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Histology_Ross.  FOLDER 18.3  FOLDER 18.4 Functional Considerations: Insulin Synthesis, an Example of Posttranslational Processing chapter 18 Digestive System III: Liver, Gallbladder, and Pancreas PANCR EAS 655 655 Recently, researchers identified expression of insulin and insulin growth factors (IGF I and IGF II) in nerve cells in several regions of the brain. It is known that insulin resis-tance characteristic of diabetes mellitus is linked to neural degeneration, cognitive dysfunction, and dementia. The reduced rate of insulin and IGF production in the brain contributes to the degeneration of brain cells, an early symptom of Alzheimer’s disease (AD). Postmortem ex-amination of the brain tissue from individuals diagnosed with AD confirmed that levels of insulin and IGFs were sig-nificantly reduced in the hippocampus (the part of the brain responsible for memory), frontal lobes, and hypothalamus. In contrast, in the cerebellum (which is generally not af-fected by AD), researchers noted normal


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Histology_Ross. in the hippocampus (the part of the brain responsible for memory), frontal lobes, and hypothalamus. In contrast, in the cerebellum (which is generally not af-fected by AD), researchers noted normal levels of these hormones. Abnormalities in insulin production in the brain do not present symptoms typical to type 1 or type 2 dia-betes mellitus, but they may indicate that AD could be a manifestation of type 3 diabetes. If these new observations are confirmed in the future, it might be possible to develop a targeted treatment for AD that is not available today. Insulin is produced within B cells in the pancreas. It is a small protein consisting of two polypeptide chains joined by disulfide bridges. Its biosynthesis presents a clear ex-ample of the importance of posttranslational processing in the achievement of the final, active structure of a protein. Insulin is originally synthesized as a single 110–amino acid polypeptide chain with a molecular weight of about 12,000 daltons. This


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Histology_Ross. in the achievement of the final, active structure of a protein. Insulin is originally synthesized as a single 110–amino acid polypeptide chain with a molecular weight of about 12,000 daltons. This polypeptide is called preproinsulin. Preproinsulin contains an amino-terminus signal sequence (24 amino acids in length) that is required for the precursor hormone to enter rER. As the molecule is inserted into the cisternae of the rER, the preproinsulin signal sequence is proteolytically cleaved to form proinsulin. Post translational processing reduces the preproinsulin to a polypeptide with a molecular weight of about 9,000 daltons. Proinsulin is a single polypeptide chain of 81 to 86 amino acids that has the approximate shape of the letter G (Fig. F18.4.1). Two disulfide bonds connect the bar of the G to the top loop. During packaging and storage of proinsulin in the Golgi apparatus, a cathepsin-like enzyme cleaves most of the side of the loop, leaving the bar of the G as an A chain of 21


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Histology_Ross. of the G to the top loop. During packaging and storage of proinsulin in the Golgi apparatus, a cathepsin-like enzyme cleaves most of the side of the loop, leaving the bar of the G as an A chain of 21 amino acids cross-linked by the disulfide bridges to the top of the loop, which becomes the B chain of 30 amino acids. The 35–amino acid peptide removed from the loop is called a C peptide (connecting peptide). It is stored in the secretory vesicles and released with the insulin in equimolar amounts. No physiologic function has been identified for the C peptide. Because C peptide has a longer half-life than insulin, higher concentrations of C peptides are detected in the peripheral blood. For these reasons, measurement of cir-culating levels of C peptides provides important clinical information about the secretory activity of B cells. Be-cause C peptide is cleared from the body by the kidney, measurement of its urinary excretion provides a useful in-formation about B cell insulin


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Histology_Ross. about the secretory activity of B cells. Be-cause C peptide is cleared from the body by the kidney, measurement of its urinary excretion provides a useful in-formation about B cell insulin secretion. C peptide mea-surements are frequently used to assess the residual B cell function in patients treated with insulin, to distinguish between types 1 and 2 diabetes and in the diagnosis and monitoring therapy of insulinoma (tumor of B cells). C peptide may also be used to monitor the progress of pan-creas or islet cell transplantation. FIGURE F18.4.1 • Posttranslational processing of insulin. Insulin is synthesized as the preproinsulin, a single polypeptide chain that undergoes posttranslational modifications. Initially, the signal sequence is removed within cysternae of the rER. Resulted shorter polypeptide chain know as proinsulin is transported to Golgi apparatus where is further modified by formation of internal disulfide bonds and removal of C chain that produces biologically active


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Histology_Ross. polypeptide chain know as proinsulin is transported to Golgi apparatus where is further modified by formation of internal disulfide bonds and removal of C chain that produces biologically active insulin. signal sequence chain B chain A chain C H2N C peptide preproinsulin proinsulin insulin COOH S H2N H2N H2N COOH COOH COOH S S S S S chain B chain A chain C S S S S S S chain B chain A S S S S S S


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Histology_Ross. The liver is the largest mass of glandular tissue in the body and the largest internal organ. It is unique because it receives its major blood sup-ply from the hepatic portal vein, which carries venous blood from the small intestine, pancreas, and spleen. Thus the liver is directly in the pathway that conveys materials absorbed in the intestine. This gives the liver the first exposure to metabolic substrates and nutrients; it also makes the liver the first organ exposed to noxious and toxic substances absorbed from the intestine. One of the major roles of the liver is to degrade or conjugate toxic substances to render them harmless. It can, however, be seriously damaged by an excess of such substances. Each liver cell has both exocrine and endocrine functions. The exocrine secretion of the liver, called bile, contains conjugated and de-graded waste products that are delivered back to the intestine for disposal. It also contains substances that bind to metabolites in the intes-tine to


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Histology_Ross. liver, called bile, contains conjugated and de-graded waste products that are delivered back to the intestine for disposal. It also contains substances that bind to metabolites in the intes-tine to aid absorption. A series of ducts of increasing diameter and complexity, beginning with bile canaliculi between individual hepatocytes and ending with the common bile duct, deliver bile from the liver and gallbladder to the duodenum. The endocrine secretions of the liver are released directly into the blood that supplies the liver cells; these secretions include albumin, nonimmune and -globulins, prothrombin, and glycoproteins, including fibronectin. Glucose, released from stored glycogen, and triiodothy-ronine (T3), the more active deiodination product of thyroxine, are also released directly into the blood. Functional units of the liver, described as lobules or acini, are made up of irregular interconnecting sheets of hepatocytes separated from one another by the blood sinusoids.


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Histology_Ross. Liver, human, H&E ×65; inset ×65. At the low magnification shown here, large numbers of hepatic cells appear to be uniformly disposed throughout the specimen. The hepatocytes are arranged in one-cell-thick plates, but when sectioned, they appear as interconnecting cords one or more cells thick, depending on the plane of section. The sinusoids appear as light areas between the cords of cells; they are more clearly shown in figure below (asterisks). Also present in this figure is a portal canal. It is a connective tissue septum that carries the branches of the hepatic artery (HA) and portal vein (PV), bile ducts (BD), and lymphatic vessels and nerves. The artery and vein, along with the bile duct, are collectively referred to as a portal triad. The hepatic artery and the portal vein are easy to identify because they are found in relation to one another within the surrounding connective tis- Liver lobule, liver, human, H&E ×160.


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Histology_Ross. The hepatic artery and the portal vein are easy to identify because they are found in relation to one another within the surrounding connective tis- Liver lobule, liver, human, H&E ×160. The terminal hepatic venules or central veins (CV) are the most distal radicals of the hepatic vein, and like the hepatic vein, they also travel alone. Their distinguishing features are the sinusoids that penetrate the wall of the vein and the paucity of surrounding connective tissue. These characteristics are shown to advantage in Plate 66.


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Histology_Ross. It is best to examine low-magnification views of the liver to define the boundaries of a lobule. A lobule is best identifed when it is cut in cross section. The central vein then appears as a circular profle, and the hepatic sue of the portal canal. The vein is typically thin walled; the artery is smaller in diameter and has a thicker wall. The bile ducts are composed of a simple cuboidal or columnar epithelium, depending on the size of the duct. Multiple profiles of the blood vessels and bile ducts may be evident in the canal because of either branching or their passage out of the plane of section and then back in again.


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Histology_Ross. The vessel through which blood leaves the liver is the hepatic vein. It is readily identified because it travels alone (inset) and is surrounded by an appreciable amount of connective tissue (CT). If more than one profile of a vein is present within this connective tissue, but no arteries or bile ducts are present, the second vessel will also be a hepatic vein. Such is the case in the inset, where a profile of a small hepatic vein is seen just above the larger hepatic vein (HV). cells appear as cords radiating from the central vein. Such a lobule is outlined by the dashed line in fgure above.


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Histology_Ross. cells appear as cords radiating from the central vein. Such a lobule is outlined by the dashed line in fgure above. The limits of the lobule are defned, in part, by the portal canal. In other directions, the plates of the lobule do not appear to have a limit; that is they have become contiguous with plates of an adjacent lobule. One can estimate the dimensions of the lobule, however, by approximating a circle with the central vein as its center and incorporating those plates that exhibit a radial arrangement up to the point where a portal canal is present. If the lobule has been cross-sectioned, the radial limit is set by the location of one or more of the portal canals as indicated by the bile ducts (BD) in this fgure. KEY BD, bile duct CT, connective tissue CV, central vein (terminal hepatic venule) HA, hepatic artery HV, hepatic vein L, lymphatic nodule PV, portal vein asterisks (bottom fgure), blood sinusoids dotted line (top fgure), approximates the limits of a lobule


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Histology_Ross. There are three ways of describing the liver parenchyma in terms of a functional unit, “classic” lobules, portal lobules, or acini. The classic lobule is a roughly hexagonal block of tissue that has at its center the terminal hepatic venule (central vein) and at its six corners the portal canals (portal triads) containing in each a branch of the portal vein, hepatic artery, and bile duct. The portal lobule is a triangular construct that emphasizes the exocrine secretory function. It has as its axis the bile duct of the portal triad of the classic lobule, and its outer margins are imaginary lines drawn between the central veins closest to that portal triad. The liver acinus provides the best correlation among blood perfusion, metabolic activity, and liver pathology. The acinus is a small diamondor lozenge-shaped mass of tissue that has as its short axis the fine branches of the portal triad that lie along the border of two classic lobules and as its long axis a line drawn between the


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Histology_Ross. diamondor lozenge-shaped mass of tissue that has as its short axis the fine branches of the portal triad that lie along the border of two classic lobules and as its long axis a line drawn between the two central veins closest to the short axis. The hepatocytes in each acinus are described as arranged in three concentric elliptical zones around the short axis; zone 1 is closest to, and zone 3 is farthest from, the axis.


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Histology_Ross. Central vein, liver, human, H&E ×500; inset ×800. The central vein and surrounding hepatocytes from lower figure of Plate 65 are shown here at higher magnification. The cytoplasm of the hepatocytes in this specimen has a foamy appearance because of extraction of glycogen and lipid during tissue preparation. The boundaries between individual hepatocytes are discernable in some locations but not between those cells where the knife has cut across the boundary in an oblique plane. Frequently, when cell boundaries are observed at still higher magnification (inset), a very small circular or oval profile is observed midway along the boundary. These profiles represent the bile canaliculi (BC).


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Histology_Ross. The cells that line the sinusoids (S) show little, if any, cytoplasmic detail in routine preparations. Perisinusoidal macrophages (Kupffer cells [KC]) are generally recognized by their ovoid nuclei and the projection of the cell into the lumen. The endothelial cell, in contrast, is a squamous cell that has a smaller, attenuated or elongated nucleus. Some nuclei of this description are evident in the micrograph. The termination of two of the sinusoids and their union with the central vein (CV) is indicated by the curved arrows. Note that the wall of the vein is strengthened by connective tissue, mostly collagen, which appears as homogeneous eosin-stained material (asterisks). Fibroblasts (F) within this connective tissue can be identified and distinguished from the endothelial cell (EN) lining of the vein. Hepatic sinusoids, liver, rat, glutaraldehyde–osmium fxation, toluidine blue ×900.


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Histology_Ross. This figure shows a plastic-embedded liver specimen fixed by the method normally used for electron microscopy. In contrast to the H&E–stained preparation, it demonstrates to advantage the cytologic detail of the hepatocytes and the sinusoids (S). The hepatocytes are deeply colored with toluidine blue. Note that the cytoplasm exhibits irregular magenta masses (arrows). This is glycogen that has been retained by the glutaraldehyde fixation and stained metachromatically by toluidine blue. Also evident are lipid droplets (L) of varying size that have been preserved and stained black by the osmium used as the secondary fixative. The quantities of lipid and glycogen are variable and, under normal conditions, reflect dietary intake. Examination of the hepatocyte cytoplasm also reveals small, punctate, dark-blue bodies contrasted against the lighter-blue background of the cell. These are the mitochondria. Another feature of this specimen is the clear representation of the bile canaliculi (BC)


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Histology_Ross. dark-blue bodies contrasted against the lighter-blue background of the cell. These are the mitochondria. Another feature of this specimen is the clear representation of the bile canaliculi (BC) between liver cells. They appear as empty circular profiles when cross-sectioned and as elongate channels (lower right) when longitudinally sectioned.


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Histology_Ross. The sinusoidal lining cells are of two distinct types. The Kupffer cells (KC) are the more prominent cells. They exhibit a large nucleus and a substantial amount of cytoplasm. They protrude into the lumen and may give the appearance of occluding it. However, they do not block the channel. The surface of the Kupffer cell exhibits a very irregular or jagged contour because of the numerous processes that provide the cell with an extensive surface area. The endothelial cell (EN) has a smaller nucleus, attenuated cytoplasm, and a smooth surface contour. A third cell type, the less frequently observed perisinusoidal lipocyte (Ito cell), is not seen in this micrograph. This cell would appear as a light cell containing numerous lipid droplets. The lipid droplets contain stored vitamin A.


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Histology_Ross. KEY BC, bile canaliculus CV, central vein EN, endothelial cell F, fibroblast KC, Kupffer cell L, lipid droplet S, sinusoid arrows, glycogen asterisks, connective tissue of central vein curved arrows, opening of sinusoid into central vein The gallbladder concentrates and stores bile for delivery to the duodenum. The bile is concentrated by the active transport of salt from the bile and the passive movement of water in response to the salt transport. The mucosa is characterized by a tall columnar absorptive epithe-lium that closely resembles that of the intestine and the colon in both its morphology and function. The epithelial cells are characterized by nu-merous short apical microvilli, apical junctional complexes, concentrations of mitochondria in the apical and basal cytoplasm, and complex lateral plications. In addition, Na+-K+–activated ATPase is localized on the lateral plasma membrane of the epithelial cell. Gallbladder, human, H&E ×45.


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Histology_Ross. Gallbladder, human, H&E ×45. The gallbladder is a hollow, pear-shaped organ that concentrates and stores the bile. The full thickness of its wall is shown here. It is composed of a mucosa (Muc), muscularis (Mus), and adventitia (Adv) and, on its free surface (not shown), a serosa. The mucosa is considered at higher magni fication in figure below. The muscularis consists of interlacing bundles of smooth muscle (SM). The adventitia (Adv) consists of irregular dense con660 nective tissue through which the larger blood vessels (BV) travel and, more peripherally, of varying amounts of adipose tissue (AT). Mucosa, gallbladder, human, H&E ×325.


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Histology_Ross. Mucosa, gallbladder, human, H&E ×325. The mucosa consists of a tall simple columnar absorptive epithelium (Ep) resting on a lamina propria of loose irregular connective tissue (CT). The epithelium has characteristics that distinguish it from the absorptive epithelium of other organs, such as the intestines. Only one cell type, tall columnar cells, is present in the epithelial layer (see upper right figure). The nuclei are in the basal portion of the cell. The cells possess a thin apical striated bor- Mucosa, gallbladder, human, H&E ×550. The smaller of the two gland-like structures is composed of mucous cells (MC) and represents a section through a mucous gland. This specimen was taken from a site near the neck of the gallbladder where mucous glands are often present. Note the characteristic flattened nuclei at the base of the cell and the lightly stained appearance of the cytoplasm, features characteristic


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Histology_Ross. The mucosa is thrown into numerous folds that are particularly pronounced when the muscularis is highly contracted. This is the usual histologic appearance of the gallbladder unless, of course, steps are taken to fix and preserve it in a distended state. Occasionally, the section cuts through a recess in a fold, and the recess may then resemble a gland (arrows). The mucosa, however, does not possess glands, except in the neck region, where some mucous glands are present (see lower right figure).


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Histology_Ross. der. However, this is not always evident in routine H&E–stained sections. The cytoplasm stains rather uniformly with eosin. This is related to its absorptive function and is in contrast to the staining of cells that are engaged in the production of protein. Lastly, with respect to its absorptive function, the epithelial cells frequently exhibit distended intercellular spaces at their basal aspect (see upper right figure arrows). This is a feature associated with the transport of fluid across the epithelium and, as noted above, commonly seen in intestinal absorptive cells. Mucosa, gallbladder, human, H&E ×550. The lamina propria underlying the epithelium is usually very cellular. In this specimen, in addition to lymphocytes (L), a relatively common finding, a large number of plasma cells (PC) is also present within the lamina propria. (The high concentration of plasma cells suggests chronic inflammation.)


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Histology_Ross. Another feature of note in the lamina propria is the presence of several out-pouching of the mucosa, called Rokitansky-Aschoff sinuses (RAS), other than those seen in the mucosa and noted above. These are readily apparent in figure on right and two of these structures, marked by RAS are shown at higher magnification in figure below. of mucin-secreting cells. In contrast, the epithelium of the large gland-like profile that is only partially included in the micrograph has rounded or ovoid nuclei. This epithelial-lined structure is not a true gland but represents an invagination of the mucous membrane that extends into and often through the thickness of the muscularis. These invaginations are known as Rokitansky-Aschoff sinuses.


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Histology_Ross. KEY Adv, adventitia AT, adipose tissue BV, blood vessel CT, connective tissue, lamina propria Ep, epithelium RAS, Rokitansky-Aschoff sinus L, lymphocytes MC, mucous cells Muc, mucosa Mus, muscularis PC, plasma cells SM, smooth muscle arrows: Top left fgure, recess in luminal surface; Top right figure, intercellular spaces


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Histology_Ross. The pancreas is an elongated extramural digestive gland with a head nestled in the C-shaped bend of the duodenum, a body that crosses the midline of the abdomen, and a tail extending across the back of the abdomen. It is a mixed gland containing both an exocrine component and an endocrine component that have distinctive characteristics. The exocrine component is a compound tubuloacinar gland with a branching network of ducts that convey the exocrine secretions to the duodenum. These secretions consist primarily of inactive forms of potent prote-olytic enzymes, as well as amylase, lipase, nucleases, and electrolytes, particularly HCO3 . The endocrine component is isolated as highly vascularized islets of epithelioid tissue (islets of Langerhans). The islet cells secrete a va-riety of polypeptide and protein hormones, most notably insulin and glucagon, which regulate glucose metabolism throughout the other tis-sues of the body. Other hormones secreted by islet cells include


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Histology_Ross. of polypeptide and protein hormones, most notably insulin and glucagon, which regulate glucose metabolism throughout the other tis-sues of the body. Other hormones secreted by islet cells include somatostatin, pancreatic polypeptide, vasoactive intestinal peptide, secretin, motilin, and substance P. All of these substances, with the exception of insulin, are also secreted by the population of enteroendocrine cells in the intestine, the organ from which the pancreas is derived during embryonic development. While insulin and glucagon act primarily in en-docrine regulation of distant cells, the other hormones (and glucagon) have significant roles in the paracrine regulation of the insulin-secreting B cells of the pancreatic islet.


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Histology_Ross. Pancreas, human, H&E ×160; inset ×360. The pancreas is surrounded by a delicate capsule of moderately dense connective tissue. Septa from the capsule divide the pancreas into lobules, one of which is shown here, bounded by connective tissue (CT). Larger blood vessels (BV ) travel in the connective tissue septa; nerves also travel in the septa, but they are seen infrequently. Within the lobule are the numerous acini of the exocrine component, an intralobular duct (InD), intercalated ducts (not readily evident at this low magnification), and islets of Langerhans (IL). Also within the lobule are the small blood vessels and the connective tissue serving as a stroma for the parenchymal elements of the gland. Pancreas, human, H&E ×600.


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Histology_Ross. Pancreas, human, H&E ×600. Acini of the pancreas consist of serous cells. In sections, the acini present circular and irregular profiles. The lumen of the acinus is small, and only in fortuitous sections through an acinus is the lumen included (asterisks). The nucleus is characteristically in the base of the acinar cell. There is a region of intense basophilia adjacent to the nucleus. This is the ergastoplasm (Er), and it reflects the presence of rER that is active in the synthesis of pancreatic enzymes. Some acini reveal a centrally positioned cell with cytoplasm that shows no special staining characteristics in H&E–stained paraffin sections. These are centroacinar cells (CC). They are the beginning of the intercalated ducts. This figure demonstrates particularly well the morphology and relationships of the intercalated ducts. Note, first, the cross-sectioned intralobular duct (InD) consisting of cuboidal epithelium. (There are no striated


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Histology_Ross. This figure shows an islet of Langerhans (IL) among the far more numerous acini. (Islets are most numerous in the tail of the pancreas and least numerous in the head). Cells within the islets are arranged as irregular cords. In routine preparations, it is not possible to identify the various cell types within the islets. Note, however, that B cells are the most numerous; these produce insulin. The next most numerous are A cells; these produce glucagon. The inset also shows numerous capillaries (arrows). The labels A and B are not intended to identify specific cells but rather to show those parts of the islets where A and B cells are found in greatest number.


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Histology_Ross. ducts in the pancreas.) Leading to the intralobular duct is an intercalated duct (ID), which is seen in cross section at the furthest distance from the intralobular duct and then, in longitudinal section, in the center of the illustration as it travels toward the intralobular duct. The lumen is evident where the intercalated duct is seen in cross section but is not evident where it is seen in longitudinal section. This is because the plane of section cuts chiefly through the cells rather than the lumen. As a consequence, this figure provides a good view of the nuclei of the duct cells. They are elongate, with their long axis oriented in the direction of the duct. In addition, they display a staining pattern similar to that of centroacinar cells and different from that of nuclei of the parenchymal cells.


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Histology_Ross. Once the cells of the intercalated duct have been identified in one part of the section, their staining characteristics and location can be used to identify the intercalated ducts in other parts of the lobule, several of which are marked (ID). KEY A, region with most A cells B, region with most B cells BV, blood vessels CC, centroacinar cells CT, connective tissue Er, ergastoplasm ID, intercalated ducts IL, islets of Langerhans InD, intralobular duct arrows, capillaries asterisks, lumen of acini


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Histology_Ross. OVERVIEW OF THE RESPIRATORY SYSTEM / 664 NASAL CAVITIES / 665 Vestibule of the Nasal Cavity / 665 Respiratory Region of the Nasal Cavity / 666 Olfactory Region of the Nasal Cavity / 667 Paranasal Sinuses / 670 PHARYNX / 670 LARYNX / 670 TRACHEA / 670 Tracheal Epithelium / 672 Basement Membrane and Lamina Propria / 673 BRONCHI / 676 BRONCHIOLES / 677 Bronchiolar Structure / 677 Bronchiolar Function / 678 ALVEOLI / 678 BLOOD SUPPLY / 687 LYMPHATIC VESSELS / 687 NERVES / 687 Folder 19.1 Clinical Correlations: Squamous Metaplasia in the Respiratory Tract / 672 Folder 19.2 Clinical Correlations: Cystic Fibrosis / 685 Folder 19.3 Clinical Correlations: Emphysema and Pneumonia / 686 The respiratory system consists of the paired lungs and a series of air passages that lead to and from the lungs. Within the lung, the air passages branch into increasingly smaller tubes until the very smallest air spaces, called alveoli, are reached (Fig. 19.1).


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Histology_Ross. Three principal functions are performed by this system: air conduction, air filtration, and gas exchange (respiration). The latter occurs in the alveoli. In addition, air passing through the larynx is used to produce speech, and air passing over the olfactory mucosa in the nasal cavities carries stimuli for the sense of smell. The respiratory system also participates to a lesser degree in endocrine functions (hormone production and secretion), as well as regulation of immune responses to inhaled antigens. The lungs develop in the embryo as a ventral evagination of the foregut; thus, the epithelium of the respiratory system is of endodermal origin. This initial respiratory diverticulum grows into the thoracic mesenchyme. The bronchial cartilages, smooth muscle, and the other connective tissue elements are derived from the thoracic mesenchyme. The air passages of the respiratory system consist of a conducting portion and a respiratory portion.


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Histology_Ross. The air passages of the respiratory system consist of a conducting portion and a respiratory portion. The conducting portion of the respiratory system consists of those air passages that lead to the sites of respiration within the lung where gas exchange takes place. The conducting passages include those located outside as well as within the lungs. The passages external to the lungs consist of the following:  Nasal cavities that represent two large air-filled spaces in the uppermost part of the respiratory system (and, during forced breathing, the oral cavity residing inferior to the nasal cavities).  Nasopharynx that lies behind the nasal cavities and above the level of the soft palate and communicate inferiorly with oropharynx that is posterior to the oral cavity.  Larynx that is a hollow tubular organ containing cartilaginous framework responsible for producing sounds.


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Histology_Ross.  Larynx that is a hollow tubular organ containing cartilaginous framework responsible for producing sounds.  Trachea that is a flexible air tube that extend from the larynx to the thorax. It serves as a conduit for air and in the mediastinum it birurcates into paired main bronchi.  Paired main (primary) bronchi that enter root of the right or left lung. FIGURE 19.1 • Diagram of respiratory passages. The nasal cavities, nasopharynx, oropharynx, larynx, trachea, bronchi, and bronchioles constitute the conducting portion of the respiratory system. The respiratory portion of the system, where gas exchange occurs, is composed of respiratory bronchioles, alveolar ducts, alveolar sacs, and alveoli. (Based on Boileau G. A Method of Anatomy. Baltimore: Williams & Wilkins, 1980.)


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Histology_Ross. Within the lungs, the main bronchi undergo extensive branching to give rise ultimately to the distributing bronchioles. The bronchioles represent the terminal part of the conducting passages. Collectively, the internal bronchi and the bronchioles constitute the bronchial tree. The respiratory portion is that part of the respiratory tract in which gas exchange occurs. Sequentially, it includes these:  Respiratory bronchioles that are involve in both air conduction and gas exchange.  Alveolar ducts that are elongated airways formed from the confluence openings to alveoli.  Alveolar sacs that respresnt spaces surrounded by clusters of alveoli.  Alveoli that are the primary sites of gas exchange.


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Histology_Ross. Blood vessels enter the lung with the bronchi. The arteries branch into smaller vessels as they follow the bronchial tree into the substance of the lung. Capillaries come into intimate contact with the terminal respiratory units, the alveoli. This intimate relationship between the alveolar air spaces and the pulmonary capillaries is the structural basis for gas exchange within the lung parenchyma. The essential features of the lung blood supply are described on page 687. Air passing through the respiratory passages must be conditioned before reaching the terminal respiratory units.


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Histology_Ross. Air passing through the respiratory passages must be conditioned before reaching the terminal respiratory units. Conditioning of the air occurs in the conducting portion of the respiratory system and includes warming, moistening, and removal of particulate materials. Mucous and serous secretions play a major role in the conditioning process. These secretions moisten the air and also trap particles that have managed to slip past the special short thick hairs, called vibrissae, in the nasal cavities. Mucus, augmented by these serous secretions, also prevents the dehydration of the underlying epithelium by the moving air. Mucus covers almost the entire luminal surface of the conducting passages and is continuously produced by goblet cells and mucus-secreting glands in the walls of the passages. The mucus and other secretions are moved toward the pharynx by means of coordinated sweeping movements of cilia and are then normally swallowed.


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Histology_Ross. The nasal cavities are paired chambers separated by a bony and cartilaginous septum. They are elongated spaces with a wide base that rests on the hard and soft palate and a narrow apex that points toward the anterior cranial fossa. The skeletal framework of the nasal cavities is formed by bones and cartilages; most are located centrally in the skull except for the small anterior region that is enclosed within the external nose. Each cavity or chamber communicates anteriorly with the external environment through the anterior nares (nostrils), posteriorly with the nasopharynx through the choanae, and laterally with the paranasal sinuses and nasolacrimal duct, which drains tears from the eye into the nasal cavity (Fig. 19.2). The chambers are divided into three regions:  Nasal vestibule, which is a dilated space of the nasal cav ity just inside nostrils and lined by skin  Respiratory region, which is the largest part (inferior two-thirds) of the nasal cavities and lined by respiratory


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Histology_Ross. is a dilated space of the nasal cav ity just inside nostrils and lined by skin  Respiratory region, which is the largest part (inferior two-thirds) of the nasal cavities and lined by respiratory mucosa  Olfactory region, which is located at the apex (upper one- third) of each nasal cavity and lined by specialized olfac


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Histology_Ross. Vestibule of the Nasal Cavity The nasal vestibule forms a part of the external nose and communicates anteriorly with the external environment. It is lined with stratified squamous epithelium, a continuation of the skin of the face, and contains a variable number of vibrissae that entrap large particulate matter before it is carried in the air stream to the rest of the cavity. Sebaceous glands are also present, and their secretions assist in the entrapment of particulate matter. Posteriorly, where the vestibule ends, the stratified squamous epithelium becomes thinner and undergoes a transition to the pseudostratified epithelium that characterizes the respiratory region. At this site, sebaceous glands are absent.


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Histology_Ross. trachea cricoid cartilage thyroid cartilage larynx epiglottis hyoid bone oral cavity soft palate hard palate vestibule nasal mucosa conchae olfactory mucosa choanae orifice of auditory tube nasopharynx oropharynx ventricular fold vocal fold esophagus laryngopharynx FIGURE 19.2 • Diagram of the relationship of the pharynx to the respiratory and digestive systems. The pharynx is divided into three parts: nasopharynx, oropharynx, and laryngopharynx. It is located posterior to the nasal and oral cavities and extends inferiorly past the larynx. The pharynx serves both respiratory and digestive systems. This midsagittal section also transects the cartilages forming the skeleton of the larynx (i.e., epiglottis, thyroid cartilage, and cricoid cartilage). Note the ventricular and vocal folds in the middle of the larynx, approximately at the level of the thyroid cartilage. This part of the larynx represents the narrowest portion of the respiratory system and is responsible for producing sound


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Histology_Ross. middle of the larynx, approximately at the level of the thyroid cartilage. This part of the larynx represents the narrowest portion of the respiratory system and is responsible for producing sound by audible vibration of the vocal folds.


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Histology_Ross. Respiratory Region of the Nasal Cavity The respiratory region constitutes most of the volume of the nasal cavities. It is lined by the respiratory mucosa that contains a ciliated, pseudostratified columnar epithelium on its surface. The underlying lamina propria is firmly attached to the periosteum and perichondrium of the adjacent bone or cartilage. The medial wall of the respiratory region, the nasal septum, is smooth, but the lateral walls are thrown into folds by the presence of three shelf-like, bony projections called conchae or turbinates. The conchae divide each nasal cavity into separate air chambers and play a dual role. They increase surface area and cause turbulence in airflow to allow more efficient conditioning of inspired air.


Histology_Ross

Histology_Ross. The ciliated, pseudostratified columnar epithelium of the respiratory mucosa is composed of five cell types:  Ciliated cells, tall columnar cells with cilia that project into the mucus covering the surface of the epithelium  Goblet cells that synthesize and secrete mucus  Brush cells, a general name for those cells in the respira tory tract that bear short, blunt microvilli  Small granule cells (Kulchitsky cells) that resemble basal cells but contain secretory granules. These are enteroendocrine cells of the APUD system  Basal cells, stem cells from which the other cell types arise The epithelium of the respiratory region of the nasal cavity is essentially the same as the epithelium lining most of the parts that follow in the conducting system. Because the respiratory epithelium of the trachea is studied and examined in preference to that of the nasal cavity, the above cell types are discussed in the section on the trachea (page 672).


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Histology_Ross. The mucosa of the respiratory region warms, moistens, and filters inspired air. The lamina propria of the respiratory mucosa has a rich, vascular network that includes a complex set of capillary loops. The arrangement of the vessels allows the inhaled air to be warmed by blood flowing through the part of the loop closest to the surface. The capillaries that reside near the surface are arranged in rows; the blood flows perpendicular to the airflow, much as one would find in a mechanical heat exchange system. These same vessels may become engorged and leaky during allergic reactions or viral infections such as the common cold. The lamina propria then becomes distended with ﬂuid, resulting in marked swelling of the mucous membrane with consequent restriction of the air passage, making breathing difficult. The lamina propria also contains mucous glands, many exhibiting serous demilunes. Their secretions supplement that of the goblet cells in the respiratory epithelium.


Histology_Ross

Histology_Ross. By increasing surface area, the conchae (turbinates) increase the efficiency with which the inspired air is warmed. The turbinates also increase the efficiency of filtration of inspired air through the process of turbulent precipitation. The air stream is broken into eddies by the turbinates. Particulate matter suspended in the air stream is thrown out of the stream and adheres to the mucus-covered wall of the nasal cavity. Particles trapped in this layer of mucus are transported to the pharynx by means of coordinated sweeping movements of cilia and are then swallowed. Olfactory Region of the Nasal Cavity


Histology_Ross

Histology_Ross. Olfactory Region of the Nasal Cavity The olfactory region is located on part of the dome of each nasal cavity and, to a variable extent, the contiguous lateral and medial nasal walls. It is lined with a specialized olfactory mucosa. In living tissue, this mucosa is distinguished by its slight yellowish brown color caused by pigment in the olfactory epithelium and the associated olfactory glands. In humans, the total surface area of the olfactory mucosa is only about 10 cm2; in animals with an acute sense of smell, the total surface area of the olfactory mucosa is considerably more extensive. For instance, certain dogs species have more than 150 cm2. The lamina propria of the olfactory mucosa is directly contiguous with the periosteum of the underlying bone (Plate 69, page 688). This connective tissue contains numerous blood and lymphatic vessels, unmyelinated olfactory nerves, myelinated nerves, and olfactory glands.


Histology_Ross

Histology_Ross. The olfactory epithelium, like the epithelium of the respiratory region, is also pseudostratified, but it contains very different cell types. Also, it lacks goblet cells (Fig. 19.3 and Plate 69, page 688). The olfactory epithelium is composed of the following cell types:  Olfactory receptor cells are bipolar neurons that span the thickness of the epithelium and enter the central nerve system.


Histology_Ross

Histology_Ross. FIGURE 19.3 • Olfactory mucosa of the nasal cavity. a. This diagram shows the three major cell types located within the olfactory epithelium: the olfactory cell, supporting (sustentacular) cell, and basal cell. The olfactory cell is the receptor cell; it has an apical expansion, the olfactory vesicle, from which long, nonmotile cilia extend. At its basal surface it extends an axon into the connective tissue that joins with axons of other olfactory cells to form an olfactory nerve. The basal cells are small and cuboidal. They are restricted to the basal part of the epithelium. The supporting cells, in contrast, are columnar and extend the full thickness of the epithelium; their nuclei are located in the upper portion of the cell. Note the olfactory (Bowman’s) gland and its duct that empties on the surface of the mucosa. b. Photomicrograph of the olfactory mucosa. The olfactory epithelium exhibits nuclei through much of its thickness, but the individual cell types to which they belong


Histology_Ross

Histology_Ross. on the surface of the mucosa. b. Photomicrograph of the olfactory mucosa. The olfactory epithelium exhibits nuclei through much of its thickness, but the individual cell types to which they belong are not discernible. The underlying connective tissue is largely occupied by numerous olfactory (Bowman’s) glands, olfactory nerves, and blood vessels. Note that the ducts of the olfactory glands extend from the secretory portion of the gland to the epithelial surface. 240.


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Histology_Ross.  Supporting or sustentacular cells are columnar cells that are similar to neuroglia cells and provide mechanical and metabolic support to the olfactory receptor cells. They synthesize and secrete odorant-binding proteins.  Basal cells are stem cells from which new olfactory receptor cells and supporting cells differentiate.  Brush cells are the same cell type that occurs in the respi ratory epithelium. Olfactory receptor cells are bipolar neurons that possess an apical projection bearing cilia.


Histology_Ross

Histology_Ross. The apical domain of each olfactory receptor cell has a single dendritic process that projects above the epithelial surface as a knoblike structure called the olfactory vesicle. A number of long, thin cilia (10 to 23) with typical basal bodies arise from the olfactory vesicle and extend radially in a plane parallel to the epithelial surface (see Fig. 19.3). The cilia are usually up to 200 m long and may overlap with cilia of adjacent olfactory receptor cells. The cilia are regarded as nonmotile, although some research suggests that they may have limited motility. The basal domain of the cell gives rise to an unmyelinated axonal process that leaves the epithelial compartment. Collections of axons from olfactory receptor cells do not come together as a single nerve, but instead they are grouped into bundles that pass through a thin cribriform plate of the ethmoid bone, course through the dura and arachnoid matters, and finally are surrounded by pia matter, entering the olfactory bulb


Histology_Ross

Histology_Ross. into bundles that pass through a thin cribriform plate of the ethmoid bone, course through the dura and arachnoid matters, and finally are surrounded by pia matter, entering the olfactory bulb of the brain. The collections of axons from olfactory receptor cells form the olfactory nerve (cranial nerve I). The olfactory axons are very fragile, and can be harmed during traumatic head injury. They can be permanently severed, resulting in anosmia (loss of the sense of smell).


Histology_Ross

Histology_Ross. Autoradiographic studies show that olfactory receptor cells have a lifespan of about 1 month. If injured, they are quickly replaced. Olfactory receptor cells (and some neurons of the enteric division of the autonomic nervous system) appear to be the only neurons in the nervous system that are readily replaced during postnatal life. Entire olfactory transduction pathways occurs within the cilia of the olfactory receptor cells.


Histology_Ross

Histology_Ross. All the molecules that are involved in olfactory transduction are located within long cilia that arise from the olfactory bulb. The chemical signals (the odorants) are detected and selectively bind to the odorant-binding proteins (OBPs) that are concentrated in the olfactory mucus (Fig 19.4). The OBPs are small (10 to 30 kilodalton), water-soluble proteins that are synthesized and secreted by supporting cells. First, incoming odorant molecules are solubilized in the olfactory mucus, and then OBPs act as molecular carriers that transport odorants and deliver them to the olfactory receptors (ORs) located in the plasma membrane of the cilia. Olfactory receptors are specific for the olfactory receptor cells and belong to the family of G protein–coupled receptors (known as Golf ). When stimulated by odorant molecules, Golf ORs activate enzyme adenylyl cyclase and initiate the cyclic adenosine monophosphate (cAMP) cascade of evens (see Fig 19.4). These include binding of cAMP to specific Na


Histology_Ross

Histology_Ross. by odorant molecules, Golf ORs activate enzyme adenylyl cyclase and initiate the cyclic adenosine monophosphate (cAMP) cascade of evens (see Fig 19.4). These include binding of cAMP to specific Na and Ca2 channel proteins and influx of Na and Ca2, which is responsible for plasma membrane depolarization that generates action potential. To accurately detect several thousands of known odor molecules by only 350 known different ORs in humans requires a special coding system for different impulses. This is achieved by a population coding scheme, in which each OR protein binds to different odorants with different sensitivity. Thus, the olfactory system must decode olfactory impulses not from only one cell, but from the entire population of cells within the olfactory epithelium.


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Histology_Ross. Supporting cells provide mechanical and metabolic support for the olfactory receptor cells.


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Histology_Ross. Supporting cells are the most numerous cells in the olfactory epithelium. The nuclei of these tall columnar or sustentacular cells occupy a more apical position in the epithelium than do those of the other cell types, thus aiding in their identification in the light microscope (see Fig. 19.3 and Plate 69, page 688). They have numerous microvilli on their apical surface, and abundant mitochondria. Numerous profiles of smooth endoplasmic reticulum (sER) and, to a more limited extent, rough endoplasmic reticulum (rER) are observed in the cytoplasm. They also possess lipofuscin granules. Adhering junctions are present between these cells and the olfactory receptor cells, but gap and tight junctions are absent. The supporting cells function in a manner comparable to that of neuroglial cells, providing both metabolic support (secretion of OBP molecules) and physical support to the olfactory receptor cells. Brush cells are columnar cells specialized for transduction of general sensation.


Histology_Ross

Histology_Ross. Brush cells are columnar cells specialized for transduction of general sensation. The olfactory epithelium also contains cells present in much smaller numbers, called brush cells. As noted, these cells are present in the epithelium of other parts of the conducting air passages. With the electron microscope (EM), brush cells exhibit large, blunt microvilli at their apical surface, a feature that gives them their name. The basal surface of a brush cell is in synaptic contact with nerve fibers that penetrate the basal lamina. The nerve fibers are terminal branches of the trigeminal nerve (cranial nerve V) that function in general sensation rather than olfaction. Brush cells appear to be involved in transduction of general sensory stimulation of the mucosa. In addition, presence of a microvillous border, vesicles near the apical cell membrane, and a well-defined Golgi apparatus suggest that brush cells might be involved in an absorptive as well as a secretory functions.


Histology_Ross

Histology_Ross. Basal cells are progenitors of the other mature cell types. Basal cells are small, rounded cells located close to the basal lamina. Their nuclei are frequently invaginated and lie at a level below those of the olfactory receptor cell nuclei. The cytoplasm contains few organelles, a feature consistent with their role as a reserve or stem cell. A feature consistent with their differentiation into supporting cells is the observation of


Histology_Ross

Histology_Ross. FIGURE 19.4 • Diagram of olfactory transduction pathway. This diagram shows interactions of the odorant molecules with proteins associated with olfactory receptor cell. Incoming in inhaled air odorant molecules are solubilized in the olfactory mucus and bind to olfactory binding proteins, which deliver them to the olfactory receptors. Note that different odorant molecules bind with different affinity to the olfactory receptors. Strong signal (see green G protein–coupled olfactory receptor) is produced by high affinity binding where odorant molecule (green) matches perfectly the binging site on the receptor. Other olfactory receptors (yellow and pink) show less affinity binding, thus producing weaker signals. Stimulated by odorant molecules olfactory receptors activate enzyme adenylyl cyclase and initiate the cAMP cascade of evens leading to opening of specific Na and Ca2channels. Influx of Na and Ca2 is responsible for cell depolarization. Generated action potential travels on axons


Histology_Ross

Histology_Ross. and initiate the cAMP cascade of evens leading to opening of specific Na and Ca2channels. Influx of Na and Ca2 is responsible for cell depolarization. Generated action potential travels on axons of olfactory receptor cells from nasal cavity passing through the ethmoid bone and surrounding brain coverings to the olfactory bulb of the brain.


Histology_Ross

Histology_Ross. processes in some basal cells that partially ensheathe the first portion of the olfactory receptor cell axon. They thus maintain a relationship to the olfactory receptor cell even in their undifferentiated state. Olfactory glands are a characteristic feature of the olfactory mucosa. The olfactory glands (Bowman’s glands), a characteristic feature of the mucosa, are branched tubuloalveolar serous glands that deliver their proteinaceous secretions via ducts onto the olfactory surface (see Fig. 19.3 and Plate 69, page 688). Lipofuscin granules are prevalent in the gland cells, and in combination with the lipofuscin granules in the supporting cells of the olfactory epithelium, they give the mucosa its natural yellow-brown coloration. Short ducts composed of cuboidal cells lead from the glands and pass through the basal lamina into the olfactory epithelium, where they continue to the epithelial surface to discharge their contents.


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Histology_Ross. The serous secretion of the olfactory glands serves as a trap and solvent for odoriferous substances. Constant flow from the glands rids the mucosa of remnants of detected odoriferous substances so that new scents can be continuously detected as they arise. The identifying feature of the olfactory region of the nasal mucosa in a histologic preparation is the presence of the olfactory nerves in combination with olfactory glands in the lamina propria. The nerves are particularly conspicuous because of the relatively large diameter of the individual unmyelinated fibers that they contain (see Figs. 19.3 and 19.4). Paranasal sinuses are air-filled spaces in the bones of the walls of the nasal cavity.


Histology_Ross

Histology_Ross. Paranasal sinuses are air-filled spaces in the bones of the walls of the nasal cavity. The paranasal sinuses are extensions of the respiratory region of the nasal cavity and are lined by respiratory epithelium. The sinuses are named for the bone in which they are found (i.e., the ethmoid, frontal, sphenoid, and maxillary bones). The sinuses communicate with the nasal cavities via narrow openings onto the respiratory mucosa. The mucosal surface of the sinuses is a thin, ciliated, pseudostratified columnar epithelium with numerous goblet cells. Mucus produced in the sinuses is swept into the nasal cavities by coordinated ciliary movements. The sinuses are often subject to acute infection after viral infection of the upper respiratory tract. Severe infections may require physical drainage.


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Histology_Ross. The pharynx connects the nasal and oral cavities to the larynx and esophagus. It serves as a passageway for air and food and acts as a resonating chamber for speech. The pharynx is located posterior to the nasal and oral cavities and is divided regionally into the nasopharynx and oropharynx, respectively (see Fig. 19.2). The auditory (Eustachian) tubes connect the nasopharynx to each middle ear. Diffuse lymphatic tissue and lymphatic nodules are present in the wall of the nasopharynx. The concentration of lymphatic nodules at the junction between the superior and posterior walls of the pharynx is called the pharyngeal tonsil.


Histology_Ross

Histology_Ross. The passageway for air between the oropharynx and trachea is the larynx (see Fig. 19.2). This complex tubular region of the respiratory system is formed by irregularly shaped plates of hyaline and elastic cartilage (the epiglottis and the vocal processes of the arytenoid cartilages). In addition to serving as a conduit for air, the larynx serves as the organ for producing sounds. Vocal folds control the flow of air through the larynx and vibrate to produce sound.


Histology_Ross

Histology_Ross. Vocal folds control the flow of air through the larynx and vibrate to produce sound. The vocal folds, also referred to as vocal cords, are two folds of mucosa that project into the lumen of the larynx (Fig. 19.5 and Plate 70, page 690). They are oriented in an anteroposterior direction and define the lateral boundaries of the opening of the larynx, the rima glottidis. A supporting ligament and skeletal muscle, the vocalis muscle, is contained within each vocal fold. Ligaments and the intrinsic laryngeal muscles join the adjacent cartilaginous plates and are responsible for generating tension in the vocal folds and for opening and closing the glottis. The extrinsic laryngeal muscles insert on cartilages of the larynx but originate in extralaryngeal structures. These muscles move the larynx during deglutition (swallowing).


Histology_Ross

Histology_Ross. Expelled air from lungs passing through a narrow space of rima glottidis causes the vocal folds to vibrate. The vibrations are altered by modulating the tension on the vocal folds and by changing the degree of glottal opening. This alteration of the vibrations produces sounds of different pitch. Sounds created in the larynx during the process of phonation are modified in upper parts of the respiratory system (nasopharynx, nasal cavities, and paranasal sinuses) and the oral cavity (oropharynx, soft and hard palate, tongue, teeth, lips, etc.) to produce the individual speech sounds (different vowels and consonants). The ventricular folds located above the vocal folds are the “false vocal cords.”


Histology_Ross

Histology_Ross. The ventricular folds located above the vocal folds are the “false vocal cords.” Above the vocal folds is an elongated recess in the larynx called the ventricle. Immediately above the ventricle is another pair of mucosal folds, the ventricular folds, or false vocal cords (see Fig. 19.5 and Plate 70, page 690). These folds do not have the intrinsic muscular investment of the true vocal cords and therefore, do not modulate in phonation. They and the ventricle, however, are important in creating sound resonance. Inﬂammation and swelling of the larynx caused by viruses (such as in common cold virus) and other microbial agents is called acute laryngitis. Symptoms of acute laryngitis may include hoarseness or, in more severe cases, the total loss of voice, coughing, and difficulty with swallowing and breathing. Chronic laryngitis is usually caused by prolonged exposure of irritating agents such as tobacco smoke, dust, and/or polluted air.


Histology_Ross

Histology_Ross. Stratified squamous and ciliated pseudostratified columnar epithelium line the larynx. The luminal surface of the vocal cords is covered with stratified squamous epithelium, as is most of the epiglottis (Plate 70, page 690). The epithelium serves to protect the mucosa from abrasion caused by the rapidly moving air stream. The rest of the larynx is lined with the ciliated, pseudostratified columnar epithelium that characterizes the respiratory tract (see Fig. 19.5 and Plate 70, page 690). The connective tissue of the larynx contains mixed mucoserous glands that secrete through ducts onto the laryngeal surface.


Histology_Ross

Histology_Ross. The trachea is a short, flexible, air tube about 2.5 cm in diameter and about 10 cm long. It serves as a conduit for air; additionally, its wall assists in conditioning inspired air. The trachea extends from the larynx to about the middle of the thorax, where it divides into the two main (primary) bronchi. The lumen of the trachea stays open because of the arrangement of the series of cartilaginous rings. vestibule of the larynx stratified squamous epithelium


Histology_Ross

Histology_Ross. FIGURE 19.5 • Photomicrograph of a frontal section of the larynx. a. This photomicrograph shows three parts of the larynx: the vestibule above the ventricular folds, the ventricles between the vestibular folds and superior to the vocal folds, and the infraglottic cavity that extends from the vocal folds to the cricoid cartilage. Note that mucous glands are prominent in the ventricular folds and are covered by the typical pseudostratified ciliated epithelium. The vocal fold is composed of the epithelium, vocal ligament, and underlying vocalis muscle. Numerous lymph nodules are also present within the mucosa of the larynx (arrows). 10. b. High magnification of the area of the ventricular fold indicated by the upper rectangle in a shows on the left the pseudostratified ciliated epithelium that lines most of the larynx. Many nonsmoking adults and virtually all smokers exhibit patches of stratified squamous epithelium, as seen on the right of the micrograph. 240. c. High magnification of


Histology_Ross

Histology_Ross. lines most of the larynx. Many nonsmoking adults and virtually all smokers exhibit patches of stratified squamous epithelium, as seen on the right of the micrograph. 240. c. High magnification of the area of the vocal fold indicated by the lower rectangle in a reveals normal stratified squamous epithelium at this site. Just beneath the epithelium is the connective tissue known as Reinke’s space. This clinically important site lacks lymphatic vessels and is poorly vascularized. The vocal ligament, inscribed by the dashed line, is seen at the bottom of the micrograph. 240.


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Histology_Ross. The wall of the trachea consists of four definable layers:  Mucosa, composed of a ciliated, pseudostratified epithelium and an elastic, fiber-rich lamina propria  Submucosa, composed of a slightly denser connective tissue than the lamina propria  Cartilaginous layer, composed of C-shaped hyaline cartilages  Adventitia, composed of connective tissue that binds the trachea to adjacent structures A unique feature of the trachea is the presence of a series of C-shaped hyaline cartilages that are stacked one on top of each other to form a supporting structure (Fig. 19.6). These cartilages, which might be described as a skeletal framework, prevent collapse of the tracheal lumen, particularly during  FOLDER 19.1 Clinical Correlation: Squamous Metaplasia in the Respiratory Tract


Histology_Ross

Histology_Ross. In human respiratory mucosa, ciliated pseudostratified in certain regions to a stratified squamous form. The alcolumnar epithelium may change to stratified squamous ep-tered epithelium is more resistant to physical stress and inithelium. This change from columnar to squamous epithelium sult, but it is less effective functionally. In smokers, a similar epithelium is referred as columnar-to-squamous metapla-epithelial change occurs. Initially, the cilia on ciliated cells sia or simply the squamous metaplasia. Epithelial alter-lose their synchronous beating pattern as a result of noxations of this kind are reversible and are characterized by ious elements in smoke. As a result, removal of mucus is change from one type of fully differentiated adult cell to a dif-impaired. To compensate, the individual begins to cough, ferent type of adult cell. A given mature cell does not change thereby facilitating the expulsion of accumulated mucus in to another type of mature cell; rather, basal cell


Histology_Ross

Histology_Ross. begins to cough, ferent type of adult cell. A given mature cell does not change thereby facilitating the expulsion of accumulated mucus in to another type of mature cell; rather, basal cell proliferation the airway, particularly in the trachea. With time, the numgives rise to the new differentiated cell type. These cellular ber of ciliated cells decreases because of chronic cough-changes are considered to be controlled and adaptive. ing. This reduction in ciliated cells further impairs the


Histology_Ross

Histology_Ross. Squamous metaplasia is a normal occurrence on the normal epithelium and results in its replacement with stratrounded, more exposed portions of the turbinates, on the ified squamous epithelium at affected sites in the airway. If vocal folds, and in certain other regions. factors (i.e., tobacco smoking) that predispose to squa- Changes in the character of the respiratory epithelium mous metaplasia are not eliminated, the metaplastic epmay, however, occur in other ciliated epithelial sites when ithelium may undergo malignant transformation. Therefore, the pattern of airflow is altered or when forceful airflow oc-one of the two most common forms of cancer in the respicurs, as in chronic coughing. Typically, in chronic bronchi-ratory tract, the squamous cell carcinoma, has its origin tis and bronchiectasis, the respiratory epithelium changes from the squamous metaplastic cells.


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Histology_Ross. expiration. Fibroelastic tissue and smooth muscle, the trachealis muscle, bridge the gap between the free ends of the C-shaped cartilages at the posterior border of the trachea, adjacent to the esophagus. Tracheal epithelium is similar to respiratory epithelium in other parts of the conducting airway. Ciliated columnar cells, mucous (goblet) cells, and basal cells are the principal cell types in the tracheal epithelium (Figs. 19.7 and 19.8). Brush cells are also present, but in small numbers, as are small granule cells.


Histology_Ross

Histology_Ross. 19.7 and 19.8). Brush cells are also present, but in small numbers, as are small granule cells.  Ciliated cells, the most numerous of the tracheal cell types, extend through the full thickness of the epithelium. Cilia appear in histologic sections as short, hair-like profiles projecting from the apical surface (Plate 71, page 692). Each cell has approximately 250 cilia. Immediately below the cilia is a dark line formed by the aggregated ciliary basal bodies (Fig. 19.9). The cilia provide a coordinated sweeping motion of the mucous coat from the farthest reaches of the air passages toward the pharynx. In effect, the ciliated cells function as a “mucociliary escalator” that serves as an important protective mechanism for removing small inhaled particles from the lungs.


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Histology_Ross.  Mucous cells are similar in appearance to intestinal goblet cells and are thus often referred to by the same name. They are interspersed among the ciliated cells and also extend through the full thickness of the epithelium (see Fig. 19.9). They are readily seen in the light microscope after they have accumulated mucinogen granules in their cytoplasm. Although the mucinogen is typically washed out in hematoxylin and eosin (H&E) preparations, the identity of the cell is made apparent by the remaining clear area in the cytoplasm and the lack of cilia at the apical surface. In contrast to ciliated cells, the number of mucous cells increases during chronic irritation of the air passages.


Histology_Ross

Histology_Ross.  Brush cells have the same general features as those described for the respiratory epithelium of the nasal cavity (Fig. 19.10). They are columnar cells that bear blunt microvilli. The basal surface of the cells is in synaptic contact with an afferent nerve ending (epitheliodendritic synapse). Thus, the brush cell is regarded as a receptor cell.


Histology_Ross

Histology_Ross.  Small granule cells (Kulchitsky cells) are respiratory representatives of the general class of enteroendocrine cells of the gut and gut derivatives (see Fig. 19.10). Their presence is explained by the development of the respiratory tract and lungs from an evagination of the primitive foregut. Small granule cells usually occur singly in the trachea and are sparsely dispersed among the other cell types. They are difficult to distinguish from basal cells in the light microscope without special techniques such as silver staining, which reacts with the granules. The nucleus is located near the basement membrane; the cytoplasm is somewhat more extensive than that of the smaller basal cells. With the transmission electron microscope (TEM), a thin, tapering cytoplasmic process is sometimes observed extending to the lumen. Also, with the TEM, the cytoplasm exhibits numerous, membrane-bounded, dense-core granules. In one type of small granule cell, the secretion is a catecholamine. A second


Histology_Ross

Histology_Ross. extending to the lumen. Also, with the TEM, the cytoplasm exhibits numerous, membrane-bounded, dense-core granules. In one type of small granule cell, the secretion is a catecholamine. A second cell type produces polypeptide hormones such as serotonin, calcitonin, and gastrin-releasing peptide


Histology_Ross

Histology_Ross. FIGURE 19.6 • Photomicrograph of a section of the trachea and esophagus. a. This specimen, obtained from an elderly individual, shows the relationship between the trachea and the esophagus at the base of the neck. The cartilaginous tracheal rings, which keep the trachea patent, have a C-shaped appearance. The cartilage gap, where the trachea is adjacent to the esophageal wall, is spanned by a fibroelastic membrane. It contains the trachealis muscle and numerous seromucous glands. In this specimen, the tracheal ring has been transformed, in part, to bone, a process that occurs in aging. The darker-staining material represents cartilage, whereas the lighter-staining material has been replaced by bone tissue. The very light areas (arrows) are marrow spaces. 3.25. b. This high-magnification photomicrograph shows an area of the tracheal ring that has partially transformed into bone. The top of the micrograph shows the tracheal mucosa and submucosa. Below is part of the tracheal ring. In


Histology_Ross

Histology_Ross. photomicrograph shows an area of the tracheal ring that has partially transformed into bone. The top of the micrograph shows the tracheal mucosa and submucosa. Below is part of the tracheal ring. In this particular region, however, a substantial portion of the cartilage has been replaced by bone tissue and marrow. The bone tissue exhibits typical lamellae and osteocytes. The cartilage tissue, in contrast, exhibits nests of chondrocytes. 100.


Histology_Ross

Histology_Ross. (bombesin). Some small granule cells appear to be innervated. The function of these cells is not well understood. Some are present in groups in association with nerve fibers, forming neuroepithelial bodies, which are thought to function in reflexes regulating the airway or vascular caliber.  Basal cells serve as a reserve cell population that maintains individual cell replacement in the epithelium. Basal cells tend to be prominent because their nuclei form a row in close proximity to the basal lamina. Although nuclei of other cells reside at this same general level within the epithelium, they are relatively sparse. Thus, most of the nuclei near the basement membrane belong to basal cells. A thick “basement membrane” is characteristic of tracheal epithelium.


Histology_Ross

Histology_Ross. A thick “basement membrane” is characteristic of tracheal epithelium. Located beneath the tracheal epithelium is a distinctive layer typically referred to as a basement membrane (see Fig. 19.9). It usually appears as a glassy or homogeneous light-staining layer approximately 25 to 40 m thick. Electron microscopy reveals that it consists of densely packed collagenous fibers that lie immediately under the epithelial basal lamina. Structurally, it can be regarded as an unusually thick and dense reticular lamina and, as such, is part of the lamina propria. In smokers, particularly those who experience chronic coughing, this layer may be considerably thicker, a response to mucosal irritation.


Histology_Ross

Histology_Ross. The lamina propria, excluding that part just designated as basement membrane, appears as a typical loose connective tissue. It is very cellular, containing numerous lymphocytes, many of which infiltrate the epithelium. Plasma cells, mast cells, eosinophils, and fibroblasts are the other cell types readily observed in this layer. Lymphatic tissue, in both diffuse and nodular forms, is consistently present in the lamina propria and submucosa of the tracheal wall. It is also present in other parts of the respiratory system involved primarily with air conduction. This lymphatic tissue is the developmental and functional equivalent of the bronchus-associated lymphatic tissue (BALT).


Histology_Ross

Histology_Ross. FIGURE 19.7 • Electron micrograph of human trachea. This electron micrograph shows the three main cell types of this respiratory epithelium. They are represented by ciliated epithelial cells extending to the surface, where they possess cilia; goblet cells with mucinogen granules; and basal cells, which are confined to the basal portion of the epithelial layer near the connective tissue. 1,800. (Courtesy of Dr. Johannes A. G. Rhodin.) The boundary between mucosa and submucosa is defined by an elastic membrane. Interspersed among the collagenous fibers are numerous elastic fibers. Where the lamina propria ends, the elastic material is more extensive, and in specimens stained for these fibers, a distinct band of elastic material is seen. This band or elastic membrane marks the boundary between the lamina propria and submucosa. In H&E preparations, however, the boundary is not obvious.


Histology_Ross

Histology_Ross. The submucosa is unlike that of most other organs, in which this connective tissue typically has a dense character. In the trachea, the submucosa is a relatively loose connective tissue similar in appearance to the lamina propria, which makes it difficult to determine where it begins. Diffuse lymphatic tissue and lymphatic nodules characteristically extend into this layer from the lamina propria. The submucosa contains the larger distributing vessels and lymphatics of the tracheal wall. Submucosal glands composed of mucus-secreting acini with serous demilunes are also present in the submucosa. Their ducts consist of a simple cuboidal epithelium and extend through the lamina propria to deliver their product, largely glycoproteins, on the epithelial surface. The glands are


Histology_Ross

Histology_Ross. FIGURE 19.8 • Scanning electron micrograph of the luminal surface of a bronchus. The nonciliated cells are the goblet cells (G). Their surface is characterized by small blunt microvilli that give a stippled appearance to the cell at this low magnification. The cilia of the many ciliated cells occupy the remainder of the micrograph. Note how all are “synchronously” arrayed (i.e., uniformly leaning in the same direction) appearing just as they were when fixed at a specific moment during their wavelike movement. 1,200. especially numerous in the cartilage-free gap on the posterior portion of the trachea. Some penetrate the muscle layer at this site and, therefore, also lie in the adventitia. The submucosal layer ends where its connective tissue fibers blend with the perichondrium of the cartilage layer. The tracheal cartilages and trachealis muscle separate submucosa from adventitia.


Histology_Ross

Histology_Ross. The tracheal cartilages and trachealis muscle separate submucosa from adventitia. The tracheal cartilages, which number about 16 to 20 in humans, represent the next layer of the tracheal wall. As noted, the cartilages are C shaped. They sometimes anastomose with


Histology_Ross

Histology_Ross. FIGURE 19.9 • Photomicrograph of tracheal epithelium. Three major cell types are evident in the tracheal epithelium (Ep): ciliated columnar cells; mucus-secreting goblet cells (G) interspersed between the ciliated cells; and basal cells, which are close to the basement membrane (BM ). The ciliated columnar cells extend from the basement membrane to the surface. At their free surface they contain numerous cilia that, together, give the surface a brushlike appearance. At the base of the cilia is a dense eosinophilic line. This is owing to the linear aggregation of structures referred to as basal bodies, located at the proximal end of each cilium. Although basement membranes are not ordinarily seen in H&E preparations, a structure identified as such is seen regularly under the epithelium in the human trachea. The underlying lamina propria (LP ) consists of loose connective tissue. The more deeply located submucosa (SM) contains dense irregular connective tissue with blood and lymphatic


Histology_Ross

Histology_Ross. the human trachea. The underlying lamina propria (LP ) consists of loose connective tissue. The more deeply located submucosa (SM) contains dense irregular connective tissue with blood and lymphatic vessels, nerves, and numerous mucus-secreting tracheal glands. 400.


Histology_Ross

Histology_Ross. adjacent cartilages, but their arrangement provides flexibility to the tracheal pipe and also maintains patency of the lumen. With age, the hyaline cartilage may be partially replaced by bone tissue (see Fig. 19.6), causing it to lose much of its flexibility. The adventitia, the outer layer, lies peripheral to the cartilage rings and trachealis muscle. It binds the trachea to adjacent


Histology_Ross

Histology_Ross. The adventitia, the outer layer, lies peripheral to the cartilage rings and trachealis muscle. It binds the trachea to adjacent FIGURE 19.10 • Diagram of a brush cell and small granule cell. a. The brush cell, as illustrated here, is interposed between type I and type II alveolar cells of an alveolus. Blunt microvilli are distinctive features of the brush cell. The cytoplasm typically shows a Golgi apparatus, lysosomes, mitochondria, and glycogen inclusions. b. This small granule cell is shown located between two Clara cells, as in a terminal or respiratory bronchiole. The cell contains small secretory vesicles, most of which are in the basal portion of the cell. In addition to the vesicles, the most conspicuous organelles of the cell are rough-surfaced endoplasmic reticulum (rER), a Golgi apparatus, and mitochondria. A nerve terminal is shown within the epithelium adjacent to the cell.


Histology_Ross

Histology_Ross. structures in the neck and mediastinum and contains the largest blood vessels and nerves that supply the tracheal wall, as well as the larger lymphatics that drain the wall.


Histology_Ross

Histology_Ross. The trachea divides into two branches forming the main (primary) bronchi. Anatomically, these divisions are more frequently described as simply the right and left main bronchi, terms that are more useful because of the physical difference between the two. The right bronchus is wider and significantly shorter than the left. On entering the hilum of the lung, each main bronchus divides into the lobar bronchi (secondary bronchi). The left lung is divided into two lobes; the right lung is divided into three lobes. Thus, the right bronchus divides into three lobar bronchial branches, and the left into two lobar bronchial branches, with each branch supplying one lobe. The left lung is further divided into 8 bronchopulmonary segments and the right lung into 10 such segments. Thus, in the right lung the lobar bronchi give rise to 10 segmental bronchi (tertiary bronchi); the lobar bronchi of the left lung give rise to 8 segmental bronchi.


Histology_Ross

Histology_Ross. A segmental bronchus and the lung parenchyma that it supplies constitute a bronchopulmonary segment. The significance of the bronchopulmonary segment in the human lung becomes apparent when considering the need for surgical resection, which may be required in certain disease states. The segments, each with their own blood supply and connective tissue septa, are convenient subunits that facilitate surgical resection.


Histology_Ross

Histology_Ross. Initially, the bronchi have the same general histologic structure as the trachea. At the point where the bronchi enter the lungs to become intrapulmonary bronchi, the structure of the bronchial wall changes. The cartilage rings are replaced by cartilage plates of irregular shape. The plates are distributed in a linear array around the entire circumference of the wall, giving the bronchi a circular or cylindrical shape in contrast to the ovoid shape with a flattened posterior wall of the trachea. As the bronchi decrease in size because of branching, the cartilage plates become smaller and less numerous. The plates ultimately disappear at the point where the airway reaches a diameter of about 1 mm, whereupon the branch is designated a bronchiole. Bronchi can be identified by their cartilage plates and a circular layer of smooth muscle.


Histology_Ross

Histology_Ross. Bronchi can be identified by their cartilage plates and a circular layer of smooth muscle. The second change observed in the wall of the intrapulmonary bronchus is the addition of smooth muscle to form a complete circumferential layer. The smooth muscle becomes an increasingly conspicuous layer as the amount of cartilage diminishes. Initially, the smooth muscle is arranged in interlacing bundles forming a continuous layer. In the smaller bronchi, the smooth muscle may appear discontinuous.


Histology_Ross

Histology_Ross. Because the smooth muscle forms a separate layer, namely, a muscularis, the wall of the bronchus can be regarded as having five layers:  Mucosa, composed of a pseudostratified epithelium with the same cellular composition as the trachea. The height of the cells decreases as the bronchi decrease in diameter. In H&E specimens the “basement membrane” is conspicuous in the primary bronchi but quickly diminishes in thickness and disappears as a discrete structure in the secondary bronchi. The lamina propria is similar to that of the trachea but is reduced in amount in proportion to the diameter of the bronchi.  Muscularis, a continuous layer of smooth muscle in the larger bronchi. It is more attenuated and loosely organized in smaller bronchi, where it may appear discontinuous because of its spiral course. Contraction of the muscle regulates the appropriate diameter of the airway.


Histology_Ross

Histology_Ross.  Submucosa remains as a relatively loose connective tissue. Glands are present as well as adipose tissue in the larger bronchi.  Cartilage layer consists of discontinuous cartilage plates that become smaller as the bronchial diameter diminishes.  Adventitia is moderately dense connective tissue that is continuous with that of adjacent structures, such as pulmonary artery and lung parenchyma.


Histology_Ross

Histology_Ross.  Adventitia is moderately dense connective tissue that is continuous with that of adjacent structures, such as pulmonary artery and lung parenchyma. The bronchopulmonary segments are further subdivided into pulmonary lobules; each lobule is supplied by a bronchiole. Delicate connective tissue septa that partially separate adjacent lobules may be represented on the surface of the lung as faintly outlined polygonal areas. Pulmonary acini are smaller units of structure that make up the lobules. Each acinus consists of a terminal bronchiole and the respiratory bronchioles and alveoli that it aerates (Fig. 19.11). The smallest functional unit of pulmonary structure is thus the respiratory bronchiolar unit. It consists of a single respiratory bronchiole and the alveoli that it supplies.


Histology_Ross

Histology_Ross. Bronchioles are air-conducting ducts that measure 1 mm or less in diameter. The larger bronchioles represent branches of the segmental bronchi. These ducts branch repeatedly, giving rise to the smaller terminal bronchioles that also branch. The terminal bronchioles finally give rise to the respiratory bronchioles. Cartilage plates and glands are not present in bronchioles. The larger-diameter bronchioles initially have a ciliated, pseudostratified columnar epithelium that gradually transforms into a simple ciliated columnar epithelium as the duct narrows. Goblet cells are still present in the largest bronchioles but are not present in the terminal bronchioles that follow. An exception is in smokers and others exposed to irritants in the air. There are no subepithelial glands in


Histology_Ross

Histology_Ross. FIGURE 19.11 • Photomicrograph showing the respiratory portion of the bronchial tree. In this photomicrograph a terminal bronchiole (TB) is shown longitudinally sectioned as it branches into two respiratory bronchioles (RB). The terminal bronchiole is the most distal part of the conducting portion of the respiratory system and is not engaged in gas exchange. The respiratory bronchiole engages in gas exchange and is the beginning of the respiratory portion of the bronchial tree. Respiratory bronchioles give rise to alveolar ducts (AD), which are elongate airways that have almost no walls, only alveoli surrounding the duct space. Alveolar sacs (AS) are spaces at the termination of the alveolar ducts that, likewise, are surrounded by alveoli. 120.


Histology_Ross

Histology_Ross. bronchioles. Cartilage plates, characteristic of bronchi, are absent in bronchioles. Instead, small elements of cartilage may be present, particularly at branching points. A relatively thick layer of smooth muscle is present in the wall of all bronchioles. Small bronchioles have a simple cuboidal epithelium. The smallest conducting bronchioles, the terminal bronchioles, are lined with a simple cuboidal epithelium in which Clara cells are interspersed among the ciliated cells (Fig. 19.12). Clara cells increase in number as the ciliated cells decrease along the length of the bronchiole. Occasional brush cells and small granule cells are also present. A small amount of connective tissue underlies the epithelium, and a circumferential layer of smooth muscle underlies the connective tissue in the conducting portions. Clara cells are nonciliated cells that have a characteristic rounded or dome-shaped apical surface projection. They display TEM characteristics of protein-secreting cells


Histology_Ross

Histology_Ross. Clara cells are nonciliated cells that have a characteristic rounded or dome-shaped apical surface projection. They display TEM characteristics of protein-secreting cells FIGURE 19.12 • Scanning electron micrograph of a terminal bronchiole. This scanning photomicrograph shows a longitudinal section throughout the terminal bronchiole and surrounding alveoli (A). Note that the apical surfaces of the Clara cells possess no cilia and have a characteristic dome-shaped appearance. 150. The inset shows some of the Clara cells at a higher magnification and the cilia of a neighboring ciliated cell, which are present in very small numbers at this level. Note the relatively few cilia present on these small cells. 1,200.


Histology_Ross

Histology_Ross. (Fig. 19.13). They have a well-developed basal rER, a lateral or supranuclear Golgi apparatus, secretory granules that stain for protein, and numerous cisternae of sER in the apical cytoplasm. Clara cells secrete a surface-active agent, a lipoprotein that prevents luminal adhesion should the wall of the airway collapse on itself, particularly during expiration. In addition, Clara cells produce a 16-kilodalton protein known as Clara cell secretory protein (CC16), which is an abundant component of the airway secretion. Chronic lung diseases such as chronic obstructive pulmonary disease (COPD) and asthma are associated with changes in the abundance of CC16 in airway ﬂuid and serum. CC16 is used as a measurable pulmonary marker in bronchoalveolar lavage ﬂuid and serum. Secretion of CC16 into the bronchial tree decreases during lung injury (because of damage to the Clara cells), whereas serum levels of CC16 may increase because of leakage across the air–blood barrier.


Histology_Ross

Histology_Ross. FIGURE 19.13 • Diagram of a Clara cell between bronchiolar ciliated epithelial cells. The nucleus is in a basal location. Rough-surfaced endoplasmic reticulum (rER), a Golgi apparatus, and mitochondria are chiefly in basal and paranuclear locations of the cell. Smooth-surfaced endoplasmic reticulum (sER) and secretory vesicles are chiefly in the apical cytoplasm. One of the secretory vesicles is shown discharging its contents onto the surface of the cell. Respiratory bronchioles are the first part of the bronchial tree that allows gas exchange.


Histology_Ross

Histology_Ross. Respiratory bronchioles are the first part of the bronchial tree that allows gas exchange. Respiratory bronchioles constitute a transitional zone in the respiratory system; they are involved in both air conduction and gas exchange. They have a narrow diameter and are lined by cuboidal epithelium. The epithelium of the initial segments of the respiratory bronchioles contains both ciliated cells and Clara cells (see Fig. 19.12). Distally, Clara cells predominate. Occasional brush cells and dense-core granule cells are also present along the length of the respiratory bronchiole. Scattered, thin-walled outpocketings, alveoli, extend from the lumen of the respiratory bronchioles (see Fig. 19.11). Alveoli are the sites at which air leaves and enters the bron chiole to allow gas exchange. Alveoli are the site of gas exchange.


Histology_Ross

Histology_Ross. Alveoli are the site of gas exchange. The surface area available for gas exchange is increased by the lung alveoli. Alveoli are the terminal air spaces of the respiratory system and are the actual sites of gas exchange between the air and the blood. Each alveolus is surrounded by a network of capillaries that brings blood into close proximity to inhaled air inside the alveolus. About 150 to 250 million alveoli are found in each adult lung; their combined internal surface area is approximately 75 m2, roughly the size of a tennis court. Each alveolus is a thin-walled polyhedral


Histology_Ross

Histology_Ross. FIGURE 19.14 • Photomicrograph showing an alveolar sac with adjacent alveoli. This photomicrograph shows the terminal components of the respiratory system, namely, the alveolar sac (AS) and the surrounding alveoli (A). The alveoli are surrounded and separated from one another by a thin connective tissue layer, the interalveolar septa, containing blood capillaries. On the right is the lung surface, which is covered by visceral pleura containing simple squamous epithelium and an underlying layer of connective tissue. 360. chamber approximately 0.2 mm in diameter that is confluent with an alveolar sac (Fig. 19.14).  Alveolar ducts are elongated airways that have almost no walls, only alveoli, as their peripheral boundary. Rings of smooth muscle are present in the knoblike interalveolar septa (see the next paragraph). Alveolar sacs are spaces surrounded by clusters of alveoli. The surrounding alveoli open into these spaces.


Histology_Ross

Histology_Ross. The surrounding alveoli open into these spaces. Alveolar sacs usually occur at the termination of an alveolar duct but may occur anywhere along its length. Alveoli are surrounded and separated from one another by an exceedingly thin connective tissue layer that contains blood capillaries. The tissue between adjacent alveolar air spaces is called the alveolar septum or septal wall (Fig. 19.15). Alveolar epithelium is composed of type I and II alveolar cells and occasional brush cells.


Histology_Ross

Histology_Ross. Alveolar epithelium is composed of type I and II alveolar cells and occasional brush cells. The alveolar surface forms a vulnerable biologic interface that is subject to many destabilizing surface forces and to continuous exposure to inhaled particles, pathogens, and toxins. The alveolar epithelium is composed of several specialized cells and their products, some of which play defensive and protective roles:  Type I alveolar cells, also known as type I pneumocytes, comprise only 40% of the entire alveolar lining cells. They are extremely thin squamous cells; they line most (95%) of the surface of the alveoli (see Fig. 19.15). These cells are joined to one another and to the other cells of the alveolar epithelium by occluding junctions (Fig. 19.16). The junctions form an effective barrier between the air space and the components of the septal wall. Type I alveolar cells are not capable of cell division.


Histology_Ross

Histology_Ross.  Type II alveolar cells, also called type II pneumocytes or septal cells, are secretory cells. These cuboidal cells are interspersed among the type I cells but tend to congregate at septal junctions. Type II cells account for 60% of the alveolar lining cells, but because of their different shape they cover only about 5% of the alveolar air surface. Like Clara cells, type II cells tend to bulge into the air space (see Fig. 19.16). Their apical cytoplasm is filled with granules that are resolved with the TEM (Fig. 19.17) as stacks of parallel membrane lamellae, the lamellar bodies. They are rich in a mixture of phospholipids, neutral lipids, and proteins, that is secreted by exocytosis to form an alveolar lining, surface-active agent called surfactant. In addition to secretion of surfactant, type II alveolar cells are progenitor cells for type I alveolar cells. After lung injury, they proliferate and restore both types of alveolar cells within the alveolus. Hyperplasia of type II


Histology_Ross

Histology_Ross. type II alveolar cells are progenitor cells for type I alveolar cells. After lung injury, they proliferate and restore both types of alveolar cells within the alveolus. Hyperplasia of type II alveolar cells is an important marker of alveolar injury and repair of alveoli.


Histology_Ross

Histology_Ross.  Brush cells are also present in the alveolar wall, but they are few in number. They may serve as receptors that monitor air quality in the lung. Surfactant decreases the alveolar surface tension and actively participates in the clearance of foreign materials.


Histology_Ross

Histology_Ross. The surfactant layer produced by type II alveolar cells reduces the surface tension at the air–epithelium interface. The most critical agent for air space stability is a specific phospholipid called dipalmitoylphosphatidylcholine (DPPC), which accounts for almost all surface tension–reducing properties of surfactant. Surfactant synthesis in the fetus occurs after the 35th week of gestation and is modulated by a variety of hormones, including cortisol, insulin, prolactin, and thyroxine. Without adequate secretion of surfactant, the alveoli would collapse on each successive exhalation. Such collapse occurs in premature infants whose lungs have not developed sufficiently to produce surfactant, causing neonatal respiratory distress syndrome (RDS). Prophylactic administration of exogenous surfactant at birth to extremely premature infants and administration to symptomatic newborns reduces the risk of RDS. In addition, administration of cortisol to mothers with threatened premature delivery


Histology_Ross

Histology_Ross. at birth to extremely premature infants and administration to symptomatic newborns reduces the risk of RDS. In addition, administration of cortisol to mothers with threatened premature delivery decreases neonatal mortality.


Histology_Ross

Histology_Ross. Surfactant proteins help organize the surfactant layer and modulate alveolar immune responses. In addition to phospholipids, hydrophobic proteins are necessary for the structure and function of surfactant. These proteins are listed here:  Surfactant protein A (SP-A), the most abundant surfactant protein. SP-A is responsible for surfactant homeostasis (regulating synthesis and secretion of surfactant by type II alveolar cells). It also modulates immune responses to viruses, bacteria, and fungi.


Histology_Ross

Histology_Ross. FIGURE 19.15 • Electron micrograph of lung alveoli. This electron micrograph shows two alveolar spaces separated by an alveolar septum containing capillaries, some of which contain red blood cells. Note the areas of thin and thick portions of the alveolar septum. These are shown at a higher magnification in Figure 19.19. 5,800. Inset. Photomicrograph of an alveolus for comparison with the alveolar wall as seen in an electron micrograph. Arrows indicate alveolar capillaries containing red blood cells. 480.  Surfactant protein B (SP-B), an important protein for the transformation of the lamellar body into the thin surface film of surfactant. SP-B is a critical surfactant-organizing protein responsible for adsorption and spreading of surfactant onto the surface of the alveolar epithelium.


Histology_Ross

Histology_Ross.  Surfactant protein C (SP-C), which represents only 1% of the total mass of surfactant protein. Along with SP-B, SP-C aids in orientation of DPPC within the surfactant and maintenance of the thin film layer within the alveoli.  Surfactant protein D (SP-D), a primary protein involved in host defense. It binds to various microorganisms (e.g., Gram-negative bacteria) and to lymphocytes. SP-D participates in a local inﬂammatory response to acute lung injury and with SP-A modulates an allergic response to various inhaled antigens. The alveolar septum is the site of the air–blood barrier.


Histology_Ross

Histology_Ross. The alveolar septum is the site of the air–blood barrier. The air–blood barrier refers to the cells and cell products across which gases must diffuse between the alveolar and capillary compartments. The thinnest air–blood barrier consists of a thin layer of surfactant, a type I epithelial cell and its basal lamina, and a capillary endothelial cell and its basal lamina. Often, these two basal laminae are fused (Fig. 19.18). Connective tissue cells and fibers that may be present between the two basal laminae widen the air–blood barrier. These two arrangements produce a thin portion and a thick portion of the barrier (Fig. 19.19). It is thought that most gas exchange occurs across the thin portion of the barrier. The thick portion is thought to be a site in which tissue fluid can accumulate and even cross into the alveolus. Lymphatic vessels in the connective tissue of the terminal bronchioles drain fluid that accumulates in the thick portion of the septum.


Histology_Ross

Histology_Ross. Alveolar macrophages remove inhaled particulate matter from the air spaces and red blood cells from the septum. Alveolar macrophages are unusual in that they function both in the connective tissue of the septum and in the air FIGURE 19.16 • Electron micrograph of a type II alveolar cell. The type II alveolar cell has a dome-shaped apical surface with a number of short microvilli at its periphery and a relatively smooth-contoured apical center. The lateral cell margins are overlain to a variable degree by the type I alveolar cells that are joined to the type II cell by occluding junctions. Both cell types rest on the basal lamina (BL). The secretory vesicles (G) in this specimen are largely dissolved, but their lamellar character is shown to advantage in Figure 19.17b. 24,000.


Histology_Ross

Histology_Ross. space of the alveolus (Fig. 19.20). In air spaces, they scavenge the surface to remove inhaled particulate matter (e.g., dust and pollen), thus giving them one of their alternative names, dust cells. Alveolar macrophages are derived from blood monocytes and belong to the mononuclear phagocytotic system (see page 185). They phagocytize red blood cells that may enter the alveoli in heart failure (see Fig. 19.20). Some engorged macrophages pass up the bronchial tree in the mucus and are disposed of by swallowing or expectoration when they reach the pharynx. Other macrophages return to or remain in the septal connective tissue, where, filled with accumulated phagocytized material, they may remain for much of an individual’s life. Thus, at autopsy, the lungs of urban dwellers and smokers usually show many alveolar and septal macrophages filled with carbon particles, anthracotic pigment, and birefringent needle-like particles of silica. Alveolar macrophages also phagocytose infectious