminal bronchiole (Figure 1-7). As the number of alveoli increases, the lamina propria diminishes;

FIGURE 1-7 Respiratory bronchiole (hematoxylin-eosin stain). Epithelium (arrows), pulmonary artery (A), and distal branches (B). Reproduced with permission from Fraser RS, Mller NL, Colman N, Par PD, Diagnosis of Diseases of the Chest, IV edition. Philadelphia: WB Saunders; 1999.

FIGURE 1-8 Alveoli (hematoxylin-eosin stain). Septa are composed of capillaries and a small amount of connective tissue (short arrow). In some foci (curved arrow), the latter appears to be thicker. Precapillary arteriole (a). (Airspaces contain fluid and red blood cells secondary to left heart failure.) Reproduced with permission from Fraser RS, Mller NL, Colman N, Par PD, Diagnosis of Diseases of the Chest, IV edition. Philadelphia: WB Saunders; 1999.

Anatomy

FIGURE 1-10 Type II epithelial cell (electron micrograph). Secretory granules with lamellar inclusions (arrows).

FIGURE 1-9 Airblood barrier (electron micrograph). Red blood cell (R), capillary lumen (L), and alveolar airspace (A). Type I epithelial cytoplasm (long arrows) and endothelial cytoplasm (short arrows) are separated by a small amount of fused epithelialendothelial basement membrane. (The interstitial tissue adjacent to the capillary is abnormally thickened by collagen.)

sheet 50 m or more over the alveolar surface and is about 0.3 to 0.4 m thick (Figure 1-9). Adjacent type I cells are joined to one another by tight junctions that provide a more or less complete barrier to the diffusion of fluid and watersoluble substances into the alveolar airspace.49 The cell cytoplasm contains pinocytotic vesicles that can theoretically transport material in either direction across the airblood barrier. Type II epithelial cells tend to be located near corners where alveoli meet.50 Their cytoplasm contains a welldeveloped endoplasmic reticulum, a prominent Golgi complex, and numerous membrane-bound, secretory granules (Figure 1-10). The latter contain characteristic lamellar inclusions that are the source of surfactant, the substance responsible for modifying alveolar surface tension.51 Type II cells have a number of other important functions. A small number are mitotically active and are able to differentiate into type I cells, repopulating the alveolar surface as the latter die. There is also evidence that type II cells synthesize a variety of substances involved in alveolar structure and defense, including fibronectin and 1-antitrypsin,52,53 and are able to suppress lymphocyte proliferation and enhance macrophage function in the alveolar septa.54 Surfactant can be identified on transmission electron microscopy as an extremely thin (4 nm) layer of osmiophilic

material that covers the alveolar epithelial surface.55 It appears to consist of two components: (1) a film facing the alveolar airspace, which is composed of densely spaced, highly surface-active phospholipids, and (2) a deep layer containing surface-active phospholipids in a different physicochemical configuration and linked to proteins. Components of the superficial layer are thought to be recruited from the deeper layer (hypophase) during expansion of the lung and may reenter it at low lung volumes. The hypophase contains aggregates of lipid termed tubular myelin that have a characteristic fingerprint-like pattern. A more or less continuous basement membrane is present adjacent to the type I and type II cells. Focally, it is fused with the basement membrane underlying the endothelial cells of the alveolar capillaries. Connective tissue, as well as endothelial and epithelial cell nuclei, tend to be absent from this region of basement membrane fusion. This portion of the septumconsisting of the thin type I cell sheet, the endothelial cell cytoplasm, and the fused basement membranesis about 0.4 to 0.5 m thick and is the principal site of gas exchange across the airblood barrier. Elsewhere, endothelial and epithelial basement membranes are separated by an interstitial space of variable width that contains connective tissue (including elastic and collagen fibers) and a variety of cells.56 The most prominent of these is the myofibroblast (contractile interstitial cell), which, as the name suggests, has ultrastructural features suggestive of both fibroblast and muscle differentiation (Figure 1-11).57 Possible functions of these cells include local regulation of alveolar gas exchange /Q ) (their contraction resulting in a reduction in capillary (V bloodflow), regulation of the fluid content of the alveolar interstitium, and production of connective tissue, both in the normal state and in pathologic alveolar fibrosis.56,57 Scattered macrophages are present in the alveolar interstitium and on its epithelial surface. Ultrastructurally, they have prominent surface microvilli and an abundance of membrane-bound primary and secondary lysosomes.58

Histology and Gross Anatomy of the Respiratory Tract

FIGURE 1-11 Alveolus with interstitial cell (electron micrograph). Interstitial cell nucleus (arrow), collagen (T), and capillary lumen (L).

Although they are morphologically similar, it is possible that these and other pulmonary macrophages have different functional capabilities. In fact, they have been considered to form several groups on the basis of their anatomic location59: (1) the airway macrophage, situated on or beneath the epithelial lining of conducting airways; (2) the alveolar interstitial macrophage; (3) the alveolar surface macrophage; (4) the intravascular macrophage, located adjacent to the capillary endothelial cell60; and (5) the pleural macrophage.61 In addition to macrophages, a variety of other cells involved in parenchymal defense can be found in the alveolar interstitium, including mast cells,62 lymphocytes, and CD4, Ia dendritic cells.63 Numerically, the alveolar macrophage is the most important nonepithelial cell in the parenchyma. Bronchoalveolar lavage of normal human airspaces yields a cell population including approximately 95% macrophages; dendritic cells (0.5%), lymphocytes (1 to 2%), monocyte-like cells of uncertain nature (2%), and polymorphonuclear leukocytes (less than 1%) account for the remainder.63 The number of alveoli in the adult human lung has been estimated to be about 300 106.64 However, one group documented considerable variation in this figure among different individuals, with computed values ranging from 212 106 to 605 106.65 In adults, both maximal diameter and depth of the alveolus (measured from the opening at the alveolar duct or sac to the base) are about 250 to 300 m.66

FIGURE 1-12 Secondary lobule and acinus (hematoxylin-eosin stain). Interlobular septa (curved arrows), pleura (p), central bronchiole (b), and respiratory bronchiole (straight arrow). The tissue between straight lines corresponds approximately to an acinus. Reproduced with permission from Fraser RS, Mller NL, Colman N, Par PD, Diagnosis of Diseases of the Chest, IV edition. Philadelphia: WB Saunders; 1999.

the periphery of the lung, where they are continuous with the pleura (Figure 1-13). They are most numerous in the apical, anterior, and lateral aspects of the upper lobe and in the lateral and anterior regions of the lower lobes. In the central regions of the lung, septa are often difficult to identify or absent altogether. Because of this deficiency, there is an alternative definition of the lobule as consisting of pulmonary parenchyma supplied by a cluster of three to five terminal bronchioles.67 The pulmonary acinus comprises all lung tissue distal to the terminal bronchiole and is composed of respiratory bronchioles, alveolar ducts, alveolar sacs, alveoli, and their accompanying vessels and connective tissue (see Figure 1-12).

LUNG UNIT
The most widely accepted subdivisions of lung parenchyma that have been proposed as the fundamental unit of lung structure are the secondary lobule and the pulmonary acinus. The former can be defined as the smallest discrete portion of the lung surrounded by connective tissue septa (Figure 1-12). It is somewhat polyhedral in shape, usually measures 1 to 2.5 cm in diameter, and contains a central membranous bronchiole, which gives rise to several respiratory bronchioles. Interlobular septa are best developed in

FIGURE 1-13 Interlobular septa (electron micrograph). Septa (arrows) are clearly evident as a result of thickening by carcinoma.

Anatomy

Measurements of acinar diameter vary between 6 and 10 mm, depending to some extent on the technique and the pressure at which the lung is inflated.68

CHANNELS OF PERIPHERAL AIRWAY AND ACINAR COMMUNICATION


The best understood of these structures are alveolar pores, small discontinuities in the alveolar septa also known as pores of Kohn. The size of the aperture is usually between 2 and 10 m, and there are as many as 5 to 20 pores per alveolus.69,70 They are generally round, and their edges are lined by type I epithelial cells. By transmission electron microscopy, they are usually free of cellular or other material in airway-fixed material; however, in vascular-perfused tissue, they are typically occluded by a thin film of surfactant.69 Since it is probable that vascular-perfused tissue more closely represents the normal state of the alveolar airspace, the presence of this surfactant casts some doubt on the significance of the pores as a mechanism for collateral ventilation. Direct communications between alveolar sacs and membranous bronchioles (canals of Lambert)71 consist of epitheliallined tubular structures that, in lungs fixed in deflation, range in diameter from practically closed to 30 m in diameter. It is not known whether they provide accessory communication solely within acini or whether interacinar connections capable of subserving collateral ventilation occur as well. The results of experimental studies in both animals and humans indicate that particles considerably larger than either alveolar pores or most canals of Lambert are able to pass through collateral channels in lung parenchyma.72 The precise anatomic correlate of these pathways is unclear.

FIGURE 1-14 Pulmonary artery (hematoxylin-eosin stain). Conventional (c) and accessory (a) branches.

PULMONARY VASCULATURE PULMONARY ARTERIES


Pulmonary arteries are intimately related to the airways and divide with them, a branch accompanying the adjacent airway to the level of the respiratory bronchioles. In addition to these conventional vessels, many accessory branches arise at points other than corresponding airway divisions and extend directly into the adjacent lung parenchyma (Figure 1-14). Elastic arteries include the main pulmonary artery and its lobar, segmental, and subsegmental branches extending approximately to the junction of bronchi and bronchioles. The elastic laminae are located in the media and are organized in layers, which become less numerous as the vessels decrease in size. At a diameter of about 1,000 to 500 m, only two layersinternal and externalcan be identified, at which point the vessels are considered muscular arteries. Beginning at a diameter of about 100 m, the arteries gradually lose their medial smooth muscle to become arterioles, so that, at a diameter of about 70 m, the vessels are composed solely of a thin intima and a single elastic lamina that is continuous with the external elastic lamina of the parent artery. Arterioles continue to divide within the acinus, some accompanying bronchioles and alveolar ducts to the level of the alveolar sacs and others

penetrating the adjacent parenchyma directly.73 The smaller branches ramify to form the capillary network of the alveoli. The pulmonary capillaries form a dense network of short interconnecting segments (Figure 1-15).64 Measurements of the external diameter of these segments in fresh lung average about 8.6 m; assuming the average thickness of the capillary endothelium to be about 0.3 m, the average internal capillary diameter is thus about 8 m. However, these values vary substantially with both lung volume and capillary pressure.74,75 The average axial length of capillary segments is about 10 m. At all levels of the arterial tree, the intima is very thin, consisting of an endothelial cell layer and its adjacent basement membrane. The endothelial cells tend to be organized in an interlocking mosaic.76 Like type I epithelial cells, they possess cytoplasm that extends as thin, plate-like processes measuring as little as 0.1 to 0.3 m in thickness. Short, microvillus-like projections are present on the luminal surface, particularly in arteries.77 These greatly increase the cell

FIGURE 1-15 Pulmonary capillaries (hematoxylin-eosin stain). En face view of an alveolar wall shows numerous interconnecting capillary segments.

Histology and Gross Anatomy of the Respiratory Tract

parenchyma or in the connective tissue septa that delimit the secondary lobules. As in the pulmonary arterial system, numerous supernumerary vessels join the veins as they run to the hilum.83 Histologically, pulmonary venules are indistinguishable from arterioles. Veins have a variable number of elastic laminae, between which are small bundles of smooth muscle cells. No valves are present within venous lumina. However, regularly spaced annular constrictions related to local accumulations of smooth muscle have been identified in the veins of some animals and have been hypothesized to be important in the control of pulmonary bloodflow.84

BRONCHIAL VASCULATURE
Most individuals have two to four bronchial arteries, a relatively common pattern being one on the right (originating from the third intercostal artery) and two on the left (arising directly from the aorta).85 At the hila, the vessels form an intercommunicating circular arc around the main bronchi from which several branches (usually two or three on opposite sides of the airway wall) extend into the peribronchial connective tissue (see Figure 1-1). These branches send smaller twigs into the bronchial wall that ramify to form a vascular plexus in the submucosa. The latter can comprise as much as 10 to 20% of the volume of the normal subepithelial tissue, and it has been hypothesized that significant airway narrowing may occur when these vessels become congested.86 Most arteries stop at the level of the terminal bronchioles. The bronchial circulation has a dual venous drainage. One portion, related to the trachea and proximal bronchi, drains into the bronchial veins to the right side of the heart via the azygos and hemiazygos veins. The other, which drains the major portion of the intrapulmonary bronchial flow,87 originates in anastomoses with small precapillary and postcapillary pulmonary vessels and courses via the pulmonary veins into the left atrium.

FIGURE 1-16 Pulmonary capillary endothelial cell (electron micrograph). Red blood cell (R), endothelial cell caveolae (long arrows), and type I epithelial cell (short arrow).

surface area and may play a role in the metabolism of various blood substances as well as facilitating metabolite transfer between the blood and the endothelial cells. Small vesicles (caveolae intracellulare) can also be seen in endothelial cells, particularly those lining alveolar capillaries (Figure 1-16). In the latter, they are most prominent in the relatively thick, nongas-exchanging part of the cell, at either the luminal or the abluminal surface.78 Small electron-dense granules, considered to represent enzyme complexes responsible for various metabolic functions, can be seen at the bases of the vesicles. In addition to metabolic activity, the vesicles are believed to function in the transport of fluid and proteins between blood and interstitial tissues and across the airblood barrier.79 Adjacent endothelial cells are joined by tight junctions.79 For the most part, these are continuous; however, occasional intercellular clefts measuring up to 4 nm in thickness can be observed in alveolar capillaries. As determined by freezefracture techniques, these junctions are less complex than those of the alveolar epithelium, suggesting that the main site of solute impermeability in the airblood barrier is the epithelium. The complexity of the endothelial junctions is variable in different parts of the vasculature, being greater in arterioles than in the more permeable venules, and greater in the base than at the apex of the lung.80 Several cell types can be found within the arterialarteriolar wall in addition to smooth muscle and endothelial cells. Pericytes are located between the basement membrane and endothelial cells, predominantly in capillaries but also to some extent in arterioles. They have thin microfilament-containing processes that extend toward and attach to the endothelial cell surface.81 Mast cells are also present in the connective tissue adjacent to pulmonary vessels, where they have been hypothesized to function as mediators of hypoxic vasoconstriction.82

LYMPHATIC SYSTEM
Lymph flows along two major pathways in the lung, one located in the peribronchovascular connective tissue and the other in interlobular septal connective tissue (Figure 1-17).88 Anastomotic channels up to 4 cm long connect the two pathways, particularly in the basal portion of the lower lobes. Lymphatic capillaries originate in the region of the distal respiratory bronchioles.89 Some lymphatics are located immediately adjacent to alveolar airspaces in the interlobular, peribronchial, and perivascular connective tissue. These channels have been termed juxtaalveolar lymphatics because of their close topographic and possible functional relationship with the alveolar airspaces.90 Histologically, pulmonary lymphatics can be divided into capillaries and collecting channels, the latter defined by the presence of mural smooth muscle cells or valves. With the use of scanning electron microscopy, three types of vessel have been distinguished91: (1) relatively broad, ribbon-like structures that are closely linked to lymphatic capillaries (reservoir lymphatics); (2) tubular structures that may

PULMONARY VEINS
Unlike pulmonary arteries, pulmonary veins and venules are not associated with airways and course instead in the

10

Anatomy

FIGURE 1-17 Perivascular lymphatic (hematoxylin-eosin stain). Membranous bronchiole (M), pulmonary artery (A), and lymphatic distended by fluid (L).

contain valves and extend for long distances without side branches (conduit lymphatics); and (3) complexes of plexiform vessels that surround the arteries, veins, and bronchi (sacculotubular lymphatics). The basement membrane beneath lymphatic capillary endothelial cells is discontinuous, and intercellular junctions are absent between some endothelial cells. The resulting gaps in the vessel wall provide a relatively easy route for interstitial fluid that has leaked from alveolar septal capillaries to enter the lymphatic capillary lumen. The cytoplasm of the endothelial cells contains numerous microfilaments, which have been hypothesized to constitute an actin-like contractile system that regulates opening or closing of the intercellular gaps.89 Numerous valves 1 to 2 mm apart direct lymph flow in both the pleural and intrapulmonary lymphatics. Although they appear to be bicuspid in two-dimensional histologic sections, stereomicroscopic studies have shown most to be monocuspid and shaped like a funnel.89 They are well adapted to unidirectional flow since they cannot be inverted and are easily occluded by flow in an abnormal direction.

chest wall, diaphragm, and mediastinum.92 The two join at the hila. Extensions of visceral pleura into the underlying lung form fissures (one major and one minor on the right and a single major one on the left) that divide the lung into lobes. The visceral pleura can be considered to consist of three layers (Figure 1-18): (1) a superficial endopleura, composed of a continuous layer of mesothelial cells overlying a thin network of collagen and elastic fibers; (2) an external elastic lamina, which consists of a layer of collagen and elastic tissue whose thickness varies,93 possibly as a result of differences in pleural stress during the respiratory cycle; and (3) a vascular (interstitial) layer that consists of connective tissue containing lymphatic and blood vessels. The last-named is continuous with the interstitial tissue of the interlobular septa and overlies a thin internal elastic lamina that encases the entire lung parenchyma and separates alveoli from the pleura, interlobular septa, and bronchovascular bundles. The parietal pleura consists of a layer of connective tissue adjacent to the endothoracic fascia of the chest wall. It is divided into two parts by a layer of fibroblastic tissue, with most of the vessels being located in the part furthest from the pleura. Mesothelial cells form a continuous layer overlying the entire visceral and parietal pleural surface. Their size and shape vary with transpulmonary pressure, the cells becoming more flattened as the lung expands.92 Characteristically, the cell surface is covered by numerous long, thin microvilli. Fine strands approximately 150 nm in diameter emanate from the surface glycocalyx and extend between the microvilli; it has been suggested that fluid trapped in compartments formed by these strands and by the microvilli themselves protects the mesothelial cells from the trauma of normal pleural movement.94 Mesothelial cells are metabolically active and appear to have several functions. They are likely to be responsible, at least in part, for regulating the composition and amount of pleural fluid, and there is evidence that they have the ability to produce components of the submesothelial connective tissue.95 Surface-active phospholipids similar to alveolar

PLEURA
The pleural space is enclosed by the visceral pleura, which covers the lungs, and by the parietal pleura, which lines the
FIGURE 1-18 Visceral pleura (elastic van Giesen stain). Mesothelial cells (thin arrow), external elastic lamina (thick arrows), internal elastic lamina (curved arrow), and interstitial layer (T).

Histology and Gross Anatomy of the Respiratory Tract

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surfactant, most likely produced by mesothelial cells, have been found in the pleural space, where they may act as lubricants to facilitate pleural surface movement.96

PULMONARY INNERVATION
The lung is innervated by fibers that travel in the vagus nerve and in nerves derived from the second to fifth thoracic ganglia of the sympathetic trunk.97 These fibers carry afferents and efferents of the parasympathetic and sympathetic autonomic nervous systems. In addition, there is pharmacologic and physiologic evidence for a nonadrenergic, noncholinergic, neural inhibitory efferent system (nonadrenergic inhibitory system), the anatomic pathway of which has not been well defined.98 Although both excitatory and inhibitory components have been demonstrated in rodents, the human lung does not seem to have an excitatory pathway. The vagus nerve contains preganglionic, parasympathetic efferent fibers and afferent fibers from various lung receptors. The sympathetic fibers are largely postganglionic efferent in type. Fibers of these two systems enter the hila, join with branches from the cardiac autonomic plexus, and form large posterior and smaller anterior plexuses in the peribronchovascular connective tissue. From these plexuses arise peribronchial and perivascular nerve fibers that extend distally. These connect with ganglia in the airway wall (Figure 1-19), where the vagal preganglionic fibers synapse with postganglionic neurons. At numerous points along their course, the airway nerves send out branches into the submucosa and mucosa that terminate in bronchial muscle, mucous glands, and small blood vessels. Thicker fibers thought to be largely of an afferent sensory type bypass the ganglia. Some of these originate in receptors within the airway epithelium and lamina propria, tracheobronchial smooth muscle, the perichondrial tissue of large airways, the pulmonary parenchyma, and the pulmonary and bronchial arteries and veins.99 Afferent receptors themselves have been divided into three groups on the basis of

their distribution and physiologic response to various stimuli. The irritant or cough receptors are located predominantly in the trachea and large bronchi, their number decreasing progressively as the smaller peripheral airways are approached.100 They are highly arborized myelinated nerve fibers with numerous free nerve endings that terminate in the airway epithelium. Their stimulation results in reflex bronchoconstriction, and their role is probably to inhibit inhalation of toxic material.101 The second major group of myelinated afferent nerves originates in stretch receptors. The latter are found in airway smooth muscle, where they are organized in tendril-like structures closely applied to the surface of individual muscle cells. They are responsible for sending information regarding lung volume to the respiratory center; integration of their input results in off-switch activity in the respiratory center. The third type of lung afferent originates in the J (juxtacapillary) receptor.102 The nerve endings of these small, nonmyelinated fibers are situated in the lung parenchyma adjacent to alveolar septa and pulmonary capillaries and in the walls of the conducting airways. Efferent innervation of the lung includes preganglionic fibers from vagal nuclei, which descend in the vagus to synapse with postganglionic neurons in the ganglia around the airways, and postganglionic fibers from the cervical sympathetic ganglia. Postganglionic cholinergic fibers supply the mucous glands of the large airways and the goblet cells, their stimulation causing an increase in secretion in both structures. Vagal efferent fibers also supply airway smooth muscle as well as pulmonary and bronchial vascular smooth muscle; stimulation of these cholinergic fibers causes airway smooth muscle contraction (resulting in airway narrowing) and vascular smooth muscle relaxation (leading to pulmonary and bronchial vascular dilatation). The nerves to the pulmonary arteries run in the perivascular adventitia as far as parenchymal arterioles and connect extensively with the peribronchial nerves. Two plexuses of cholinergic fibers have been identified in the larger vessels, one located in the outer adventitia, and the other at the adventitiamedia junction; in smaller vessels, only a single (inner) plexus is present.103 Many nerves related to the pulmonary veins extend into the inner media, where they form a complex subendothelial network. The bronchial arteries contain a prominent nerve plexus at the mediaadventitia junction, presumably consisting of efferent supply to the smooth muscles of these vessels; this plexus also sends numerous branches to the bronchial mucous glands.

RESPIRATORY MUSCLES
The respiratory muscles can be divided into four groups, each with different functions and mechanisms of action the upper airway muscles, the diaphragm, the intercostal and accessory inspiratory muscles, and the abdominal muscles. These muscles can be considered to be primary (those that routinely contract during tidal breathing in normal individuals) and accessory (those that are not normally active during tidal breathing but are recruited when the demand for ventilation increases). The diaphragm is the

FIGURE 1-19 Bronchial wall innervation (hematoxylin-eosin stain). Connective tissue in the periphery of an airway wall shows a nerve (curved arrow) and ganglion (straight arrow). M mucus gland.

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Anatomy 3. Stone KC, Mercer RR, Freeman BA, et al. Distribution of lung cell numbers and volumes between alveolar and nonalveolar tissue. Am Rev Respir Dis 1992;146:454. 4. Gail DB, Lenfant CJM. State of the artcells of the lung: biology and clinical implications. Am Rev Respir Dis 1983; 127:366. 5. Rhodin JAG. The ciliated cell: ultrastructure and function of the human tracheal mucosa. Am Rev Respir Dis 1966;93:1. 6. Godfrey RWA, Severs NJ, Jeffrey PK. Freezefracture morphology and quantification of human bronchial epithelial tight junctions. Am J Respir Cell Mol Biol 1992;6:453. 7. Herard AL, Zahm JM, Pierrot D, et al. Epithelial barrier integrity during in vitro wound repair of the airway epithelium. Am J Respir Cell Mol Biol 1996;15:624. 8. Widdicombe JH, Gashi AA, Basbaum CB, et al. Structural changes associated with fluid absorption by dog tracheal epithelium. Exp Lung Res 1986;10:57. 9. Nathanson I, Nadel JA. Movement of electrolytes and fluid across airways. Lung 1984;162:125. 10. Ebert RV, Terracio MJ. The bronchiolar epithelium in cigarette smokers: observations with the scanning electron microscope. Am Rev Respir Dis 1975;111:4. 11. Marsan C, Cava E, Roujeau J, et al. Cytochemical and histochemical characterization of epithelial mucins in human bronchi. Acta Cytol 1978;22:562. 12. Spicer SS, Schulte BA, Chakrin LW. Ultrastructural and histochemical observations of respiratory epithelium and gland. Exp Lung Res 1983;4:137. 13. Tamai S. Basal cells of the human bronchiole. Acta Pathol Jpn 1983;33:125. 14. Boers JE, Ambergen AW, Thunnissen FBJM. Number and proliferation of basal and parabasal cells in normal human airway epithelium. Am J Respir Crit Care Med 1988;157:2000. 15. Evans MJ, Cox RA, Shami SG, et al. Junctional adhesion mechanisms in airway basal cells. Am J Respir Cell Mol Biol 1990;3:341. 16. Widdicombe JG, Pack RJ. The Clara cell. Eur J Respir Dis 1982;63:202. 17. Massaro GD, Singh G, Mason R, et al. Biology of the Clara cell. Am J Physiol 1994;266:L101. 18. Jorens PG, Sibille Y, Goulding NJ, et al. Potential role of Clara cell protein, an endogenous phospholipase A2 inhibitor, in acute lung injury. Eur Respir J 1995;8:1647. 19. Phelps DS, Floros J. Localization of pulmonary surfactant proteins using immunohistochemistry and tissue in situ hybridization. Exp Lung Res 1991;17:985. 20. DeWater R, Willems LNA, Van Muijen GNP, et al. Ultrastructural localization of bronchial antileukoprotease in central and peripheral human airways by a gold-labeling technique using monoclonal antibodies. Am Rev Respir Dis 1986;133:882. 21. Evans MJ, Cabral-Anderson LJ, Freeman G. Role of the Clara cell in renewal of the bronchiolar epithelium. Lab Invest 1978;38:648. 22. Ito T, Nakatani Y, Nagahara N, et al. Quantitative study of pulmonary endocrine cells in anencephaly. Lung 1987;165:297. 23. Boers JE, den Brok JL, Koudstaal J, et al. Number and proliferation of neuroendocrine cells in normal human airway epithelium. Am J Respir Crit Care Med 1996;154:758. 24. Becker KL. The coming of age of a bronchial epithelial cell. Am Rev Respir Dis 1993;148:1166. 25. Watanabe H. Pathological studies of neuroendocrine cells in human embryonic and fetal lung. Light microscopical, immunohistochemical and electron microscopical approaches. Acta Pathol Jpn 1988;38:59. 26. Hance AJ. Pulmonary immune cells in health and disease. Dendritic cells and Langerhans cells. Eur Respir J 1993; 6:1213.

principal primary muscle of inspiration104; others include the scalene, parasternal, and external intercostal muscles. The accessory inspiratory muscles include the sternocleidomastoid, pectoralis, serratus anterior, trapezius, and latissimus dorsi muscles. The expiratory muscles include the abdominal, internal intercostal, and triangularis sterni muscles. The abdominal muscles include the rectus and transverse abdominis muscles and the external and internal oblique muscles; although these muscles are generally regarded as expiratory in function, they may also play an active role in inspiration.105 The diaphragm has a complex three-dimensional structure. Its central portion (the central tendon) consists of a sheet of connective tissue fibers that has a shape similar to that of a broad-bladed boomerang. The costal (chest wall) muscle fibers arise anteriorly from the xyphoid process and around the convexity of the thorax from ribs 7 to 12. Additional crural fibers arise from the lateral margins of the lumbar vertebrae. All these fibers converge toward the central tendon and are inserted into it nearly perpendicular to its margin. The greatest respiratory excursion occurs in the posterolateral portion of the hemidiaphragms, where the muscle fibers are longest. There is evidence that the diaphragm is, in fact, two distinct muscles that have separate nervous and vascular supplies, as well as functions. The costal portion of the diaphragm is mechanically in series with the intercostal and accessory muscles, and its contraction can result in both descent of the diaphragm and elevation of the rib cage; by contrast, the crural portion is in parallel with the costal portion of the diaphragm, and its contraction results in descent of the diaphragm without elevation of the rib cage.106 The diaphragm is composed of three types of muscle fiber that have different histochemical profiles, related to the different myosin heavy-chain isotypes expressed by the cells107: (1) slow-twitch oxidative fatigue-resistant units (type 1); (2) fast-twitch oxidative glycolytic fatigue-resistant units (type 2a); and (3) fast-twitch glycolytic fatigable units (type 2b). Type 1 represents approximately 50% of the muscle fibers, type 2a about 20%, and type 2b about 30%. The relative proportions of the different types of motor fibers present in the diaphragm may be important in the pathogenesis of muscle fatigue and ventilatory failure. Histologically, the muscular portion comprises multiple muscle fascicles of variable size containing individual muscle fibers that also have different ultrastructural characteristics.108 The diaphragm has an abundant blood supply derived from the phrenic and intercostal arteries and from branches of the internal thoracic (mammary) arteries. Flow can increase to approximately 250 mL/min/100 g of muscle during maximal activation (about half of the maximal bloodflow to the heart).109 An extensive lymphatic network drains fluid via collecting vessels into mediastinal channels.108

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