Histology_Ross

Histology_Ross. 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 organisms such as Mycobacterium tuberculosis, which can be recognized in the cells in appropriately stained specimens. These bacilli are not digested by macrophages, however, other infections or conditions that damage alveolar macrophages can cause release of the bacteria and recurrent tuberculosis.


Histology_Ross

Histology_Ross. Collateral air circulation through alveolar pores allows air to pass between alveoli. Scanning electron microscopic studies of alveolar structure show openings in the interalveolar septa that allow circulation of air from one alveolus to another. These alveolar pores (of Kohn) can be of great significance in some pathologic conditions in which obstructive lung disease blocks the normal pathway of air to the alveoli. The alveoli distal to the blockage may continue to be aerated, via the pores, from an adjacent lobule or acinus. A basic summary of information related to the respiratory system is included in Figure 19.21. surfactant discharged into lumen of alveolus


Histology_Ross

Histology_Ross. surfactant discharged into lumen of alveolus FIGURE 19.17 • Diagram of a type II alveolar cell and electron micrograph of lamellar bodies. a. Surfactant is an oily mixture of proteins, phospholipids, and neutral lipids that are synthesized in the rER from precursors in the blood. These precursors are glucose, fatty acids, choline, and amino acids. The protein constituents of surfactant are produced in the rER and stored in the cytoplasm within lamellar bodies, which are discharged into the lumen of the alveolus. With the aid of surfactant protein, surfactant is distributed, on the surface of epithelial cells lining the alveolus, as a thin film that reduces the surface tension. b. Higher-magnification electron micrograph showing the typical lamellar pattern of the secretory vesicles of type II alveolar cells. These vesicles contain the pulmonary surfactant precursor proteins. 38,000. (Courtesy of Dr. A. Mercuri.)


Histology_Ross

Histology_Ross. FIGURE 19.18 • Diagram of the interalveolar septum. This diagram shows the thick and thin portions of the interalveolar septum. The thin portion forms the air–blood barrier and is responsible for most of the gas exchange that occurs in the lung. Arrows indicate the direction of CO2 and O2 exchange between the alveolar air space and the blood. The thick portion of the interalveolar septum plays an important role in fluid distribution and its dynamics. It contains connective tissue cells. Note the macrophage in the thick portion that extends its processes into the lumen of the alveolus.


Histology_Ross

Histology_Ross. FIGURE 19.19 • Electron micrograph of the alveolar septum. This high-magnification micrograph shows the thin portion of the air–blood barrier where it consists of type I alveolar cells, capillary endothelium, and the fused basal lamina shared by both cells. In the thick portion, the type I alveolar cell (arrows) rests on a basal lamina, and on the opposite side is connective tissue in which collagen fibrils and elastic fibers are evident. 33,000. FIGURE 19.20 • Photomicrograph of alveolar macrophages.


Histology_Ross

Histology_Ross. FIGURE 19.20 • Photomicrograph of alveolar macrophages. This high-magnification photomicrograph shows the structure of the alveolar septum and the lumen of an alveolus containing alveolar macrophages and red blood cells. The cytoplasm of the alveolar macrophages, when they are present in significant numbers, often contains the brown pigment hemosiderin from phagocytosed red blood cells. These hemosiderin-laden macrophages (often called “heart failure cells”) are typically found in heart disease, mostly left ventricular failures that cause pulmonary congestion and edema. This results in enlargement of the alveolar capillaries and small hemorrhages into the alveoli. 560. trachea main bronchus lobar bronchus segmental bronchus terminal bronchiole respiratory bronchioles alveolar duct alveolar sacs alveoli RESPIRATORY CONDUCTING FIGURE 19.21 • Divisions of the bronchial tree and summary of its histological features. 684  FOLDER 19.2 Clinical Correlation: Cystic Fibrosis


Histology_Ross

Histology_Ross. Cystic fibrosis (CF, mucoviscidosis) is a chronic obstructive pulmonary disease of children and young adults. It is an autosomal recessive disorder caused by a mutation in a gene called the cystic fibrosis transmembrane conductance regulator (CFTR) located on chromosome 7. The product of this gene the Cl channel protein is involved in final alteration of mucus and digestive secretions, sweat, and tears. All mutations of CFTR gene results in abnormal epithelial transport of Cl that affects the viscosity of the secretion of the exocrine glands. Almost all exocrine glands secrete abnormally viscid mucus that obstructs the glands and their excretory ducts. The course of the disease is largely determined by the the CFTR gene could lead to the use of gene therapy in degree of pulmonary involvement. At birth, the lungs are the near future.


Histology_Ross

Histology_Ross. The course of the disease is largely determined by the the CFTR gene could lead to the use of gene therapy in degree of pulmonary involvement. At birth, the lungs are the near future. FIGURE F19.2.1 • Schematic diagram of pathology in cystic fibrosis. In cystic fibrosis, secretion of Cl anions into the lumen of the bronchial tree is markedly decreased because of a defective or nonexistent chloride channel protein. Na resorption from the lumen of the bronchial tree is then increased, causing movement of water into the cell. As a result, the mucous layer within the bronchial tree becomes dehydrated and viscous. This thick mucus is difficult to move by the mucociliary escalator mechanism, and it clogs the lumen of the bronchial tree, obstructing airflow.


Histology_Ross

Histology_Ross. normal. However, the defective Cl channel protein in the bronchial epithelium causes decreased Cl secretion and increased Na and water reabsorption from the lumen (Fig. F19.2.1). As a result, the “mucociliary escalator” malfunctions, with consequent accumulation of an unusually thick, viscous mucous secretion. The pulmonary lesion is probably initiated by obstruction of the bronchioles. Bronchiolar obstruction blocks the airways and leads to thickening of the bronchiole walls and to other degenerative changes in the alveoli. Because fluids remain trapped in the lungs, individuals with cystic fibrosis have frequent respiratory tract infections. The cloning of


Histology_Ross

Histology_Ross. Emphysema is a condition of the lung characterized by permanent enlargement of the air spaces distal to the ter-minal bronchiole. This enlargement is caused by chronic obstruction of airflow, most often because of narrowing of the bronchioles, and is accompanied by destruction of the alveolar wall (Fig. F19.3.1). Thus, significant area for gas exchange is lost in this disease. Emphysema is relatively common; it is seen in about half of all autopsies and is eas-ily recognized. Pathologists identify several types of em-physema. The severity of the disease is clinically more important, however, than recognition of the specific type. Emphysema is often caused by chronic inhalations of foreign particulate material such as coal dust, textile fibers, and construction dust. The most common cause, however, is cigarette smoking. The destruction of the alveolar wall may be associated with excess lysis of elastin and other structural proteins in the alveolar septa. Elastase and other proteases


Histology_Ross

Histology_Ross. however, is cigarette smoking. The destruction of the alveolar wall may be associated with excess lysis of elastin and other structural proteins in the alveolar septa. Elastase and other proteases are derived from lung neutrophils, macrophages, and monocytes. A specific genetic disease, 1-antitrypsin deficiency, causes a particularly severe form of emphy-sema in both heterozygous and homozygous individuals and/or chronic obstructive pulmonary disease (COPD). It is usually fatal in homozygotes if untreated, but its sever-ity can be reduced by supplying the enzyme inhibitor ex-ogenously. FIGURE F19.3.1 • Photomicrographs of emphysema and pneumonia. a. This photomicrograph from the lung of an individual with emphysema shows the partial destruction of interalveolar septa, resulting in permanent enlargement of the air spaces. Note that the changes in the lung parenchyma are accompanied by thickening of the wall of the pulmonary vessels (arrows) and the presence of numerous cells within the


Histology_Ross

Histology_Ross. enlargement of the air spaces. Note that the changes in the lung parenchyma are accompanied by thickening of the wall of the pulmonary vessels (arrows) and the presence of numerous cells within the air spaces. These cells are the alveolar macrophages and are shown at higher magnification in Figure 19.20. 240. b. This photomicrograph is from the lung of an individual in the early stages of acute pneumonia (inflammation of the lung). Note that the air spaces are filled with exudate containing white blood cells (mainly neutrophils), red blood cells, and fibrin. The capillaries in the alveolar septum are enlarged and congested with red blood cells. Pathologists recognize this stage as the red hepatization stage of the pneumonia. At this stage, the affected portion of the lung on gross examination appears red (because of enlarged capillaries), firm (because of the lack of air spaces), and heavy (because of the presence of exudate within the alveoli); the term hepatization stems from the


Histology_Ross

Histology_Ross. appears red (because of enlarged capillaries), firm (because of the lack of air spaces), and heavy (because of the presence of exudate within the alveoli); the term hepatization stems from the tissue’s resemblance to the liver. 240. Inset. Part of an alveolus at a higher magnification. Note the enlarged, congested capillary within the alveolar septum. The air space is filled with neutrophils and red blood cells. The lower right corner shows early organization of the intra-alveolar exudate; observe that the developing fibrin network contains entrapped neutrophils and several red blood cells. 420. aaaaa bbbbb  FOLDER 19.3 Clinical Correlation: Emphysema and Pneumonia


Histology_Ross

Histology_Ross. The lung has both pulmonary and bronchial circulations. The pulmonary circulation supplies the capillaries of the alveolar septum and is derived from the pulmonary artery that leaves the right ventricle of the heart. The branches of the pulmonary artery travel with those of the bronchi and bronchioles and carry blood down to the capillary level at the alveoli. This blood is oxygenated and collected by pulmonary venous capillaries that join to form venules. They ultimately form the four pulmonary veins that return blood to the left atrium of the heart. The pulmonary venous system is located at a distance from the respiratory passages at the periphery of the bronchopulmonary segments.


Histology_Ross

Histology_Ross. The bronchial circulation, via bronchial arteries that branch from the aorta, supplies all of the lung tissue other than the alveoli (i.e., the walls of the bronchi and bronchioles and the connective tissue of the lung other than that of the alveolar septum). The finest branches of the bronchial arterial tree also open into the pulmonary capillaries. Therefore, the bronchial and pulmonary circulations anastomose at about the level of the junction between the conducting and respiratory passages. Bronchial veins drain only the connective tissue of the hilar region of the lungs. Most of the blood reaching the lungs via the bronchial arteries leaves the lungs via the pulmonary veins.


Histology_Ross

Histology_Ross. A dual lymphatic drainage of the lungs parallels the dual blood supply. One set of lymphatic vessels drains the parenchyma of the lung and follows the air passages to the hilum. Lymph nodes are found along the route of the larger lymphatic vessels. A second set of lymphatic vessels drains the surface of the lung and travels in the connective tissue of the visceral pleura, a serous membrane consisting of a surface mesothelium and the underlying connective tissue. Most of the nerves that serve the lung are not visible at the level of the light microscope. They are components of the sympathetic and parasympathetic divisions of the autonomic nervous system and mediate reflexes that modify the dimensions of the air passages (and blood vessels) by contraction of the smooth muscle in their walls.


Histology_Ross

Histology_Ross. Olfactory mucosa is located in the roof and part of the walls of the nasal cavity. Its pseudostratified epithelium is thicker than that of nonsen-sory epithelium, and it serves as the receptor for smell. Olfactory epithelium consists of olfactory cells, supporting (sustentacular) cells, basal cells, and brush cells. Olfactory cells are bipolar neurons. The apex of the cell is expanded into the olfactory vesicle from which nonmotile cilia, the actual recep-tors, extend into surface secretions. The base of the cell tapers into an axonal process that enters the lamina propria and joins axons from other receptor cells to form the olfactory nerve. Large, cuboidal Schwann cells are a prominent feature of these axons, giving the nerve an un-usual appearance. Supporting cells are columnar cells with apical microvilli. They attach to the receptor cells through adhering junctions and provide me-chanical and metabolic support to the olfactory cells. Basal cells are stem cells from which


Histology_Ross

Histology_Ross. cells with apical microvilli. They attach to the receptor cells through adhering junctions and provide me-chanical and metabolic support to the olfactory cells. Basal cells are stem cells from which olfactory and supporting cells differentiate. Brush cells are the same cell type that occurs in nonsensory respiratory epithelium. The lamina propria is directly contiguous with periosteum. It contains numerous blood and lymphatic vessels, unmyelinated and myelinated nerves, and olfactory (Bowman’s) glands. These are tubuloalveolar serous glands whose watery secretion serves as a trap and solvent for odorant substances and continuously washes the olfactory surface.


Histology_Ross

Histology_Ross. Olfactory mucosa, nasal cavity, human, Azan ×75. This low-magnification orientation micrograph shows part of the wall of the nasal cavity. The olfactory mucosa (OM ) and adjacent ethmoid bone (EB ) are indicated. The olfactory mucosa is directly attached to the bone tissue; no submucosa is present. In this specimen, however, the mucosa is separated from the bone tissue because of shrinkage, a frequently encountered artifact. The olfactory epithelium (OEp) is pseudostratified, like respiratory epithelium; however, it is typically thicker. Note the respiratory epithelium (REp) included in the lower right of the micrograph. The feature that is most useful in identifying olfactory mucosa is the presence of numerous large, unmyelinated nerves (N ) and extensive olfactory (Bowman’s) glands (BG) in the connective tissue of the mucosa. Note that the adjacent respiratory mucosa lacks the nerves and exhibits a relative paucity of glands. Olfactory mucosa, nasal cavity, human, Azan ×375.


Histology_Ross

Histology_Ross. At this higher magnification, it is possible to distinguish in a general way the three principal cell types of the olfactory epithelium on the basis of nuclear location and appearance, as well as by certain cytoplasmic characteristics. For example, the nuclei of the supporting cells (SC ) are relatively dense and are located closest to the epithelial surface. They are arranged in an almost discrete single layer. The supporting cell has a cylindrical shape and extends from the basement membrane through the full thickness of the epithelium. Immediately beneath this layer are the cell bodies of the olfactory receptor cells (OC ). They lie at different levels within the thickness of the epithelium. Careful examination of the nuclei of these bipolar neuronal cells reveals that they contain more euchromatin than the nuclei of the supporting cells and often exhibit several nucleoli. In this preparation, the nucleoli appear as small round red bodies. In some cases, particularly when there is


Histology_Ross

Histology_Ross. euchromatin than the nuclei of the supporting cells and often exhibit several nucleoli. In this preparation, the nucleoli appear as small round red bodies. In some cases, particularly when there is shrinkage, the thin tapering dendritic process that extends to the olfactory surface may be observed. Similarly, an axonal process may sometimes be observed extending basally. The basal cells (BC ), the least numerous of the principal cell types, are characterized by their small round nuclei and scant cytoplasm. They are irregularly spaced and lie in proximity to the basement membrane. Note that the olfactory mucosa in contrast to respiratory mucosa lacks goblet cells.


Histology_Ross

Histology_Ross. The lamina propria contains numerous blood vessels (capillaries [C ], veins [V ]), lymphatics, olfactory nerves (N ), and olfactory (Bowman’s) glands (BG ). The Bowman’s glands are branched tubuloalveolar structures. They exhibit a very small lumen (arrows). The duct elements extend from the secretory portion of the gland beginning in close proximity to the overlying epithelium (arrowhead) and pass directly through the epithelium to deliver their secretions at the surface. The ducts are very short, making it difficult to identify them. The very thin axonal processes (AP ) of the olfactory cells are sometimes evident within the lamina propria prior to being ensheathed by Schwann cells to form the prominent olfactory nerves. The nuclei present within the olfactory nerves represent Schwann cell nuclei (ScC ).


Histology_Ross

Histology_Ross. KEY A, artery AP, axonal process BC, basal cells BG, Bowman’s glands C, capillary EB, ethmoid bone ES, ethmoid sinus N, olfactory nerves OC, olfactory cells OEp, olfactory epithelium OM, olfactory mucosa REp, respiratory epithelium SC, supporting cell nuclei ScC, Schwann cell nuclei V, vein arrows, lumina of Bowman’s glands arrowhead, duct of a Bowman’s gland entering epithelium


Histology_Ross

Histology_Ross. The larynx is the passageway for air between the oropharynx and the trachea that functions in the production of sound. It consists of a carti-laginous framework to which both extrinsic and intrinsic muscles are attached and a mucosal surface that varies in character from pseudos-tratified to stratified squamous in regions subject to abrasion by the air stream. The muscles move certain cartilages with respect to others, thus increasing or decreasing the opening of the rima glottis and increasing or decreasing the tension on the vocal folds (cords). In this way, vibrations of different wavelengths are generated in the passing air, and sound is produced. Larynx, monkey, H&E ×15.


Histology_Ross

Histology_Ross. Larynx, monkey, H&E ×15. The vocal folds are ridge-like structures that are oriented in an anteroposterior (ventral-dorsal) direction. In frontal sections, the vocal folds (VF ) are cross-sectioned, giving the appearance seen here. The two vocal folds and the space between them constitute the glottis. Just above each vocal fold is an elongated recess called the ventricle (V ), and above the ventricle is another ridge called the ventricular fold (VnF ) or, sometimes, the false vocal fold. Below and lateral to the vocal folds are the vocalis muscles (VM ). Within the vocal fold is a considerable amount of elastic material, although it is usually not evident in routine H&E preparations. This elastic material is part of the vocal ligament. It lies in an anteroposterior direction within the substance of the vocal fold and plays an important role in phonation.


Histology_Ross

Histology_Ross. Ventricular and vocal folds, larynx, monkey, H&E ×160. the contact between surfaces is considerable. Laterally, the surfaces consist of stratified columnar epithelium (SCE). The contact between these surfaces The surfaces of a vocal fold and the facing ventricular fold is less wearing. Small glands (Gl) are in the lamina propria of the laryngeal within rectangle 1 in top figure are turned 90° clockwise and mucosa. shown at higher magnification in this figure. Medially, both are lined by stratified squamous epithelium (SSE). Here, Infraglottic cavity, larynx, monkey, H&E ×160. infraglottic cavity. It shows the junction between the stratified squamous epithelium (SSE ), with its flat surface cells, and the stratified columnar


Histology_Ross

Histology_Ross. Infraglottic cavity, larynx, monkey, H&E ×160. infraglottic cavity. It shows the junction between the stratified squamous epithelium (SSE ), with its flat surface cells, and the stratified columnar Rectangle 2 in top figure is shown at higher magnification in epithelium (SCE ), with its columnar surface cells. The lamina propria this figure. This area of the larynx below the ventricles and consists of loose connective tissue in which glands (Gl ) are present. rima glottidis communicates with trachea and is called the Infraglottic cavity, larynx, monkey, H&E ×160.


Histology_Ross

Histology_Ross. Epithelium of the infraglottic cavity of the larynx just below the portion shown in top figure changes again, giving way, below, to the ciliated pseudostratified columnar epithelium (PSE) shown here. Note the cylinders of cytoplasm that clearly indicate the columnar nature of the surface cells. In the upper part of the figure, the epithelium is stratified columnar; in the lower part of the figure, it is pseudostratified columnar. This distinction is difficult to make from the examination of a single sample such as that shown here, and other information is needed to make the assessment. The additional information is the presence of cilia on the pseudostratified columnar epithelium; this epithelium is typically ciliated. Although not evident in the photomicrographs, note that stratified columnar epithelium has a very limited distribution, usually occurring between stratified squamous epithelium and some other epithelial types (e.g., pseudostratified columnar here or simple columnar at


Histology_Ross

Histology_Ross. epithelium has a very limited distribution, usually occurring between stratified squamous epithelium and some other epithelial types (e.g., pseudostratified columnar here or simple columnar at the anorectal junction, Plate 64). The lamina propria is a loose cellular connective tissue, and it also shows some glands (Gl ).


Histology_Ross

Histology_Ross. KEY Gl, glands PSE, pseudostratified columnar epithelium SCE, stratified columnar epithelium SSE, stratified squamous epithelium V, ventricles VF, vocal folds VM, vocalis muscles VnF, ventricular folds


Histology_Ross

Histology_Ross. The trachea is a short tube about 2.5 cm in diameter and about 10 cm long. It extends from the larynx to about the middle of the thorax, where it divides into the two main bronchi (primary bronchi). Its major function is to serve as a conduit for air. The lumen of the trachea is held open by a series of C-shaped hyaline cartilages that are stacked on one another to form a supporting structure. Fibroelastic tissue and smooth muscle (the trachealis muscle) bridge the gap between the free ends of the cartilages at the posterior border of the trachea, adja-cent to the esophagus. Typical respiratory (ciliated pseudostratified columnar) epithelium lines the trachea and primary bronchi. On entering the lungs, the primary bronchi branch immediately to give rise to the lobar bronchi (secondary bronchi) that supply the two lobes of the left lung and the three lobes of the right lung. Within the lung, the C-shaped cartilages are replaced by an investment of (some-times overlapping) cartilaginous


Histology_Ross

Histology_Ross. that supply the two lobes of the left lung and the three lobes of the right lung. Within the lung, the C-shaped cartilages are replaced by an investment of (some-times overlapping) cartilaginous plates that completely surround the bronchi.


Histology_Ross

Histology_Ross. Trachea, human, H&E ×90. This low-magnification micrograph of the posterior wall of the human trachea shows the pseudostratified ciliated columnar epithelium (EP ) subtended by a well-developed basement membrane (Bm). The basement membrane, which consists of tightly packed, fine collagen fibers, is actually an unusually thick and dense reticular layer and is, thus, part of the lamina propria. It is particularly distinct in the human trachea and may thicken with Trachea, human H&E ×65. This micrograph shows the wall of the trachea at the level of one end of the C-shaped tracheal cartilage (TC ). The portion of the pseudostratified ciliated columnar epithelium (EP ) does not exhibit as many goblet cells as are seen in the figure above. However, the basement membrane (Bm) is clear, as are the cellular lamina propria (LP ) and the submucosa (SM ) of the tra- Trachea, human, H&E ×250; inset ×500.


Histology_Ross

Histology_Ross. In this higher-magnification micrograph of the tracheal wall and in the inset, the cilia of the pseudostratified ciliated columnar epithelium (EP ) are particularly well demonstrated, as is the dense line (BB) formed by the basal bodies of the cilia in the apical cytoplasm of the epithelial cells. Goblet cells (GC ) are easily recognized, and the displacement of the flattened nucleus (N ) toward the base of the cell is well demonstrated. The thickness chronic irritation, as in smokers. Numerous goblet cells (GC ) are evident as clear ovoid spaces in the respiratory epithelium. A thin lamina propria (LP ) and a dense thick submucosa (SM ) underlie the respiratory epithelium. Seromucous glands (Gl ) are seen on both sides of the trachealis muscle (TM), a band of smooth muscle that fills the gap between the posterior ends of the C-shaped tracheal cartilages (not shown) and serves to separate the trachea from the esophagus. Adipose tissue (Ad ) is also present in the submucosa between


Histology_Ross

Histology_Ross. the gap between the posterior ends of the C-shaped tracheal cartilages (not shown) and serves to separate the trachea from the esophagus. Adipose tissue (Ad ) is also present in the submucosa between the esophagus and trachea.


Histology_Ross

Histology_Ross. chea. Again, seromucous glands (Gl ) are evident beneath the submucosa. The ends of the bundles of the trachealis muscle (TM ) are located toward the posterior midline from the glands. A small lymphatic nodule (LN ) is located adjacent to the end of one of the bundles. A significant amount of adipose tissue (Ad ) is found in the connective tissue between the trachealis muscle and the wall of the esophagus (not shown in this figure). and the density of the basement membrane (Bm) are more easily seen here than in the lower-magnification views in the other figures. A venule (V ) containing red cell ghosts is seen in the middle of the submucosa, and some inflammatory cells (IC ), probably lymphocytes, are seen adjacent to the vein as well as distributed lightly through the submucosa and more densely in the lamina propria. Portions of the seromucous glands (Gl ) are just visible at the bottom edge of the figure.


Histology_Ross

Histology_Ross. KEY Ad, adipose tissue BB, brush border Bm, basement membrane C, cilia EP, epithelium GC, goblet cells Gl, glands IC, inflammatory cells LN, lymphatic nodule LP, lamina propria N, nuclei of goblet cells SM, submucosa TC, tracheal cartilage TM, trachealis muscle V, vein


Histology_Ross

Histology_Ross. The primary bronchus that enters each lung divides into smaller secondary and tertiary bronchi. As the bronchi become smaller, some compo-nents of the wall are lost or reduced in amount. Ultimately, the respiratory passage has distinctly different features than those of a bronchus, and it is called a bronchiole. The features that characterize the bronchiole are the absence of cartilage, loss of submucosal glands, and grad-ual disappearance of goblet cells. The epithelium changes from pseudostratified columnar to simple ciliated columnar, and some columnar cells even lack cilia. Smooth muscle occupies a relatively larger portion of the bronchiolar wall than of the bronchial wall. The smallest diameter conducting bronchioles, the terminal bronchioles, are lined with simple ciliated cuboidal epithelium in which Clara cells, cells that secrete a surface-active agent that prevents luminal adhesion of bronchiolar walls during expiration, are found among the cili-ated cells. Respiratory


Histology_Ross

Histology_Ross. epithelium in which Clara cells, cells that secrete a surface-active agent that prevents luminal adhesion of bronchiolar walls during expiration, are found among the cili-ated cells. Respiratory bronchioles are the first part of the bronchial tree that allows gas exchange to occur. Respiratory bronchioles consti-tute a transition zone in which both air conduction and gas exchange occur. Scattered, thin-walled evaginations of the lumen of the respiratory bronchiole are called alveoli; these are the structures in which gas exchange between the air passages and the blood capillaries occurs.


Histology_Ross

Histology_Ross. Bronchiole, lungs, human, H&E ×75. A typical bronchiole is shown here. Characteristically, blood vessels (BV ) are adjacent to the bronchiole. The main features of the bronchiolar wall that are evident in the figure are bundles of smooth muscle (SM ) and the lining epithelium (shown at higher magnification in Plate 73). Higher magnification would reveal that the epithelium is ciliated. The connective tissue is mini mal and, at this low magnification, not conspicuous. Nevertheless, it is present and separates the muscle into bundles (i.e., the muscle layer is not a single continuous layer). The connective tissue contains collagenous and some elastic fibers. Glands are not present in the wall of the bronchiole. Surrounding the bronchiole, comprising most of the lung substance, are the air spaces or alveoli of the lung. Bronchiole and respiratory bronchioles, lungs, human, H&E ×75.


Histology_Ross

Histology_Ross. Bronchiole and respiratory bronchioles, lungs, human, H&E ×75. In this figure, a short length of a bronchiole (B) is shown longitudinally sectioned as it branches into two respiratory bronchioles (RB ). The last portion of a bronchiole that leads into respiratory bronchioles is called a terminal bronchiole. It is not engaged in exchange of air with the blood; the respiratory bronchiole does engage in air exchange. Arrows mark the place where the terminal bronchiole ends. Not uncommonly, as shown here, cartilage (C ) is found in the bronchiolar wall where branching occurs. Blood vessels (BV ) and a nodule of lymphocytes (L) are adjacent to the bronchiole.


Histology_Ross

Histology_Ross. The respiratory bronchiole has a wall composed of two components: One consists of recesses that have a wall similar to that of the alveoli and are thus capable of gas exchange; the other has a wall formed by small cuboidal cells that appear to rest on a small bundle of eosinophilic material. This is smooth muscle surrounded by a thin investment of connective tissue. Both of these components are shown at higher magnification in Plate 73. Alveoli, lungs, human, H&E ×75. The outer surface of lung tissue is the serosa (S); it consists of a lining of mesothelial cells resting on a small amount of connective tissue. This is the The most distal component of the respiratory passage is the layer that gross anatomists refer to as the visceral pleura. alveolus. Groups of alveoli clustered together and sharing a common opening are referred to as an alveolar sac (AS). Alveoli that form a tube are referred to as alveolar ducts (AD).


Histology_Ross

Histology_Ross. alveolus. Groups of alveoli clustered together and sharing a common opening are referred to as an alveolar sac (AS). Alveoli that form a tube are referred to as alveolar ducts (AD). KEY AD, alveolar ducts AS, alveolar sacs B, bronchiole BV, blood vessels C, cartilage L, nodule of lymphocytes RB, respiratory bronchiole S, serosa SM, smooth muscle arrows, end of terminal bronchiole PLATE 73 Terminal Bronchiole, Respiratory Bronchiole, and Alveolus


Histology_Ross

Histology_Ross. Respiratory bronchioles continue to divide to form alveolar ducts, passages lined solely with rows of alveoli that have rings of smooth muscle in knob-like interalveolar septa. The alveolar ducts terminate in alveolar sacs, enlarged spaces surrounded by clusters of alveoli that open into the spaces. The alveoli are lined with type I alveolar cells, extremely thin squamous cells that cover about 95% of the alveolar surface, and with type II alveolar cells, cuboidal cells that secrete surfactant, a surface-active agent that reduces surface tension at the air-epithelium surface. The tissue between adjacent alveoli is called the alveolar septum. This consists of the alveolar epithelial cells and their basal lamina, the basal lamina of the underlying capillary endothelium and the endothelial cells, themselves, and any other connective tissue elements that may lie between the two basal laminae. The alveolar septum is the site of the air-blood barrier.


Histology_Ross

Histology_Ross. Terminal bronchiole, lungs, human, H&E ×550. The histologic features of the terminal bronchiolar wall are shown here. Ciliated epithelium extends from the top of the figure to the diamond. This is ciliated pseudostratified columnar epithelium (PsEp). Some basal cells are still present and, therefore, the designation pseudostratified columnar. Elsewhere, the epithelium might be ciliated simple columnar, and just be Respiratory bronchiole, lungs, human, H&E ×550.


Histology_Ross

Histology_Ross. Respiratory bronchiole, lungs, human, H&E ×550. The wall of a respiratory bronchiole is shown here and in lower left figure. The alveoli (A) are terminal air spaces on the left in each of the two figures. The lumen of the respiratory bronchiole is on the right. Characteristically, the wall of the respiratory bronchiole consists of alternating thick and fore it becomes a respiratory bronchiole, the epithelium may include cuboidal or low columnar nonciliated cells. These nonciliated cells are Clara cells (CC, beyond the diamond). Clara cells produce a surface-active agent that is instrumental in expansion of the lungs. The smooth muscle (SM) in the bronchiolar wall is organized in bundles; other cells under the epithelium and around the smooth muscle belong to the connective tissue.


Histology_Ross

Histology_Ross. thin regions. The thick regions are similar to the wall of the bronchiole except that cuboidal Clara cells instead of columnar epithelium form the surface. Thus, as seen here, Clara cells (CC) are the surface-lining cells of the thick regions, and smooth muscle bundles (SM) are under the Clara cells, with a small amount of intervening connective tissue. The thin regions have a wall similar to the alveolar wall; this is considered below. Respiratory bronchiole, lungs, human, H&E ×550. Structurally, it shows essentially the same features as those seen in upper right figure except that there are fewer Clara cells and the smooth muscle is The respiratory bronchiole shown in lower left figure is somewhat thinner. slightly more distal than the area seen in top right figure. Alveolus, lungs, human, H&E ×800.


Histology_Ross

Histology_Ross. The respiratory bronchiole shown in lower left figure is somewhat thinner. slightly more distal than the area seen in top right figure. Alveolus, lungs, human, H&E ×800. The central component of the alveolar wall is the capillary (C) and, in certain locations, associated connective tissue. On each side, where it faces the alveolus (A), a flat squamous cell is interposed between the capillary and the air spaces. This is a pneumocyte type I cell. In some places, the type I cell is sep arated from the capillary endothelial cell by a single basal lamina shared by the two cells. This is the thin portion of the alveolar-capillary complex, readily seen in the upper part of the figure (arrows). Gas exchange occurs through the thin portion of the alveolar-capillary complex. Elsewhere, connective tissue is interposed between the pneumocyte type I cell and the endothelial cell of the capillary; each of these epithelial cells retains its own basal lamina.


Histology_Ross

Histology_Ross. A second cell type, the pneumocyte type II cell or septal cell (SC), also lines the alveolar air space. This cell typically displays a rounded (rather than flattened) shape, and the nucleus is surrounded by a noticeable amount of cytoplasm, some of which may appear clear. The septal cell produces a surface-active agent different from that of the Clara cell, which also acts in permitting the lung to expand. KEY A, alveolus C, capillary CC, Clara cells PsEp, pseudostratified squamous epithelium SC, septal cell SM, smooth muscle arrows, thin portion of alveolar-capillary complex diamond, junction between pseudostratified columnar epithelium and Clara cells PLATE 73


Histology_Ross

Histology_Ross. OVERVIEW OF THE URINARY SYSTEM / 698 GENERAL STRUCTURE OF THE KIDNEY / 699 Capsule / 699 Cortex and Medulla / 700 Kidney Lobes and Lobules / 701 The Nephron / 702 General Organization of the Nephron / 702 Tubes of the Nephron / 703 Types of Nephrons / 703 Collecting Tubules and Ducts / 703 Filtration Apparatus of the Kidney / 705 Mesangium / 710 Juxtaglomerular Apparatus / 711 KIDNEY TUBULE FUNCTION / 714 Proximal Convoluted Tubule / 715 Proximal Straight Tubule / 716 Thin Segment of Loop of Henle / 717 Distal Straight Tubule / 718 Distal Convoluted Tubule / 718 Collecting Tubules and Collecting Ducts / 719 INTERSTITIAL CELLS / 720 HISTOPHYSIOLOGY OF THE KIDNEY / 720 BLOOD SUPPLY / 721 LYMPHATIC VESSELS / 723 NERVE SUPPLY / 723 URETER, URINARY BLADDER, AND URETHRA / 723 Ureters / 725 Urinary Bladder / 726 Urethra / 726 Folder 20.1 Functional Considerations: Kidney and Vitamin D / 699 Folder 20.2 Clinical Correlation: Antiglomerular Basement Membrane Antibody-Induced


Histology_Ross

Histology_Ross. Ureters / 725 Urinary Bladder / 726 Urethra / 726 Folder 20.1 Functional Considerations: Kidney and Vitamin D / 699 Folder 20.2 Clinical Correlation: Antiglomerular Basement Membrane Antibody-Induced Glomerulonephritis; Goodpasture Syndrome / 712 Folder 20.3 Clinical Correlation: Examination of the Urine—Urinalysis / 714 Folder 20.4 Clinical Correlation: Renin–Angiotensin–Aldosterone System and Hypertension / 714 Folder 20.5 Functional Considerations: Structure and Function of Aquaporin Water Channels / 717 Folder 20.6 Functional Considerations: Hormonal Regulation of Collecting Duct Function / 721


Histology_Ross

Histology_Ross. The urinary system consists of the paired kidneys; paired ureters, which lead from the kidneys to the urinary bladder; and the urethra, which leads from the bladder to the exterior of the body. The kidneys conserve body fluid and electrolytes and remove metabolic waste. Like the lungs and liver, the kidneys retrieve essential materials and dispose of wastes. They conserve water, essential electrolytes, and metabolites, and they remove certain waste products of metabolism from the body. The kidneys play an important role in regulating and maintaining the composition and volume of extracellular fluid. They also are essential in maintaining acid–base balance by excreting hydrogen ions when bodily fluids become too acidic or excreting bicarbonates when bodily fluids become too basic.


Histology_Ross

Histology_Ross. The kidneys are highly vascular organs; they receive approximately 25% of the cardiac output. The kidneys produce urine, initially a glomerular ultrafiltrate of the blood or primary urine, which is then modified by selective resorption  FOLDER 20.1 Functional Considerations: Kidney and Vitamin D


Histology_Ross

Histology_Ross. Despite its name, vitamin D is actually an inactive precursor that undergoes a series of transformations to become the fully active hormone that regulates plasma calcium levels. In the human body vitamin D is derived from two sources:  Skin, in which vitamin D3 (cholecalciferol) is rapidly produced by the action of ultraviolet light on the precur-sor 7-dehydrocholesterol. The skin is the major source of vitamin D3, especially in regions where food is not supple-mented with vitamin D. Typically, 30 minutes to 2 hours of sunlight exposure per day can provide enough vitamin D to fulfill daily body requirements for this vitamin.  Diet, from which vitamin D3 is absorbed by the small intestine in association with chylomicrons. In the blood vitamin D3 is bound to vitamin D–binding protein and transported to the liver. The first transforma-tion occurs in the liver and involves hydroxylation of vitamin D3 to form 25-OH vitamin D3. This compound is released into the bloodstream and undergoes


Histology_Ross

Histology_Ross. transported to the liver. The first transforma-tion occurs in the liver and involves hydroxylation of vitamin D3 to form 25-OH vitamin D3. This compound is released into the bloodstream and undergoes a second hydroxyla-tion in the proximal tubules of the kidney to produce the highly active 1,25-(OH)2 vitamin D3 (calcitriol). The pro-cess is regulated indirectly by an increase in plasma Ca2concentration, which triggers secretion of PTH, or directly by a decrease in circulating phosphates, which in turn stim-ulates activity of 1 -hydroxylase responsible for conver-sion of 25-OH vitamin D3 into active 1,25-(OH)2 vitamin D3. Active 1,25-(OH)2 vitamin D3 stimulates intestinal absorption of Ca2and phosphate and mobilization of Ca2from bones. It is therefore necessary for normal development and growth of bones and teeth. The related compound vitamin D2 (ergocalciferol) undergoes the same conversion steps as vitamin D3 and produces the same biologic effects. Patients with end-stage chronic


Histology_Ross

Histology_Ross. growth of bones and teeth. The related compound vitamin D2 (ergocalciferol) undergoes the same conversion steps as vitamin D3 and produces the same biologic effects. Patients with end-stage chronic kidney diseases have inadequate conversion of vitamin D into active metabolites resulting in vitamin D3 deficiency. In adults, vitamin D3 defi-ciency is manifested by impaired bone mineralization and reduced bone density. Therefore, patients with chronic kidney diseases, especially those on prolonged renal hemodialysis are often supplemented with vitamin D3 and calcium to avoid severe disturbance of calcium homeostasis because of sec-ondary hyperparathyroidism, a condition prevalent in these patients. Vitamin D3 deficiency in childhood results in rickets, a disease that causes abnormal bone ossification.


Histology_Ross

Histology_Ross. and specific secretion by the cells of the kidney. The final urine is conveyed by the ureters to the urinary bladder, where it is stored until discharged via the urethra. The final urine contains water and electrolytes as well as waste products, such as urea, uric acid, and creatinine, and breakdown products of various substances. The kidney also functions as an endocrine organ. Endocrine activities of the kidneys include  Synthesis and secretion of the glycoprotein hormone erythropoietin (EPO), which acts on the bone marrow and regulates red blood cell formation in response to decreased blood oxygen concentration. EPO is synthesized by endothelial cells of the peritubular capillaries in the renal cortex and acts on specific receptors expressed on the surface of erythrocyte progenitor (Er-P) cells in the bone marrow.


Histology_Ross

Histology_Ross. The recombinant form of erythropoietin (RhEPO) is used for the treatment of anemia in patients with end-stage renal disease. It is also used to treat anemia resulting from bone marrow suppression that develops in AIDS patients undergoing treatment with antiretroviral drugs, such as azidothymidine (AZT).  Synthesis and secretion of the acid protease renin, an enzyme involved in control of blood pressure and blood volume. Renin is produced by juxtaglomerular cells and cleaves circulating angiotensinogen to release angiotensin I (see page 713).  Hydroxylation of 25-OH vitamin D3, a steroid precursor produced in the liver, to hormonally active 1,25-(OH)2 vitamin D3. This step is regulated primarily by parathyroid hormone (PTH), which stimulates activity of the enzyme 1-hydroxylase and increases the production of the active hormone (see Folder 20.1).


Histology_Ross

Histology_Ross. The kidneys are large, reddish, bean-shaped organs located on either side of the spinal column in the retroperitoneal space of the posterior abdominal cavity. They extend from the 12th thoracic to the 3rd lumbar vertebrae, with the right kidney positioned slightly lower. Each kidney measures approximately 10 cm long 6.5 cm wide (from concave to convex border) 3 cm thick. On the upper pole of each kidney, embedded within the renal fascia and a thick protective layer of perirenal adipose tissue, lies an adrenal gland. The medial border of the kidney is concave and contains a deep vertical fissure, called the hilum, through which the renal vessels and nerves pass and the expanded, funnel-shaped origin of the ureter, called the renal pelvis, exits. A section through the kidney shows the relationship of these structures as they lie just within the hilum of the kidney in a space called the renal sinus (Fig. 20.1). Although not shown in the illustration, the space between and around these


Histology_Ross

Histology_Ross. of these structures as they lie just within the hilum of the kidney in a space called the renal sinus (Fig. 20.1). Although not shown in the illustration, the space between and around these structures is filled largely with loose connective tissue and adipose tissue.


Histology_Ross

Histology_Ross. The kidney surface is covered by a connective tissue capsule. The capsule consists of two distinct layers: an outer layer of fibroblasts and collagen fibers, and an inner layer with a cellular component of myofibroblasts (Fig. 20.2). The contractility of FIGURE 20.1 • Diagram of kidney structure. The diagram represents a hemisection of a kidney, revealing its structural organization. the myofibroblasts may aid in resisting volume and pressure variations that can accompany variations in kidney function. Its specific role, however, is unknown. The capsule passes inward at the hilum, where it forms the connective tissue covering of the sinus and becomes continuous with the connective tissue forming the walls of the calyces and renal pelvis (see Fig. 20.1). Examination with the naked eye of the cut face of a fresh, hemisected kidney reveals that its substance can be divided into two distinct regions:  Cortex, the outer reddish brown part  Medulla, the much lighter-colored inner part


Histology_Ross

Histology_Ross. The color seen in the cut surface of the unfixed kidney reflects the distribution of blood in the organ. Approximately 90% to 95% of the blood passing through the kidney is in the cortex; 5% to 10% is in the medulla. The cortex is characterized by renal corpuscles and their associated tubules. The cortex consists of renal corpuscles along with the convoluted tubules and straight tubules of the nephron, the collecting tubules, collecting ducts, and an extensive vascular supply. The nephron is the basic functional unit of the kidney and is described in a following section. The renal corpuscles are spherical structures, barely visible with the naked eye. They constitute the beginning segment of the nephron and contain a unique capillary network called a glomerulus. Examination of a section cut through the cortex at an angle perpendicular to the surface of the kidney reveals a series of FIGURE 20.2 • Photomicrograph of human kidney capsule.


Histology_Ross

Histology_Ross. Examination of a section cut through the cortex at an angle perpendicular to the surface of the kidney reveals a series of FIGURE 20.2 • Photomicrograph of human kidney capsule. This photomicrograph of a Mallory-Azan–stained section shows the capsule (cap) and part of the underlying cortex. The outer layer of the capsule (OLC) is composed of dense connective tissue. The fibroblasts in this part of the capsule are relatively few in number; their nuclei appear as narrow, elongate, red-staining profiles against a blue background representing the stained collagen fibers. The inner layer of the capsule (ILC) consists of large numbers of myofibroblasts whose nuclei appear as round or elongate, red-staining profiles, depending on their orientation within the section. Note that the collagen fibers in this layer are relatively sparse and that the myofibroblast nuclei are more abundant than those of the fibroblasts in the outer layer of the capsule. 180.


Histology_Ross

Histology_Ross. vertical striations that appear to emanate from the medulla (see Fig 20.1). These striations are the medullary rays (of Ferrein). Their name reflects their appearance, as the striations seem to radiate from the medulla. Approximately 400 to 500 medullary rays project into the cortex from the medulla. Each medullary ray is an aggregation of straight tubules and collecting ducts. Each medullary ray contains straight tubules of the nephrons and collecting ducts. The regions between medullary rays contain the renal corpuscles, the convoluted tubules of the nephrons, and the collecting tubules. These areas are referred to as cortical labyrinths. Each nephron and its collecting tubule (which connects to a collecting duct in the medullary ray) form the uriniferous tubule. The medulla is characterized by straight tubules, collecting ducts, and a special capillary network, the vasa recta.


Histology_Ross

Histology_Ross. The medulla is characterized by straight tubules, collecting ducts, and a special capillary network, the vasa recta. The straight tubules of the nephrons and the collecting ducts continue from the cortex into the medulla. They are accompanied by a capillary network, the vasa recta, that runs in parallel with the various tubules. These vessels represent the vascular part of the countercurrent exchange system that regulates the concentration of the urine.


Histology_Ross

Histology_Ross. The tubules in the medulla, because of their arrangement and differences in length, collectively form a number of conical structures called pyramids. Usually 8 to 12 but as many as 18 pyramids may be present in the human kidney. The bases of the pyramids face the cortex, and the apices face the renal sinus. Each pyramid is divided into an outer medulla (adjacent to the cortex) and an inner medulla. The outer medulla is further subdivided into an inner stripe and an outer stripe. The zonation and stripes are readily recognized in a sagittal section through the pyramid of a fresh specimen. They reflect the location of distinct parts of the nephron at specific levels within the pyramid (Fig. 20.3). The renal columns represent cortical tissue contained within the medulla.


Histology_Ross

Histology_Ross. The renal columns represent cortical tissue contained within the medulla. The caps of cortical tissue that lie over the pyramids are sufficiently extensive that they extend peripherally around the lateral portion of the pyramid, forming the renal columns (of Bertin). Although renal columns contain the same components as the rest of the cortical tissue, they are regarded as part of the medulla. In effect, the amount of cortical tissue is so extensive that it “spills” over the side of the pyramid much as a large scoop of ice cream extends beyond and overlaps the sides of an ice cream cone.


Histology_Ross

Histology_Ross. The apical portion of each pyramid, which is known as the papilla, projects into a minor calyx, a cup-shaped structure that represents an extension of the renal pelvis. The tip of the papilla, also known as the area cribrosa, is perforated by the openings of the collecting ducts (Fig. 20.4). The minor calyces are branches of the two or three major calyces that in turn are major divisions of the renal pelvis (see Fig. 20.1). The number of lobes in a kidney equals the number of medullary pyramids.


Histology_Ross

Histology_Ross. The number of lobes in a kidney equals the number of medullary pyramids. Each medullary pyramid and the associated cortical tissue at its base and sides (one half of each adjacent renal column) constitutes a lobe of the kidney. The lobar organization of the kidney is conspicuous in the developing fetal kidney (Fig. 20.5). Each lobe is reflected as a convexity on the outer surface of the organ, but they usually disappear after birth. The surface convexities typical of the fetal kidney may persist, however, until the teenage years and, in some cases, into adulthood. Each human kidney contains 8 to 18 lobes. Kidneys of some animals possess only one pyramid; these kidneys are classified as unilobar, in contrast to the multilobar kidney of the human. A lobule consists of a collecting duct and all the nephrons that it drains.


Histology_Ross

Histology_Ross. A lobule consists of a collecting duct and all the nephrons that it drains. The lobes of the kidney are further subdivided into lobules consisting of a central medullary ray and surrounding cortical material (Fig. 20.6 and Plate 75, page 730). Although the center or axis of a lobule is readily identifiable, the


Histology_Ross

Histology_Ross. FIGURE 20.3 • Diagram of two types of nephrons in the kidney and their associated collecting duct systems. A long-looped nephron is shown on the left, and a short-looped nephron is shown on the right. The relative position of the cortex, medulla, papilla, and capsule are indicated. The inverted cone-shaped area in the cortex represents a medullary ray. The parts of the nephron are indicated by number: 1, renal corpuscle including the glomerulus and Bowman’s capsule; 2, proximal convoluted tubule; 3, proximal straight tubule; 4, descending thin limb; 5, ascending thin limb; 6, thick ascending limb (distal straight tubule); 7, macula densa located in the final portion of the thick ascending limb; 8, distal convoluted tubule; 9, connecting tubule; 9*, collecting tubule that forms an arch (arched collecting tubule); 10, cortical collecting duct; 11, outer medullary collecting duct; and 12, inner medullary collecting duct. (Modified from Kriz W, Bankir


Histology_Ross

Histology_Ross. L. A standard nomenclature for structures of the kidney. The Renal Commission of the International Union of Physiological Sciences (IUPS). Kidney Int 1988;33:1–7.) boundaries between adjacent lobules are not obviously demarcated from one another by connective tissue septa. The concept of the lobule has an important physiologic basis; the medullary ray containing the collecting duct for a group of nephrons that drain into that duct constitutes the renal secretory unit. It is the equivalent of a glandular secretory unit or lobule.


Histology_Ross

Histology_Ross. FIGURE 20.4 • Renal papilla and calyx. a. This scanning electron micrograph shows the conical structure that represents the renal papilla, projecting into the renal calyx. The apex of the papilla contains openings (arrows) of the collecting ducts (of Bellini). These ducts deliver urine from the pyramids to the minor calyx. The surface of the papilla containing the openings is designated the area cribrosa. (Courtesy of Dr. C. Craig Tisher.) b. Photomicrograph of an H&E–stained specimen of the papilla, showing the distal portion of the collecting ducts opening into the minor calyx. 120. The Nephron The nephron is the structural and functional unit of the kidney.


Histology_Ross

Histology_Ross. The Nephron The nephron is the structural and functional unit of the kidney. The nephron is the fundamental structural and functional unit of the kidney (see Fig. 20.3). Each human kidney contains approximately 2 million nephrons. Nephrons are responsible for the production of urine and correspond to the secretory part of other glands. The collecting ducts are responsible for the final concentration of the urine and are analogous to the ducts of exocrine glands that modify the concentration of the secretory product. Unlike the typical exocrine gland in which the secretory and duct portions arise from a single epithelial outgrowth, nephrons and their collecting tubules arise from separate primordia and only later become connected. General Organization of the Nephron The nephron consists of the renal corpuscle and a tubule system.


Histology_Ross

Histology_Ross. General Organization of the Nephron The nephron consists of the renal corpuscle and a tubule system. As stated previously, the renal corpuscle represents the beginning of the nephron. It consists of the glomerulus, a tuft of capillaries composed of 10 to 20 capillary loops, surrounded by a double-layered epithelial cup, the renal or Bowman’s capsule. Bowman’s capsule is the initial portion of the nephron, where blood flowing through the glomerular capillaries undergoes filtration to produce the glomerular ultrafiltrate. The glomerular capillaries are supplied by an afferent arteriole and are drained by an efferent arteriole that then branches, forming a new capillary network to supply the kidney tubules. The site where the afferent and efferent arterioles penetrate and exit from the parietal layer of Bowman’s capsule is called the vascular pole. Opposite this site is the urinary pole of the renal corpuscle, where the proximal convoluted tubule begins (see Fig. 20.7).


Histology_Ross

Histology_Ross. Continuing from Bowman’s capsule, the remaining parts of the nephron (the tubular parts) are as follows:  Proximal thick segment, consisting of the proximal con voluted tubule (pars convoluta) and the proximal straight tubule (pars recta) Thin segment, which constitutes the thin part of the loop of Henle  Distal thick segment, consisting of the distal straight tubule (pars recta) and the distal convoluted tubule (pars The distal convoluted tubule connects to the collecting tubule, often through a connecting tubule, thus forming the uriniferous tubule (i.e., the nephron plus collecting tubule; see Fig. 20.3). FIGURE 20.5 • Photomicrograph of fetal kidney. This photo-micrograph of an H&E–stained human fetal kidney shows the cortex, the medulla, and two associated pyramids. Note each surface convexity corresponds to a kidney lobe. During postnatal life the lobar convexities disappear and the kidney then exhibits a smooth surface. 30. Tubes of the Nephron


Histology_Ross

Histology_Ross. Tubes of the Nephron The tubular segments of the nephron are named according to the course that they take (convoluted or straight), location (proximal or distal), and wall thickness (thick or thin). Beginning from Bowman’s capsule, the sequential parts of the nephron consist of the following tubules:  Proximal convoluted tubule originates from the urinary pole of Bowman’s capsule. It follows a very tortuous or convoluted course and then enters the medullary ray to continue as the proximal straight tubule.  Proximal straight tubule, commonly referred to as the thick descending limb of the loop of Henle, descends into the medulla.  Thin descending limb is the continuation of the proximal straight tubule within the medulla. It makes a hairpin turn and returns toward the cortex.  Thin ascending limb is the continuation of the thin descending limb after its hairpin turn.


Histology_Ross

Histology_Ross.  Thin ascending limb is the continuation of the thin descending limb after its hairpin turn.  Distal straight tubule, which is also referred to as the thick ascending limb of the loop of Henle, is the continuation of the thin ascending limb. The distal straight tubule ascends through the medulla and enters the cortex in the medullary ray to reach the vicinity of its renal corpuscle of origin. The distal straight tubule then leaves the medullary ray and makes contact with the vascular pole of its parent renal corpuscle. At this point, the epithelial cells of the tubule adjacent to the afferent arteriole of the glomerulus are modified to form the macula densa. The distal tubule then leaves the region of the corpuscle and becomes the distal convoluted tubule.


Histology_Ross

Histology_Ross.  Distal convoluted tubule is less tortuous than the proximal convoluted tubule; thus, in a section showing the cortical labyrinth, there are fewer distal tubule profiles than proximal tubule profiles. At its termination, the distal convoluted tubule empties into a collecting duct that lies in the medullary ray via either an arched collecting tubule or a shorter tubule simply called the connecting tubule. The loop of Henle forms the entire U-shaped portion of a nephron. The proximal straight tubule, the thin descending limb with its hairpin turn, the thin ascending limb, and the distal straight tubule are collectively called the loop of Henle. In some nephrons, the thin descending and ascending segments are extremely short; therefore, the hairpin turn may be made by the distal straight tubule. Types of Nephrons


Histology_Ross

Histology_Ross. Types of Nephrons Several types of nephrons are identified, based on the location of their renal corpuscles in the cortex (see Fig. 20.3):  Subcapsular nephrons or cortical nephrons have their renal corpuscles located in the outer part of the cortex. They have short loops of Henle, extending only into the outer medulla. They are typical of the nephrons described previously, wherein the hairpin turn occurs in the distal straight tubule.  Juxtamedullary nephrons make up about one eighth of the total nephron count. Their renal corpuscles occur in proximity to the base of a medullary pyramid. They have long loops of Henle and long ascending thin segments that extend well into the inner region of the pyramid. These structural features are essential to the urine-concentrating mechanism, which is described in a further section.  Intermediate nephrons or midcortical nephrons have their renal corpuscles in the midregion of the cortex. Their loops of Henle are of intermediate length.


Histology_Ross

Histology_Ross.  Intermediate nephrons or midcortical nephrons have their renal corpuscles in the midregion of the cortex. Their loops of Henle are of intermediate length. The collecting tubules begin in the cortical labyrinth, as either connecting tubules or arched collecting tubules, and proceed to the medullary ray, where they join the collecting ducts. The collecting ducts within the cortex are referred to as cortical collecting ducts. When cortical collecting ducts reach the medulla, they are referred to as medullary collecting ducts. These ducts travel to the apex of the pyramid, where they merge into larger collecting ducts (up to 200 m), the papillary ducts (ducts of Bellini) that open into the minor calyx (see Fig. 20.4). The area on the papilla that contains the openings of these collecting ducts is called the area cribrosa.


Histology_Ross

Histology_Ross. FIGURE 20.6 • Diagrams and photomicrograph of an adult human kidney. The diagram in the upper left is a hemisection of the adult human kidney included for orientation. The diagram on the right represents an enlarged portion emphasizing the relationship of two nephrons and their collecting tubules and ducts ( yellow) to the cortex and medulla. The upper nephron, a midcortical nephron, extends only a short distance into the medulla and possesses a short thin segment in the loop of Henle. The lower nephron, a juxtamedullary nephron, has a long loop of Henle that extends deep into the medulla. Both nephrons drain into the collecting tubules in the medullary ray. The photomicrograph shows a section of the cortex. It is organized into a series of medullary rays containing straight tubules and collecting tubules and between them the cortical labyrinths containing the renal corpuscles and their associated proximal and distal convoluted tubules. A kidney lobule consists of a medullary ray at


Histology_Ross

Histology_Ross. collecting tubules and between them the cortical labyrinths containing the renal corpuscles and their associated proximal and distal convoluted tubules. A kidney lobule consists of a medullary ray at its center and half of the adjacent cortical labyrinth on either side. 60.


Histology_Ross

Histology_Ross. In summary, the gross appearance of the kidney parenchyma reflects the structure of the nephron. The renal corpuscle and the proximal and the distal convoluted tubules are all located in and make up the substance of the cortical labyrinths. The portions of the straight proximal and straight distal tubules and the descending thin and ascending thin limbs of the loop of Henle in the cortex are located in and make up the major portion of the medullary rays. The thin descending and thin ascending limbs of the loop of Henle are always located in the medulla. Thus, the arrangement of the nephrons (and the collecting tubules and ducts) accounts for the characteristic appearance of the cut surface of the kidney, as can be seen in Figure 20.6. foot processes (pedicels) of podocytes parietal layer of basal lamina


Histology_Ross

Histology_Ross. foot processes (pedicels) of podocytes parietal layer of basal lamina FIGURE 20.7 • Structure of the renal corpuscle. a. This schematic diagram shows the organization of the renal corpuscle and the structures associated with it at the vascular and urinary poles. Mesangial cells are associated with the capillary endothelium of the glomerulus and the glomerular basement membrane. The macula densa cells of the distal tubule are shown intimately associated with the juxtaglomerular cells of the afferent arteriole and the extraglomerular mesangial cells. (Modified from Kriz W, Sakai T. Morphological aspects of glomerular function. In: Nephrology: Proceedings of the Tenth International Congress of Nephrology. London: Bailliere-Tindall, 1987.) b. Photomicrograph of an H&E–stained specimen showing a renal corpuscle. The macula densa is seen in close proximity to the vascular pole. 160. Filtration Apparatus of the Kidney


Histology_Ross

Histology_Ross. Filtration Apparatus of the Kidney The renal corpuscle contains the filtration apparatus of the kidney, which consists of the glomerular endothelium, underlying glomerular basement membrane, and the visceral layer of Bowman’s capsule.


Histology_Ross

Histology_Ross. The renal corpuscle is spherical and has an average diameter of 200 m. It consists of the glomerular capillary tuft and the surrounding visceral and parietal epithelial layers of Bowman’s capsule (Fig. 20.8). The filtration apparatus, also called glomerular fltration barrier, enclosed by the parietal layer of Bowman’s capsule, consists of three different components:  Endothelium of the glomerular capillaries, which possesses numerous fenestrations (Fig. 20.9). These fenestrations are larger (70 to 90 nm in diameter), more numerous, and more irregular in outline than fenestrations in other capillaries. Moreover, the diaphragm that spans the fenestrations in other capillaries is absent in the glomerular capillaries. Endothelial cells of glomerular capillaries possess a large number of aquaporin-1 (AQP-1) water channels that allow the fast movement of water through the epithelium. Secretory products of endothelial cells, such as nitric oxide (NO) or prostaglandins (PGE2), play an


Histology_Ross

Histology_Ross. aquaporin-1 (AQP-1) water channels that allow the fast movement of water through the epithelium. Secretory products of endothelial cells, such as nitric oxide (NO) or prostaglandins (PGE2), play an important role in the pathogenesis of several thrombotic glomerular diseases.


Histology_Ross

Histology_Ross.  Glomerular basement membrane (GBM), a thick (300 to 370 nm) basal lamina that is the joint product of the endothelium and the podocytes, the cells of the visceral layer of Bowman’s capsule. Because of its thickness, it is prominent in histologic sections stained with the periodic acid–Schiff (PAS) procedure (see Fig. 1.2, page 6). The GMB is composed of a network consisting of type IV collagen (mainly 3, 4, and 5 chains), laminin, nidogen, entactin, together with proteoglycans such as agrin and perlecan, as well as multiadhvesive glycoproteins (see page 138). GBM can also be visualized employing immunofluorescence techniques using antibodies directed to a specific chain of type IV collagen (Fig 20.10). Mutation in the gene encoding for the 5 chain of type IV collagen gives rise to the Alport’s syndrome of Bowman’s capsule glomerular basement membrane endothelial cells with fenestrations foot process of podocytepodocyte subpodocyte spaceendothelial blood


Histology_Ross

Histology_Ross. FIGURE 20.8 • Schematic dia gram of fltration barrier. The arrow indicates movement of plasma fluid across the glomerular filtration barrier, forming the glomerular ultrafiltrate (primary urine) that accumulates in the urinary space of the Bowman’s capsule. Note the layers of the filtration barrier that include, fenestrated glomerular endothelial cells, glomerular basement membrane, and podocytes with filtration slit diaphragms spanned between their foot processes. In addition, the endothelial surface layer of glycoproteins and subpodocyte spaces are shown on this diagram. (hereditary glomerulonephritis), manifesting by hematuria (presence of the red blood cells in the urine); proteinuria (presence of significant amount of protein in the urine); and progressive renal failure. In Alport’s syndrome, the GBM becomes irregularly thickened with laminated lamina densa and fails to serve as an effective filtration barrier.


Histology_Ross

Histology_Ross. FIGURE 20.9 • Scanning electron micrograph of the interior surface of a glomerular capillary. The wall of the capillary shows horizontal ridges formed by the cytoplasm of the endothelial cell. Elsewhere, fenestrations are seen as numerous dark oval and circular profiles. 5,600. (Courtesy of Dr. C. Craig Tisher.)  Visceral layer of Bowman’s capsule, which contains specialized cells called podocytes or visceral epithelial cells. These cells extend processes around the glomerular capillaries (Fig. 20.11 and Plate 76, page 732). The podocytes arise during embryonic development from one of the blind ends of the developing nephron through invagination of the end of the tubule to form a double-layered epithelial cup. The inner cell layer (i.e., the visceral cell layer) lies in apposition to a capillary network, the glomerulus, which forms at this site. The outer layer of these cells, the parietal layer, forms the squamous cells of Bowman’s capsule. The cup eventually closes to form the


Histology_Ross

Histology_Ross. a capillary network, the glomerulus, which forms at this site. The outer layer of these cells, the parietal layer, forms the squamous cells of Bowman’s capsule. The cup eventually closes to form the spherical structure containing the glomerulus. As they differentiate, the podocytes extend processes around the capillaries and develop numerous secondary processes called pedicels or foot processes. The foot processes interdigitate with foot processes of neighboring podocytes, a feature that can be clearly seen with the scanning electron microscope (SEM; Fig. 20.12). The elongated spaces between the interdigitating foot processes, called fltration slits, are about 40 nm wide and covered by an ultrathin fltration slit diaphragm that spans the filtration slit slightly above the GBM (Fig. 20.13, inset).


Histology_Ross

Histology_Ross. Nephrin is an important structural protein of the filtration slit diaphragm. Recent studies of the fltration slit diaphragm revealed its complex protein structure as a zipper-like sheet configuration with a central density. A transmembrane protein, nephrin is


Histology_Ross

Histology_Ross. FIGURE 20.10 • Immunofuorescent-stained glomerular basement membrane in human kidney. Glomerular basement membrane (GBM) is composed of five (1 to 5) of the six chains of type IV collagen. This high magnification micrograph of the GBM within the kidney glomerulus was obtained using primary monoclonal antibodies against 1 chain of type IV collagen molecules that were visualized by secondary antibody conjugated with fluorescein dye. 1,200. (Courtesy of Dr. L. Barisoni.) a key structural and functional component of the slit diaphragm. Nephrin molecules emerging from opposite foot processes interact in the center of the slit (homophilic interactions), forming a central density with pores on both sides (Fig. 20.14). This intercellular protein sheet also contains other adhesion molecules, such as Neph-1, Neph-2, P-cadherin, FAT1, and FAT 2. The filtration slit diaphragm is firmly anchored to numerous actin filaments within the foot processes of podocytes. Regulation and maintenance of the


Histology_Ross

Histology_Ross. as Neph-1, Neph-2, P-cadherin, FAT1, and FAT 2. The filtration slit diaphragm is firmly anchored to numerous actin filaments within the foot processes of podocytes. Regulation and maintenance of the actin cytoskeleton of podocytes has emerged as a critical process for regulating size, patency, and selectivity of the filtration slits. Mutations in the nephrin gene (NPHS1) are associated with congenital nephrotic syndrome, a disease characterized by massive proteinuria and edema.


Histology_Ross

Histology_Ross. Endothelial surface layer of glomerular capillaries and subpodocyte space also make an important contribution to overall glomerular function. The filtration apparatus is a very complex semipermeable barrier, with properties that allow for high filtration rate of water, nonrestricted passage of small and middle-sized molecules, and almost total exclusion of serum albumins and other larger proteins. The filtration apparatus may thus be described as a barrier having two discontinuous cellular layers, the endothelium of glomerular capillaries and visceral layer of Bowman’s capsule applied to either side of a continuous extracellular layer of the glomerular basement membrane. These three layers have traditionally been considered as the glomerular filtration barrier. However, recently two additional physiologically important layers, the endothelial surface layer of glomerular capillaries and subpodocyte space are included as part of the filtration apparatus.


Histology_Ross

Histology_Ross.  Endothelial surface layer of the glomerular capillaries consists of a thick carbohydrate–rich meshwork (200–400 nm) attached to the luminal surface of glomerular endothelial cells. It contains glycocalyx, which refers to plasma membrane-bound negatively charged proteoglycans (such as perlecan, syndecan, and versican) associated with glycosaminoglycan side-chains (such as heparan sulphate and chondroitin sulphate) and peripheral membrane proteins. Plasma proteins (e.g., albumins) adsorbed from the blood coat the luminal surface of glycocalyx.


Histology_Ross

Histology_Ross.  Subpodocyte space represents a narrow space between the foot processes with their filtration slit diaphragms on one side and a cell body of the podocyte on the other side (see Fig. 20.13). Recent three-dimensional reconstruction of these spaces revealed their interconnected but structurally restrictive character. They cover approximately 60% of the entire surface area of the glomerular filtration barrier and may function in regulating glomerular fluid flux across the filtration apparatus. The glomerular basement membrane (GBM) acts as a physical barrier and an ion-selective filter.


Histology_Ross

Histology_Ross. The glomerular basement membrane (GBM) acts as a physical barrier and an ion-selective filter. As discussed earlier, the GBM contains type IV and XVIII collagens, sialoglycoproteins, and other noncollagenous glycoproteins (e.g., laminin, fibronectin, entactin), as well as proteoglycans (e.g., perlecan, agrin) and glycosaminoglycans, particularly heparan sulfate (Fig. 20.15). These components are localized in particular portions of the GBM:  The lamina rara externa, adjacent to the podocyte processes. It is particularly rich in polyanions, such as heparan sulfate, that specifically impede the passage of negatively charged molecules.  The lamina rara interna, adjacent to the capillary endothelium. Its molecular features are similar to those of the lamina rara externa.


Histology_Ross

Histology_Ross.  The lamina rara interna, adjacent to the capillary endothelium. Its molecular features are similar to those of the lamina rara externa.  The lamina densa, the overlapping portion of the two basal laminae, sandwiched between the laminae rarae. It contains type IV collagen, which is organized into a network that acts as a physical filter. Type XVIII collagen, perlecan, and agrin are responsible for the bulk of anionic charges found in glomerular basement membrane. The laminin and other proteins present in the laminae rara interna and externa are involved in the attachment of the endothelial cells and podocytes to the GBM.


Histology_Ross

Histology_Ross. The GBM restricts the movement of particles, usually proteins, larger than approximately 70,000 daltons or 3.6 nm radius (e.g., albumin or hemoglobin). Although albumin is not a usual constituent, it may sometimes be found in urine, indicating that the size of albumin is close to the effective pore size of the filtration barrier. The polyanionic glycosaminoglycans of the laminae rarae have strong negative charges and restrict the movement of anionic particles and molecules across the GBM, even those smaller than 70,000 daltons. Despite the ability of the filtration barrier to restrict protein, several grams of protein do pass through the barrier each day. This


Histology_Ross

Histology_Ross. FIGURE 20.11 • Transmission electron micrograph of a glomerulus in the region of the urinary pole. The nuclear and perinuclear regions of the endothelial cells (EC) that line the glomerular capillaries (C) bulge into the vascular lumen. On the outer surface of the capillaries are the processes of the podocytes (P). External to the podocytes is the urinary space (U). Bowman’s capsule (BC) is shown on the left; it is continuous at the dashed line (marked by arrowheads) with the tubule cells of the proximal tubule (PTC). Note the numerous mitochondria (M) in the base of these cells and the brush border (BB) at the apex, projecting into the urinary space. The nuclei of three adjacent mesangial cells (MC) can be seen in the upper right of the micrograph. 4,700.


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Histology_Ross. protein is reabsorbed by endocytosis in the proximal convoluted tubule. Albuminuria (presence of significant amounts of albumin in the urine) or hematuria (presence of significant amounts of red blood cells in the urine) indicate physical or functional damage to the GBM. In such cases (e.g., diabetic nephropathy), the number of anionic sites, especially in the lamina rara externa, is significantly reduced. The filtration slit diaphragm acts as a size-selective filter.


Histology_Ross

Histology_Ross. The filtration slit diaphragm acts as a size-selective filter. The narrow slit pores formed by the foot processes of podocytes and the filtration slit diaphragms act as physical barriers to restrict the movement of solutes and solvents across the filtration barrier. The discovery of specific proteins that form the slit diaphragm has led to new insights into the function of the filtration apparatus in the kidney. Most of the proteins found in the diaphragm are crucial for normal development and function of the kidney. The slit diaphragm architecture accounts for a true size-selective filter properties, which determine the molecular sieving characteristics of the glomerulus. Several mechanisms prevent clogging of the filtration slit diaphragms. These include, the negative charges of glycosaminoglycans in the GBM, negative charges of the podocyte cell membrane, and the phagocytic function of mesangial cells in the renal corpuscle.


Histology_Ross

Histology_Ross. FIGURE 20.12 • Scanning electron micrograph of a glomerulus. a. Low-magnification image revealing the tortuous course of the podocyte-covered glomerular capillaries. 700. b. A higher magnification of the area in the rectangle in a. Note the podocyte and its processes embracing the capillary wall. The primary processes (1 ) of the podocyte give rise to secondary processes (2 ), which in turn give rise to the pedicels. The space between the interdigitating pedicels creates the slit pores. 14,000. Inset. This higher magnification of the area in the rectangle reveals the slit pores and clearly shows that alternating pedicels belong to the secondary process of one cell; the intervening pedicels belong to the adjacent cell. 6,000.


Histology_Ross

Histology_Ross. FIGURE 20.13 • Transmission electron micrograph of a glomerular capillary and adjacent podocyte. The pedicels of the podocytes rest on the basal lamina adjacent to the capillary endothelium, and together, the three components—capillary endothelium, basal lamina, and podocyte—form a filtration apparatus. 5,600. Inset. The large arrows point to the fenestrations in the endothelium. On the other side of the basal lamina are the pedicels of the podocytes. Note the slit diaphragm (small arrows) spanning the gap between adjacent pedicels. 12,000. Changes in different components of the filtration apparatus influence the functions of one another.


Histology_Ross

Histology_Ross. Changes in different components of the filtration apparatus influence the functions of one another. The molecular structure and composition of each component of the glomerular filtration barrier has important consequences for adjacent components of the barrier. For instance, molecular changes in the GBM not only modify the contribution of this layer but also modify the rate at which solutes and solvents pass through the endothelium of glomerular capillaries on one side and the visceral layer of the Bowman’s capsule on the other. In addition, it is important to understand that glomerular filtration barrier is not a passive but an active structure that can remodel itself and modify its own permeability. Simple squamous epithelium constitutes the parietal layer of Bowman’s capsule.


Histology_Ross

Histology_Ross. Simple squamous epithelium constitutes the parietal layer of Bowman’s capsule. The parietal layer of Bowman’s capsule contains parietal epithelial cells and forms a simple squamous epithelium. At the urinary pole of the renal corpuscle, the parietal layer is continuous with the cuboidal epithelium of the proximal convoluted tubule (see Figs. 20.7 and 20.11). Proliferation of parietal epithelial cells is a typical diagnostic feature in certain types of glomerulonephritis (inﬂammation of the glomerulus). For an example of such a disease, see Folder 20.2. The space between the visceral and parietal layers of Bowman’s capsule is called the urinary space or Bowman’s space (see Fig. 20.11). It is the receptacle for the glomerular ultrafiltrate (primary urine) produced by the filtration apparatus of the renal corpuscle. At the urinary pole of the renal corpuscle, the urinary space is continuous with the lumen of the proximal convoluted tubule.


Histology_Ross

Histology_Ross. The renal corpuscle contains an additional group of cells called mesangial cells. These cells and their extracellular matrix constitute the mesangium. It is most obvious at the vascular stalk of the glomerulus and at the interstices of adjoining glomerular capillaries. Mesangial cells are positioned much the same as pericytes, in that they are enclosed by the GBM (Fig. 20.16). The mesangial cells are not confined entirely to the renal corpuscle; some are located outside the corpuscle along the vascular pole, where they are also designated as lacis cells and form part of what is called the juxtaglomerular apparatus (see Fig. 20.7).


Histology_Ross

Histology_Ross. Important functions of the mesangial cells follow:  Phagocytosis and endocytosis. Mesangial cells remove trapped residues and aggregated proteins from the GBM and filtration slit diaphragm, thus keeping the glomerular filter free of debris. They also endocytose and process a variety of plasma proteins including immune complexes. Maintaining the structure and function of glomerular barrier is the primary function of the mesangial cells. Structural support. Mesangial cells produce components of mesengial matrix, which provide support for the FIGURE 20.14 • Diagram of the fltration slit diaphragm.


Histology_Ross

Histology_Ross. Filtration slit diaphragm is a complex zipper-like sheet structure formed by a transmembrane protein nephrin. The extracellular domains of nephrins emerge from the opposite foot processes of neighboring podocytes and interdigitate in the center of the slit forming a central density with pores on both sides. The intracellular domains of nephrins interact with actin cytoskeleton within the cytoplasm of foot processes. The sheet of nephrin molecules is reinforced near its attachment to the foot processes by Neph1 and Neph2 proteins that interact with each other and with nephrin. The other adhesion molecules such as P-cadherin, FAT1, and FAT2 are also found in this region. Note that foot processes of podocytes are separated by the glomerular basement membrane (GBM) from fenestrated endothelial cells lining glomerular capillaries. (Redrawn from Tryggvason K, Patrakka J, Wartiovaara J. Hereditary proteinuria syndromes and mechanisms of proteinuria. N Engl J Med 2006;354:1387–401.) podocytes


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Histology_Ross. cells lining glomerular capillaries. (Redrawn from Tryggvason K, Patrakka J, Wartiovaara J. Hereditary proteinuria syndromes and mechanisms of proteinuria. N Engl J Med 2006;354:1387–401.) podocytes in the areas where the epithelial basement membrane is absent or incomplete (see Fig 20.16).


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Histology_Ross.  Secretion. Mesangial cells synthesize and secrete a variety of molecules such as interleukin 1 (IL-1), PGE2, and platelet-derived growth factor (PDGF), which play a central role in response to glomerular injury.  Modulation of glomerular distension. Mesangial cells have contractile properties. In the past, it was suggested that contraction of mesangial cells could increase the intraglomerular blood volume and filtration pressure. Recent studies revealed that mesangial contribution to glomerular filtration rate is minimal, and the mesangial cells may function in regulating glomerular distension in response to increased blood pressure.


Histology_Ross

Histology_Ross.  Clinically, it has been observed that mesangial cells proliferate in certain kidney diseases, in which abnormal amounts of protein and protein complexes are trapped in the GBM. Proliferation of mesangial cells is a prominent feature in the immunoglobulin A (IgA) nephropathy (Berger disease), membranoproliferative glomerulonephritis, lupus nephritis, and diabetic nephropathy. FIGURE 20.15 • Immunofuorescent-stained glomerulus.


Histology_Ross

Histology_Ross. FIGURE 20.15 • Immunofuorescent-stained glomerulus. This triple-exposure micrograph of a normal adult rat glomerulus is immunostained with two different antibodies. One antibody recognizes specific extracellular components, namely, basement membrane heparan sulfate proteoglycan (BM-HSPG, rhodamine label). The other antibody recognizes basement membrane chondroitin sulfate proteoglycan (BM-CSPG, fluorescein label). Because it is a triple-exposure micrograph, a yellow color occurs where the two fluorescent labels exactly codistribute. The blue fluorescence is nuclear counterstaining with Hoechst nuclear stain. The micrograph shows that compartmentalization occurs with respect to glomerular proteoglycan populations. The glomerular capillary basement membrane is composed exclu sively of BM-HSPG, whereas the mesangial matrix (yellow) contains both BM-HSPG and BM-CSPG. Bowman’s capsule appears to be strongly stained by only BM-CSPG antibodies. 360. (Courtesy of Dr. Kevin J. McCarthy.)


Histology_Ross

Histology_Ross. Embryologically, mesangial, and juxtaglomerular cells (discussed in a following paragraph) are derived from smooth muscle cell precursors. Although mesangial cells are clearly phagocytotic, they are unusual in the sense that they are not derived from the usual precursor cells of the mononuclear phagocytotic system, the blood-borne monocytes. The juxtaglomerular apparatus includes the macula densa, the juxtaglomerular cells, and the extraglomerular mesangial cells. Lying directly adjacent to the afferent and efferent arterioles and adjacent to some extraglomerular mesangial cells at the  FOLDER 20.2 Clinical Correlation: Antiglomerular Basement Membrane Antibody-Induced Glomerulonephritis; Goodpasture Syndrome


Histology_Ross

Histology_Ross. As discussed earlier in the section on the basal lamina assembly (see Chapter 5, page 139), the major building block of any basement membrane, including glomerular basement membrane (GBM), is the type IV collagen molecule. Its core structure is composed of three -chain monomers, each representing one or more of six types of -chains known for type IV collagen (see Table 6.2; page 165). Each molecule has three domains: an amino-terminus 7S domain, a middle collagenous helical domain, and a carboxy-terminus noncallagenous NC1 domain. Molecular architecture of type IV collagen is a key to understanding pathophysiology of glomerular kidney diseases. For instance, an autoimmune response to the noncollagenous NC1 domain of the 3-chain of type IV collagen [3(IV)] in the GBM is responsible for the development of anti-GBM antibody-induced glomerulonephritis. This condition is characterized by a linear deposition of immunoglobulin G (IgG) antibodies in the GBM. In some individuals, anti-GBM


Histology_Ross

Histology_Ross. the development of anti-GBM antibody-induced glomerulonephritis. This condition is characterized by a linear deposition of immunoglobulin G (IgG) antibodies in the GBM. In some individuals, anti-GBM antibodies may cross-react with alveolar basement membrane in the lungs, producing Goodpasture syndrome.


Histology_Ross

Histology_Ross. The clinical feature of Goodpasture syndrome is rapidly progressive glomerulonephritis (inflammation in the glomeruli) and pulmonary hemorrhage due to disruption of the air–blood barrier. In response to deposition of IgG in the glomerulus, the complement system is activated and circulating leukocytes elaborate a variety of proteases, leading to disruption of the GBM and deposition of fibrin. Fibrin, in turn, stimulates the proliferation of parietal cells lining Bowman’s capsule and cause influx of monocytes from the circulation. The product of these reactions is often seen within the glomerulus as a crescent, a characteristic microscopic feature of glomerulonephritis (Fig. F20.2.1). Most patients affected by Goodpasture syndrome have a severe crescentic glomerulonephritis with transiently elevated levels of circulating anti-GBM antibodies. Formation of anti-GBM antibodies is most likely triggered by viruses, cancers, pharmacologic agents, and chemical compounds found in a variety of


Histology_Ross

Histology_Ross. elevated levels of circulating anti-GBM antibodies. Formation of anti-GBM antibodies is most likely triggered by viruses, cancers, pharmacologic agents, and chemical compounds found in a variety of paints, solvents, and dyes.


Histology_Ross

Histology_Ross. Individuals with Goodpasture syndrome present with both respiratory and urinary symptoms. These include shortness of breath, cough, and bloody sputum, as well as hematuria (blood in urine), proteinuria (proteins in the urine), and other symptoms of progressing kidney failure. The main therapeutic goal in treating Goodpasture syndrome is to remove the circulating pathogenic antibodies from the blood. This is achieved by plasmapheresis, in which blood plasma is removed from the circulation and replaced by fluid, protein, or donated plasma. In addition, treatment with immunosuppressive drugs and corticosteroids is beneficial to keep the immune system from producing pathogenic autoantibodies.


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Histology_Ross. FIGURE F20.2.1 • Photomicrograph of a glomerulus in Goodpasture syndrome. a. In this Mallory trichome-stained specimen obtained from a kidney biopsy, the collagen molecules in the mesangial matrix and glomerular capillaries are stained dark blue. The bright red stain within the renal corpuscle represents fibrin, which leaked out of the glomerular capillary loops into the urinary space. A cellular crescent (outlined in dashed line) is formed by deposition of fibrin infiltrated by macrophages and proliferated parietal cells of the Bowman capsule. The light blue color surrounding the glomerulus is reflective of edematous reaction containing cells mediating inflammatory reactions. Note the basal lamina of a parietal layer of the Bowman capsule. 320. b. This immunofluorescence image of the renal corpuscle shows the glomerular basement membrane labeled with antibodies directed against human IgG and visualized with secondary antibodies conjugated with fluorescent dye. In Goodpasture


Histology_Ross

Histology_Ross. the renal corpuscle shows the glomerular basement membrane labeled with antibodies directed against human IgG and visualized with secondary antibodies conjugated with fluorescent dye. In Goodpasture syndrome, IgGs bind to the NC1 domain of type IV collagen (3 chain) found in the GMB. Note the irregular thickness pattern of the GBM surrounding capillary loops. The remaining space is occupied by the cellular crescent. 360. (Courtesy of Dr. Joseph P. Grande.) endothelial cell foot processes of podocytes glomerular basement membrane endothelial cell fenestrae of endothelial cell mesangial cell mesangial matrix foot processes of podocytes


Histology_Ross

Histology_Ross. FIGURE 20.16 • Schematic diagram showing the relationship between the intraglomerular mesangial cells and the glomerular capillaries. The mesangial cell and its surrounding matrix are enclosed by the basal lamina of the glomerular capillaries. Note that the mesangial cells are in the same compartment as the endothelium and that they can be intimately associated with the basal lamina as well as with the endothelial cells. (Modified from Sakai T, Kriz W. The structural relationship between mesangial cells and basement membrane of the renal glomerulus. Anat Embryol 1987; 176:373–386.) vascular pole of the renal corpuscle is the terminal portion of the distal straight tubule of the nephron. At this site, the wall of the tubule contains cells that are referred to collectively as the macula densa. When viewed in the light microscope, the cells of the macula densa are distinctive, in that they are narrower and usually taller than other distal tubule cells (see Fig. 20.7). The nuclei of these


Histology_Ross

Histology_Ross. When viewed in the light microscope, the cells of the macula densa are distinctive, in that they are narrower and usually taller than other distal tubule cells (see Fig. 20.7). The nuclei of these cells appear crowded, even to the extent that they appear partially superimposed over one another, thus the name “macula densa.”


Histology_Ross

Histology_Ross. In this same region, the smooth muscle cells of the adjacent afferent arteriole (and, sometimes, the efferent arteriole) are modified. They contain secretory granules, and their nuclei are spherical, as opposed to the typical elongate smooth muscle cell nucleus. These juxtaglomerular cells (see Fig. 20.7) require spe cial stains to reveal the secretory vesicles in the light microscope. The juxtaglomerular apparatus regulates blood pressure by activating the renin–angiotensin–aldosterone system.


Histology_Ross

Histology_Ross. In certain physiologic (low sodium intake) or pathologic conditions (decrease in volume of circulating blood because of hemorrhage or reduction in renal perfusion owing to compression of the renal arteries), juxtaglomerular cells are responsible for activating the renin–angiotensin–aldosterone system (RAAS). This system plays an important role in maintaining sodium homeostasis and renal hemodynamics. The granules of the juxtaglomerular cells contain an aspartyl protease, called renin, which is synthesized, stored, and released into the bloodstream from the modified smooth muscle cells. In the blood, renin catalyzes the hydrolysis of a circulating 2-globulin, angiotensinogen, to produce the decapeptide angiotensin I. Then,  Angiotensin I is converted to the active octapeptide angiotensin II by angiotensin-converting enzyme (ACE) present on the endothelial cells of lung capillaries.


Histology_Ross

Histology_Ross.  Angiotensin II stimulates the synthesis and release of the hormone aldosterone from the zona glomerulosa of the adrenal gland (see page 766).  Aldosterone, in turn, acts on collecting ducts to increase reabsorption of sodium and concomitant reabsorption of water, thereby raising blood volume and pressure.


Histology_Ross

Histology_Ross. with suspected renal disease. It typically includes several measurement of physical, biochemical, and microscopic urine characteristics such as pH, specific gravity (indirect measurement of ion concentration), bilirubin, concentration of intermediate compounds derived from the fatty acid metabolism known as ketone bodies, hemoglobin, and con-centration of the proteins. Important part of this analysis in-cludes the determination of the amount of protein excreted in the urine. The excretion of excessive amounts of protein (i.e., proteinuria [albuminuria]) is an important diagnostic sign of renal disease. Normally, less than 150 mg of protein is of protein almost always indicates renal disease, extreme exercise, such as jogging, or severe dehydration may pro-duce increased proteinuria in individuals without renal dis-ease. Microscopic examination of the urine may reveal presence of red and white blood cells, mineral crystals, and pathogenic agents such as bacteria or fungi. Often these


Histology_Ross

Histology_Ross. without renal dis-ease. Microscopic examination of the urine may reveal presence of red and white blood cells, mineral crystals, and pathogenic agents such as bacteria or fungi. Often these elements are enclosed within the cylindrical structures called urinary casts. The matrix of urinary cast is formed by an 85kilodalton protein, uromodulin (Tamm-Horsfall protein) that precipitate in the lumen of distal convoluted tubes and collecting ducts during a disease process.


Histology_Ross

Histology_Ross.  FOLDER 20.3 Clinical Correlation: Examination of the Urine—Urinalysis Urinalysis is an important part of the examination of patients excreted in the urine each day. Although excessive excretion