Histology_Ross

Histology_Ross. The glands of the alimentary tract (see Fig. 17.1) develop from invaginations of the luminal epithelium and include  mucosal glands that extend into the lamina propria.  submucosal glands that either deliver their secretions directly to the lumen of mucosal glands or via ducts that pass through the mucosa to the luminal surface.  extramural glands that lie outside the digestive tract and deliver their secretions via ducts that pass through the wall of the intestine to enter the lumen. The liver and the pan creas are extramural digestive glands (see Chapter 18) that greatly increase the secretory capacity of the digestive sys tem. They deliver their secretions into the duodenum, the first part of the small intestine. The lamina propria contains glands, vessels that transport absorbed substances, and components of the immune system.


Histology_Ross

Histology_Ross. The lamina propria contains glands, vessels that transport absorbed substances, and components of the immune system. As noted, the mucosal glands extend into the lamina propria throughout the length of the alimentary canal. In addition, in several parts of the alimentary canal (e.g., the esophagus and anal canal), the lamina propria contains aggregations of mucus-secreting glands. In general, they lubricate the epithelial surface to protect the mucosa from mechanical and chemical injury. These glands are described below in relation to specific regions of the digestive tube.


Histology_Ross

Histology_Ross. In segments of the digestive tract in which absorption occurs, principally the small and large intestines, the absorbed products of digestion diffuse into the blood and lymphatic vessels of the lamina propria for distribution. Typically, the blood capillaries are of the fenestrated type and collect most of the absorbed metabolites. In the small intestine, lymphatic capillaries are numerous and receive some absorbed lipids and proteins.


Histology_Ross

Histology_Ross. The lymphatic tissues in the lamina propria function as an integrated immunologic barrier that protects against pathogens and other antigenic substances that could potentially enter through the mucosa from the lumen of the alimentary canal. The lymphatic tissue is represented by  diffuse lymphatic tissue consisting of numerous lym phocytes and plasma cells, located in the lamina propria, and lymphocytes transiently residing in the intercellular spaces of the epithelium. lymphatic nodules with well-developed germinal centers.  eosinophils, macrophages, and sometimes neutrophils.


Histology_Ross

Histology_Ross. The diffuse lymphatic tissue and the lymphatic nodules are referred to as gut-associated lymphatic tissue (GALT). In the distal small intestine, the ileum, extensive aggregates of nodules, called Peyer’s patches, occupy much of the lamina propria and submucosa. They tend to be located on the side of the tube opposite the attachment of the mesentery. Aggregated lymphatic nodules are also present in the appendix. The muscularis mucosae forms the boundary between mucosa and submucosa. The muscularis mucosae, the deepest portion of the mucosa, consists of smooth muscle cells arranged in an inner circular and outer longitudinal layer. Contraction of this muscle produces movement of the mucosa, forming ridges and valleys that facilitate absorption and secretion. This localized movement of the mucosa is independent of the peristaltic movement of the entire wall of the digestive tract.


Histology_Ross

Histology_Ross. The submucosa consists of a dense, irregular connective tissue layer containing blood and lymphatic vessels, a nerve plexus, and occasional glands.


Histology_Ross

Histology_Ross. The submucosa contains the larger blood vessels that send branches to the mucosa, muscularis externa, and serosa. The submucosa also contains lymphatic vessels and a nerve plexus. The extensive nerve network in the submucosa contains visceral sensory fibers mainly of sympathetic origin, parasympathetic (terminal) ganglia, and preganglionic and postganglionic parasympathetic nerve fibers. The nerve cell bodies of parasympathetic ganglia and their postganglionic nerve fibers represent the enteric nervous system, the third division of the autonomic nervous system. This system is primarily responsible for innervating the smooth muscle layers of the alimentary canal and can function totally independently of the central nervous system. In the submucosa, the network of unmyelinated nerve fibers and ganglion cells constitute the submucosal plexus (also called Meissner’s plexus).


Histology_Ross

Histology_Ross. As noted, glands occur occasionally in the submucosa in certain locations. For example, they are present in the esophagus and the initial portion of the duodenum. In histologic sections, the presence of these glands often aids in identifying the specific segment or region of the tract. In most parts of the digestive tract, the muscularis externa consists of two concentric and relatively thick layers of smooth muscle. The cells in the inner layer form a tight spiral, described as a circularly oriented layer; those in the outer layer form a loose spiral, described as a longitudinally oriented layer. Located between the two muscle layers is a thin connective tissue layer. Within this connective tissue lies the myenteric plexus (also called Auerbach’s plexus), containing nerve cell bodies (ganglion cells) of postganglionic parasympathetic neurons and neurons of the enteric nervous system, as well as blood vessels and lymphatic vessels.


Histology_Ross

Histology_Ross. Contractions of the muscularis externa mix and propel the contents of the digestive tract. Contraction of the inner circular layer of the muscularis externa compresses and mixes the contents by constricting the lumen; contraction of the outer, longitudinal layer propels the contents by shortening the tube. The slow, rhythmic contraction of these muscle layers under the control of the enteric nervous system produces peristalsis (i.e., waves of contraction). Peristalsis is marked by constriction and shortening of the tube, which moves the contents through the intestinal tract.


Histology_Ross

Histology_Ross. A few sites along the digestive tube exhibit variations in the muscularis externa. For example, in the wall of the proximal portion of the esophagus (pharyngoesophageal sphincter) and around the anal canal (external anal sphincter), striated muscle forms part of the muscularis externa. In the stomach, a third, obliquely oriented layer of smooth muscle is present deep into the circular layer. Finally, in the large intestine, part of the longitudinal smooth muscle layer is thickened to form three distinct, equally spaced longitudinal bands called teniae coli. During contraction, the teniae facilitate shortening of the tube to move its contents. The circular smooth muscle layer forms sphincters at specific locations along the digestive tract.


Histology_Ross

Histology_Ross. The circular smooth muscle layer forms sphincters at specific locations along the digestive tract. At several points along the digestive tract, the circular muscle layer is thickened to form sphincters or valves. From the oropharynx distally, these structures include the following:  Pharyngoesophageal sphincter. Actually, the lowest part of the cricopharyngeus muscle is physiologically referred to as the superior (upper) esophageal sphincter. It prevents the entry of air into the esophagus.


Histology_Ross

Histology_Ross.  Inferior (lower) esophageal sphincter. As the name implies, this sphincter is located at the lower end of the esophagus; its action is reinforced by the diaphragm that surrounds this part of the esophagus as it passes into the abdominal cavity. It creates a pressure difference between the esophagus and stomach that prevents reflux of gastric contents into the esophagus. Abnormal relaxation of this sphincter allows acidic content of the stomach to return (reﬂux) into the esophagus. If not treated, this condition may progress into gastroesophageal refux disease (GERD), characterized by inﬂammation of the esophageal mucosa (reﬂux esophagitis), strictures, and difficulty in swallowing (dysphagia) with accompanying chest pain.  Pyloric sphincter. Located at the junction of the pylorus of the stomach and duodenum (gastroduodenal sphincter), it controls the release of chyme, the partially digested contents of the stomach, into the duodenum.


Histology_Ross

Histology_Ross.  Ileocecal valve. Located at the junction of the small and large intestines, it prevents reflux of the contents of the colon with its high bacterial count into the distal ileum, which normally has a low bacterial count.  Internal anal sphincter. This, the most distally located sphincter, surrounds the anal canal and prevents passage of the feces into the anal canal from the undistended rectum. Serosa or adventitia constitutes the outermost layer of the alimentary canal. The serosa is a serous membrane consisting of a layer of simple squamous epithelium, called the mesothelium, and a small amount of underlying connective tissue. It is equivalent to the visceral peritoneum described in gross anatomy. The serosa is the most superficial layer of those parts of the digestive tract that are suspended in the peritoneal cavity. As such, the serosa is continuous with both the mesentery and the lining of the abdominal cavity.


Histology_Ross

Histology_Ross. Large blood and lymphatic vessels and nerve trunks travel through the serosa (from and to the mesentery) to reach the wall of the digestive tract. Large amounts of adipose tissue can develop in the connective tissue of the serosa (and in the mesentery). Parts of the digestive tract do not possess a serosa. These include the thoracic part of the esophagus and portions of structures in the abdominal and pelvic cavities that are fixed to the cavity wall—the duodenum, ascending and descending colon, rectum, and anal canal. These structures are attached to the abdominal and pelvic wall by connective tissue, the adventitia, which blends with the connective tissue of the wall. The esophagus is a fixed muscular tube that delivers food and liquid from the pharynx to the stomach.


Histology_Ross

Histology_Ross. The esophagus is a fixed muscular tube that delivers food and liquid from the pharynx to the stomach. The esophagus courses through the neck and mediastinum, where it is attached to adjacent structures by connective tissue. As it enters the abdominal cavity, it is free for a short distance, approximately 1 to 2 cm. The overall length of the esophagus is about 25 cm. On cross section (Fig. 17.2), the lumen in its normally collapsed state has a branched appearance because of longitudinal folds. When a bolus of food passes through the esophagus, the lumen expands without mucosal injury.


Histology_Ross

Histology_Ross. The mucosa that lines the length of the esophagus has a nonkeratinized stratified squamous epithelium (Fig. 17.3 and Plate 54, page 606). In many animals, however, the epithelium is keratinized, reflecting a coarse food diet. In humans, the surface cells may exhibit some keratohyalin granules, but keratinization does not normally occur. The underlying lamina propria is similar to the lamina propria throughout the alimentary tract; diffuse lymphatic tissue is scattered throughout, and lymphatic nodules are present, often in proximity to ducts of the esophageal mucous glands (see page 573). The deep layer of the mucosa, the muscularis mucosae, is composed of longitudinally organized smooth muscle that begins near the level of the cricoid cartilage. It is unusually thick in the proximal portion of the esophagus and presumably functions as an aid in swallowing.


Histology_Ross

Histology_Ross. The submucosa consists of dense irregular connective tissue that contains the larger blood and lymphatic vessels, nerve fibers, and ganglion cells. The nerve fibers and ganglion cells make up the submucosal plexus (Meissner’s plexus). Glands are also present (see page 571). In addition, diffuse lymphatic tissue and lymphatic nodules are present mostly in the upper and lower parts of the esophagus where submucosal glands are more prevalent.


Histology_Ross

Histology_Ross. The muscularis externa consists of two muscle layers, an inner circular layer and an outer longitudinal layer (Plate 54, page 606). It differs from the muscularis externa found in the rest of the digestive tract in that the upper one third is striated muscle, a continuation of the muscle of the pharynx. Striated muscle and smooth muscle bundles are mixed and interwoven in the muscularis externa of the middle third of the esophagus; the muscularis externa of the distal third consists only of smooth muscle, as in the rest of the digestive tract. A nerve


Histology_Ross

Histology_Ross. FIGURE 17.2 • Photomicrograph of the esophagus. This low-magnification photomicrograph shows an H&E–stained section of the esophagus with its characteristically folded wall, giving the lumen an irregular appearance. The mucosa consists of a relatively thick stratified squamous epithelium, a thin layer of lamina propria containing occasional lymphatic nodules, and muscularis mucosae. Mucous glands are present in the submucosa; their ducts, which empty into the lumen of the esophagus, are not evident in this section. External to the submucosa in this part of the esophagus is a thick muscularis externa made up of an inner layer of circularly arranged smooth muscle and an outer layer of longitudinally arranged smooth muscle. The adventitia is seen just external to the muscularis externa. 8. FIGURE 17.3 • Photomicrograph of the esophageal mucosa.


Histology_Ross

Histology_Ross. FIGURE 17.3 • Photomicrograph of the esophageal mucosa. This higher-magnification photomicrograph shows the mucosa of the wall of the esophagus in an H&E preparation. It consists of a stratified squamous epithelium, lamina propria, and muscularis mucosae. The boundary between the epithelium and lamina propria is distinct, although uneven, because of the connective tissue papillae. The basal layer of the epithelium stains intensely, appearing as a dark band because the basal cells are smaller and have a high nucleus-to-cytoplasm ratio. Note that the loose connective tissue of the lamina propria is very cellular, containing many lymphocytes. The deepest part of the mucosa is the muscularis mucosae that is arranged in two layers (inner circular and outer longitudinal) similar in orientation to the muscularis externa. 240.


Histology_Ross

Histology_Ross. plexus, the myenteric plexus (Auerbach’s plexus), is present between the outer and inner muscle layers. As in the submucosal plexus (Meissner’s plexus), nerves and ganglion cells are present here. This plexus innervates the muscularis externa and produces peristaltic activity. As noted, the esophagus is fixed to adjoining structures throughout most of its length; thus, its outer layer is composed of adventitia. After entering the abdominal cavity, the short remainder of the tube is covered by serosa, the visceral peritoneum. Mucosal and submucosal glands of the esophagus secrete mucus to lubricate and protect the luminal wall. Glands are present in the wall of the esophagus and are of two types. Both secrete mucus, but their locations differ.


Histology_Ross

Histology_Ross. Glands are present in the wall of the esophagus and are of two types. Both secrete mucus, but their locations differ. FIGURE 17.4 • Photomicrograph of an esophageal submucosal gland. This photomicrograph shows a mucicarmine-stained section of the esophagus. An esophageal gland, deeply stained red by the carmine, and an adjacent excretory duct are seen in the submucosa. These small, compound, tubuloalveolar glands produce mucus that lubricates the epithelial surface of the esophagus. Note the stained mucus within the excretory duct. The remaining submucosa consists of irregular dense connective tissue. The inner layer of the muscularis externa (bottom) is composed of circularly arranged smooth muscle. 110.


Histology_Ross

Histology_Ross.  Esophageal glands proper lie in the submucosa. These glands are scattered along the length of the esophagus but are somewhat more concentrated in the upper half. They are small, compound, tubuloalveolar glands (Fig. 17.4). The excretory duct is composed of stratified squamous epithelium and is usually conspicuous when present in a section, because of its dilated appearance.  Esophageal cardiac glands are named for their similarity to the cardiac glands of the stomach and are found in the lamina propria of the mucosa. They are present in the terminal part of the esophagus and frequently, though not consistently, in the beginning portion of the esophagus.


Histology_Ross

Histology_Ross. The mucus produced by the esophageal glands proper is slightly acidic and serves to lubricate the luminal wall. Because the secretion is relatively viscous, transient cysts often occur in the ducts. The esophageal cardiac glands produce neutral mucus. Those glands near the stomach tend to protect the esophagus from regurgitated gastric contents. Under certain conditions, however, they are not fully effective, and excessive reﬂux results in pyrosis, a condition more commonly known as heartburn. This condition may progress to fully developed gastroesophageal refux disease (GERD). The muscle of the esophageal wall is innervated by both autonomic and somatic nervous systems.


Histology_Ross

Histology_Ross. The muscle of the esophageal wall is innervated by both autonomic and somatic nervous systems. The striated musculature in the upper part of the esophagus is innervated by somatic motor neurons of the vagus nerve, cranial nerve X (from the nucleus ambiguus). The smooth muscle of the lower part of the esophagus is innervated by visceral motor neurons of the vagus (from the dorsal motor nucleus). These motor neurons synapse with postsynaptic neurons whose cell bodies are located in the wall of the esophagus. The stomach is an expanded part of the digestive tube that lies beneath the diaphragm. It receives the bolus of macerated food from the esophagus. Mixing and partial digestion of the food in the stomach by its gastric secretions produce a pulpy fluid mix called chyme. The chyme then passes into the small intestine for further digestion and absorption. The stomach is divided histologically into three regions based on the type of gland that each contains.


Histology_Ross

Histology_Ross. Gross anatomists subdivide the stomach into four regions. The cardia surrounds the esophageal orifice; the fundus lies above the level of a horizontal line drawn through the esophageal (cardiac) orifice; the body lies below this line; and the pyloric part is the funnel-shaped region that leads into the pylorus, the distal, narrow sphincteric region between the stomach and duodenum. Histologists also subdivide the stomach, but into only three regions (Fig. 17.5). These subdivisions are based not on location but on the types of glands that occur in the gastric mucosa. The histologic regions are as follows:  Cardiac region (cardia), the part near the esophageal ori fice, which contains the cardiac glands (Fig. 17.6 and Plate 55, page 608) Pyloric region (pylorus), the part proximal to the pyloric sphincter, which contains the pyloric glands  Fundic region (fundus), the largest part of the stomach, which is situated between the cardia and pylorus and con tains the fundic or gastric


Histology_Ross

Histology_Ross. pyloric sphincter, which contains the pyloric glands  Fundic region (fundus), the largest part of the stomach, which is situated between the cardia and pylorus and con tains the fundic or gastric glands (see Fig. 17.6)


Histology_Ross

Histology_Ross. Longitudinal submucosal folds, rugae, allow the stomach to distend when filled. The stomach has the same general structural plan throughout, consisting of a mucosa, submucosa, muscularis externa, and serosa. Examination of the inner surface of the empty stomach reveals a number of longitudinal folds or ridges called rugae. They are prominent in the narrower regions of the stomach but poorly developed in the upper portion (see Fig. 17.5). When the stomach is fully distended, the rugae, composed of the mucosa and underlying submucosa, virtually disappear. The rugae do not alter total surface area; rather, they serve to accommodate expansion and filling of the stomach. A view of the stomach’s surface with a hand lens shows that smaller regions of the mucosa are formed by grooves or FIGURE 17.5 • Photograph of a hemisected human stomach.


Histology_Ross

Histology_Ross. FIGURE 17.5 • Photograph of a hemisected human stomach. This photograph shows the mucosal surface of the posterior wall of the stomach. Numerous longitudinal gastric folds are evident. These folds or rugae allow the stomach to distend as it fills. The histologic divisions of the stomach differ from the anatomic division. The former is based on the types of glands found in the mucosa. Histologically, the portion of the stomach adjacent to the entrance of the esophagus is the cardiac region (cardia) in which cardiac glands are located. A dashed line approximates its boundary. A slightly larger region leading toward the pyloric sphincter, the pyloric region (pylorus), contains the pyloric glands. Another dashed line approximates its boundary. The remainder of the stomach, the fundic region (fundus), is located between the two dashed lines and contains the fundic (gastric) glands.


Histology_Ross

Histology_Ross. shallow trenches that divide the stomach surface into bulging irregular areas called mamillated areas. These grooves provide a slightly increased surface area for secretion. At higher magnification, numerous openings can be observed in the mucosal surface. These are the gastric pits, or foveolae. They can be readily demonstrated with the scanning electron microscope (Fig. 17.7). The gastric glands open into the bottom of the gastric pits. Surface mucous cells line the inner surface of the stomach and the gastric pits. The epithelium that lines the surface and the gastric pits of the stomach is simple columnar. The columnar cells are designated surface mucous cells. Each cell possesses a large, apical cup of mucinogen granules, creating a glandular sheet of cells (Fig. 17.8). The mucous cup occupies


Histology_Ross

Histology_Ross. FIGURE 17.6 • Photomicrograph of esophagogastric junction. This low-magnification photomicrograph shows the junction between the esophagus and stomach. At the esophagogastric junction, the stratified squamous epithelium of the esophagus ends abruptly, and the simple columnar epithelium of the stomach mucosa begins. The surface of the stomach contains numerous and relatively deep depressions called gastric pits that are formed by the surface epithelium. The glands in the vicinity of the esophagus, the cardiac glands, extend from the bottom of these pits. The fundic (gastric) glands similarly arise at the base of the gastric pits and are evident in the remaining part of the mucosa. Note the relatively thick muscularis externa. 40.


Histology_Ross

Histology_Ross. FIGURE 17.7 • Mucosal surface of the stomach. a. Scanning electron micrograph showing the mucosal surface of the stomach. The gastric pits contain secretory material, mostly mucus (arrows). The surface mucus has been washed away to reveal the surface mucous cells. 1,000. b. Higher magnification showing the apical surface of the surface mucous cells that line the stomach and gastric pits. Note the elongate polygonal shape of the cells. 3,000.


Histology_Ross

Histology_Ross. FIGURE 17.8 • Gastric glands. a. This photomicrograph shows the fundic mucosa from an Alcian blue/PAS preparation to visualize mucus. Note that the surface epithelium invaginates to form the gastric pits. The surface mucous cells and the cells lining the gastric pits are readily identified in this preparation because the neutral mucus within these cells is stained intensely. One of the gastric pits and its associated fundic gland are depicted by the dashed lines. This gland represents a simple branched tubular gland (arrows indicate the branching pattern). It extends from the bottom of the gastric pit to the muscularis mucosae. Note the segments of the gland: the short isthmus, the site of cell divisions; the relatively long neck; and a shorter and wider fundus. The mucous secretion of mucous neck cells is different from that produced by the surface mucous cells as evidenced by the lighter magenta staining in this region of the gland. 320. b. Schematic diagram of a gastric gland,


Histology_Ross

Histology_Ross. mucous neck cells is different from that produced by the surface mucous cells as evidenced by the lighter magenta staining in this region of the gland. 320. b. Schematic diagram of a gastric gland, illustrating the relationship of the gland to the gastric pit. Note that the isthmus region contains dividing cells and undifferentiated cells; the neck region contains mucous neck cells, parietal cells, and enteroendocrine cells, including amine precursor uptake and decarboxylation (APUD) cells. Parietal cells are large, pear-shaped acidophilic cells found throughout the gland. The fundus of the gland contains mainly chief cells, some parietal cells, and several types of enteroendocrine cells.


Histology_Ross

Histology_Ross. most of the volume of the cell. It typically appears empty in routine hematoxylin and eosin (H&E) sections because the mucinogen is lost in fixation and dehydration. When the mucinogen is preserved by appropriate fixation, however, the granules stain intensely with toluidine blue and with the periodic acid–Schiff (PAS) procedure. The toluidine blue staining reflects the presence of many strongly anionic groups in the glycoprotein of the mucin, among which is bicarbonate. The nucleus and Golgi apparatus of the surface mucous cells are located below the mucous cup. The basal part of the cell contains small amounts of rough endoplasmic reticulum (rER) that may impart a light basophilia to the cytoplasm when observed in well-preserved specimens.


Histology_Ross

Histology_Ross. The mucous secretion from the surface mucous cells is described as visible mucus because of its cloudy appearance. It forms a thick, viscous, gel-like coat that adheres to the epithelial surface; thus, it protects against abrasion from rougher components of the chyme. Additionally, its high bicarbonate and potassium concentration protects the epithelium from the acidic content of the gastric juice. The bicarbonate that makes the mucus alkaline is secreted by the surface cells but is prevented from mixing rapidly with the contents of the gastric lumen by its containment within the mucous coat. Finally, prostaglandins (PGE2) appear to play an important role in protecting gastric mucosa. They stimulate secretion of bicarbonates and increase thickness of the mucus layer with accompanied vasodilatation in the lamina propria. This action improves supply of nutrients to any damaged area of gastric mucosa, thus optimizing conditions for tissue repair.


Histology_Ross

Histology_Ross. The lining of the stomach does not function in an absorptive capacity. However, some water, salts, and lipid-soluble drugs may be absorbed. For instance, alcohol and certain drugs such as aspirin or nonsteroidal anti-inﬂammatory drugs (NSAIDs) enter the lamina propria by damaging the surface epithelium. Even small doses of aspirin suppress the production of protective prostaglandins by the gastric mucosa. In addition, aspirin’s direct contact with the wall of the stomach interferes with the hydrophobic properties of the gastric mucosa. Fundic Glands of the Gastric Mucosa The fundic glands produce the gastric juice of the stomach.


Histology_Ross

Histology_Ross. The fundic glands, also called gastric glands, are present throughout the entire gastric mucosa except for the relatively small regions occupied by cardiac and pyloric glands. The fundic glands are simple, branched, tubular glands that extend from the bottom of the gastric pits to the muscularis mucosae (see Fig. 17.8). Located between the gastric pit and the gland below is a short segment known as the isthmus. Isthmus of the fundic gland is a site of stem cells location (stem cell niche) in which stem cells replicate and differentiate. Cells destined to become mucous surface cells migrate upward in the gastric pits to the stomach surface. Other cells migrate downward, maintaining the population of the fundic gland epithelium. Typically, several glands open into a single gastric pit. Each gland has a narrow, relatively long neck segment and a shorter and wider base or fundic segment. The base of the gland usually divides into two and sometimes three branches that become slightly


Histology_Ross

Histology_Ross. Each gland has a narrow, relatively long neck segment and a shorter and wider base or fundic segment. The base of the gland usually divides into two and sometimes three branches that become slightly coiled near the muscularis mucosae. The cells of the gastric glands produce gastric juice (about 2 L/day), which contains a variety of substances. In addition to water and electrolytes, gastric juice contains four major components:  Hydrochloric acid (HCl) in a concentration ranging from 150 to 160 mmol/L, which gives the gastric juice a low pH (1.0 to 2.0). It is produced by parietal cells and initiates digestion of dietary protein (it promotes acid hydrolysis of substrates). It also converts inactive pepsinogen into the active enzyme pepsin. Because HCl is bacteriostatic, most of the bacteria entering the stomach with the ingested food are destroyed. However, some bacteria can adapt to the low pH of the gastric contents. Helicobacter pylori contains large amounts of urease, the enzyme


Histology_Ross

Histology_Ross. entering the stomach with the ingested food are destroyed. However, some bacteria can adapt to the low pH of the gastric contents. Helicobacter pylori contains large amounts of urease, the enzyme that hydrolyzes urea, in its cytoplasm and on its plasma membrane. This highly active enzyme creates a protective basic “ammonia cloud” around the bacterium, allowing it to survive in the acidic environment of the stomach (Folder 17.1).


Histology_Ross

Histology_Ross.  Pepsin, a potent proteolytic enzyme. It is converted from pepsinogen produced by the chief cells by HCl at a pH lower than 5. Pepsin hydrolyzes proteins into small peptides by splitting interior peptide bonds. Peptides are further digested into amino acids by enzymes in the small intestine.  Mucus, an acid-protective coating for the stomach secreted by several types of mucus-producing cells. The mucus and bicarbonates trapped within the mucous layer maintain a neutral pH and contribute to the so-called physiologic gastric mucosa barrier. In addition, mucus serves as a physical barrier between the cells of the gastric mucosa and the ingested material in the lumen of the stomach.  Intrinsic factor, a glycoprotein secreted by parietal cells that binds to vitamin B12. It is essential for its absorption, which occurs in the distal part of the ileum. Lack of intrinsic factor leads to pernicious anemia and vitamin B-12 defciency (see Folder 17.1).


Histology_Ross

Histology_Ross. In addition, gastrin and other hormones and hormone-like secretions are produced by enteroendocrine cells in the fundic glands and secreted into the lamina propria, where they enter the circulation or act locally on other gastric epithelial cells. Fundic glands are composed of four functionally different cell types. The cells that constitute the fundic glands are of four functional types. Each has a distinctive appearance. In addition, undifferentiated cells that give rise to these cells are also present. These are the various cells that constitute the gland:  Mucous neck cells  Chief cells  Parietal cells, also called oxyntic cells  Enteroendocrine cells  Undifferentiated adult stem cells  FOLDER 17.1 Clinical Correlation: Pernicious Anemia and Peptic Ulcer Disease


Histology_Ross

Histology_Ross. Achlorhydria is a chronic autoimmune disease character-Recently, new proton pump inhibitors (e.g., omeprazole ized by the destruction of the gastric mucosa. Conse-and lansoprazole) have been designed that inhibit the quently, in the absence of parietal cells, the intrinsic factor H/K-ATPase. They suppress acid production in the pariis not secreted, thereby leading to pernicious anemia. etal cells and do not affect intrinsic factor secretion. Lack of intrinsic factor is the most common cause of vita-Although it was generally thought that the parietal cells min B12 deficiency. However, other factors such as gram-are the direct target of the H2 receptor–antagonist drugs, negative anaerobic bacterial overgrowth in the small recent evidence from a combination of in situ hybridization intestine are associated with B12 deficiency. These bacte-histochemistry and antibody staining has unexpectedly reria bind to the vitamin B12–intrinsic factor complex, pre-vealed that the immunoglobulin A


Histology_Ross

Histology_Ross. are associated with B12 deficiency. These bacte-histochemistry and antibody staining has unexpectedly reria bind to the vitamin B12–intrinsic factor complex, pre-vealed that the immunoglobulin A (IgA)–secreting plasma venting its absorption. Parasitic tapeworm infections also cells and some of the macrophages in the lamina propria produce clinical symptoms of pernicious anemia. Because display a positive reaction for gastrin receptor mRNA, not the liver has extensive reserve stores of vitamin B12, the the parietal cells. These findings indicate that the agents disease is often not recognized until long after significant used to treat peptic ulcers may act directly on plasma cells changes in the gastric mucosa have taken place. or macrophages and that these cells then transmit their ef-


Histology_Ross

Histology_Ross. Another cause of reduced secretion of intrinsic factor fects to the parietal cells to inhibit HCl secretion. The facand subsequent pernicious anemia is the loss of gastric tor that mediates the interaction between the connective epithelium in partial or total gastrectomy. Loss of functional tissue cells and the epithelial cells has not been elucidated. gastric epithelium also occurs in chronic or recurrent pep-Recent evidence, however, suggests that most common tic ulcer disease (PUD). Often, even healed ulcerated re-peptic ulcers (95%) are actually caused by a chronic infecgions produce insufficient intrinsic factor. Repeated loss of tion of the gastric mucosa by the bacterium Helicobacter epithelium and consequent scarring of the gastric mucosa pylori. Lipopolysaccharide antigens are expressed on its can significantly reduce the amount of functional mucosa. surface that mimic those on human gastric epithelial cells.


Histology_Ross

Histology_Ross. Histamine H2 receptor–antagonist drugs such as The mimicry appears to cause an initial immunologic tolerranitidine (Zantac) and cimetidine (Tagamet), which block ance to the pathogen by the host immune system, thus help-attachment of histamine to its receptors in the gastric mu-ing to enhance the infection and ultimately causing the cosa, suppress both acid and intrinsic factor production production of antibodies. These antibodies against H. pylori and have been used extensively in the treatment of peptic bind to the gastric mucosa and cause damage to the mu-ulcers. These drugs prevent further mucosal erosion and cosal cells. Treatment includes antibiotic eradication of the promote healing of the previously eroded surface. How-bacteria. These treatments for ulcerative disease have made ever, long-term use can cause vitamin B12 deficiency. the common surgical interventions of the past infrequent.


Histology_Ross

Histology_Ross. Mucous neck cells are localized in the neck region of the gland and are interspersed with parietal cells. As the name implies, the mucous neck cells are located in the neck region of the fundic gland. Parietal cells are usually interspersed between groups of these cells. The mucous neck cell is much shorter than the surface mucous cell and contains considerably less mucinogen in the apical cytoplasm. Consequently, these cells do not exhibit a prominent mucous cup. Also, the nucleus tends to be spherical compared with the more prominent, elongated nucleus of the surface mucous cell. The mucous neck cells secrete a soluble mucus compared with the insoluble or cloudy mucus produced by the surface mucous cell. Release of mucinogen granules is induced by vagal stimulation; thus, secretion from these cells does not occur in the resting stomach. Chief cells are located in the deeper part of the fundic glands.


Histology_Ross

Histology_Ross. Chief cells are located in the deeper part of the fundic glands. Chief cells are typical protein-secreting cells (Fig. 17.9 and Plate 57, page 612). The abundant rER in the basal cytoplasm gives this part of the cell a basophilic appearance, whereas the apical cytoplasm is eosinophilic owing to the presence of the secretory vesicles, also called zymogen granules because they contain enzyme precursors. The basophilia, in particular, allows easy identification of these cells in H&E sections. The eosinophilia may be faint or absent when the secretory vesicles are not adequately preserved. Chief cells secrete pepsinogen and a weak lipase. On contact with the acid gastric juice, pepsinogen is converted to pepsin, a proteolytic enzyme. Parietal cells secrete HCl and intrinsic factor.


Histology_Ross

Histology_Ross. Parietal cells secrete HCl and intrinsic factor. Parietal (oxyntic) cells are found in the neck of the fundic glands, among the mucous neck cells, and in the deeper part of the gland. They tend to be most numerous in the upper and middle portions of the neck. They are large cells, sometimes binucleate, and appear somewhat triangular in sections, with the apex directed toward the lumen of the gland and the base resting on the basal lamina. The nucleus is spherical, and the cytoplasm stains with eosin and other acidic dyes. Their size and distinctive staining characteristics


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Histology_Ross. FIGURE 17.9 • Diagram of a chief cell. The large amount of rER in the basal portion of the cell accounts for the intense basophilic staining seen in this region. Secretory vesicles (zymogen granules) containing pepsinogen and a weak lipase are not always adequately preserved, and thus the staining in the apical region of the cell is somewhat variable. This cell produces and secretes the precursor enzyme of the gastric secretion. allow them to be easily distinguished from other cells in the fundic glands.


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Histology_Ross. When examined with the transmission electron microscope (TEM), parietal cells (Fig. 17.10) are seen to have an extensive intracellular canalicular system that communicates with the lumen of the gland. Numerous microvilli project from the surface of the canaliculi, and an elaborate tubulovesicular membrane system is present in the cytoplasm adjacent to the canaliculi. In an actively secreting cell, the number of microvilli in the canaliculi increases, and the tubulovesicular system is reduced significantly or disappears. The membranes of the tubulovesicular system serve as a reservoir of plasma membrane containing active proton pumps. This membrane material can be inserted into the plasma membrane of the canaliculi to increase their surface area and the number of proton pumps available for acid production. Numerous mitochondria with complex cristae and many matrix granules supply the high levels of energy necessary for acid secretion.


Histology_Ross

Histology_Ross. HCl is produced in the lumen of the intracellular canaliculi. Parietal cells have three different types of membrane receptors for substances that activate HCl secretion: gastrin receptors, histamine H2 receptors, and acetylcholine M3 receptor. Activation of the gastrin receptor by gastrin, a gastrointestinal peptide hormone, is the major path for parietal cell stimulation (Folder 17.2). After stimulation, several steps occur in the production of HCl (Fig. 17.11): FIGURE 17.10 • Diagram of a parietal cell. The cytoplasm of the parietal cell stains with eosin largely because of the extensive amount of membrane comprising the intracellular canaliculus, tubulovesicular system, mitochondria, and the relatively small number of ribosomes. This cell produces HCl and intrinsic factor.


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Histology_Ross.  Production of H ions in the parietal cell cytoplasm by the enzyme carbonic anhydrase. This enzyme hydrolyzes carbonic acid (H2CO3) to H and HCO3 . Carbon dioxide (CO2), necessary for synthesis of carbonic acid, diffuses across the basement membrane into the cell from the blood capillaries in the lamina propria.  Transport of H ions from the cytoplasm, across the membrane to the lumen of the canaliculus by the H/ K-ATPase proton pump. Simultaneously, K from the canaliculus is transported into the cell cytoplasm in exchange for the H ions.  Transport of K and Cl ions from the parietal cell cytoplasm into the lumen of the canaliculus through activation of K and Cl channels (uniporters) in the plasma membrane.  Formation of HCl from the H and Cl that were transported into the lumen of the canaliculus.


Histology_Ross

Histology_Ross.  Formation of HCl from the H and Cl that were transported into the lumen of the canaliculus. In humans, intrinsic factor is secreted by the parietal cells (chief cells do so in some other species). Its secretion is stimulated by the same receptors that stimulate gastric acid secretion. Intrinsic factor is a 44-kilodalton glycoprotein that complexes with vitamin B12 in the stomach and duodenum, a step necessary for subsequent absorption of the vitamin in the ileum. Autoantibodies directed against intrinsic factor or parietal cells themselves lead to an intrinsic factor deficiency, resulting in malabsorption of vitamin B12 and pernicious anemia (see Folder 17.1).  FOLDER 17.2 Clinical Correlation: Zollinger-Ellison Syndrome


Histology_Ross

Histology_Ross. Excessive secretion of gastrin usually has its origin in a tumor of the gastrin-producing enteroendocrine cells located in the duodenum or in the pancreatic islet. This condition, known as the Zollinger-Ellison syndrome or gastrinomas, is characterized by excessive secretion of hydrochloric acid by continuously stimulated parietal cells. The excess acid cannot be adequately neutralized in the duodenum, thereby leading to gastric and duodenal ulcers. Gastric ulcers are present in 95% of patients with this syndrome and are six times more prevalent than the duodenal ulcers. Patients with Zollinger-Ellison syndrome may experience intermittent abdominal pain, diarrhea, and steatorrhea (excretion of stool containing a large amount of fat). Patients without symptoms who have severe ulceration of the stomach and small intestine, especially if they fail to respond to conventional treatment, should be also suspected of having a tumor that is producing excess gastrin. Treatment of


Histology_Ross

Histology_Ross. ulceration of the stomach and small intestine, especially if they fail to respond to conventional treatment, should be also suspected of having a tumor that is producing excess gastrin. Treatment of Zollinger-Ellison syndrome in the past involved blockage of the parietal cell membrane receptors that stimulate HCl production. Recently, proton pump inhibitors have become the treatment of choice in managing HCl hypersecretion. In addition, surgical excision of the tumor, when possible, removes the source of gastrin production and alleviates symptoms.


Histology_Ross

Histology_Ross. FIGURE 17.11 • Diagram of parietal cell HCl synthesis. After parietal cell stimulation, several steps occur leading to the production of HCl. Carbon dioxide (CO2) from the blood diffuses across the basement membrane into the cell to form H2CO3. The H2CO3 dissociates into H and HCO3 . The reaction is catalyzed by carbonic anhydrase, which leads to the production of H ions in the cytoplasm, which are then transported across the membrane to the lumen of the intracellular canaliculus by a H/K-ATPase proton pump. Simultaneously, K within the canaliculus is transported into the cell in exchange for the H ions. Cl ions are also transported from the cytoplasm of the parietal cell into the lumen of the canaliculus by Cl channels in the membrane. HCl is then formed from H and Cl. The HCO3 / Cl anion channels maintain the normal concentration of both ions in the cell, as well as Na/K-ATPase on the basolateral cell membrane.


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Histology_Ross. Enteroendocrine cells secrete their products into either Most of them represent small cells that rest on the basal lamina the lamina propria or underlying blood vessels. and do not always reach the lumen; they are known as enteroendocrine “closed” cells (Fig. 17.12ab and Plate 57, Enteroendocrine cells are found at every level of the fundic page 612). Some, however, have a thin cytoplasmic extension gland, although they tend to be somewhat more prevalent in the bearing microvilli that are exposed to the gland lumen base (Folder 17.3). In general, two types of enteroendocrine (Fig 17.12c); these are referred as enteroendocrine cells can be distinguished throughout the gastrointestinal tract.  FOLDER 17.3 Functional Considerations: The Gastrointestinal Endocrine System


Histology_Ross

Histology_Ross. Enteroendocrine cells are specialized cells present in the mucosa of the digestive tract. They account for less than 1% of all epithelial cells in the gastrointestinal tract, but as a whole, they collectively constitute the largest endocrine “organ” in the body. Enteroendocrine cells are also found in the ducts of the pancreas, the liver, and the respiratory sys-tem, another endodermal derivative that originates by in-vagination of the epithelium of the embryonic foregut. Because enteroendocrine cells closely resemble neurose-cretory cells of the central nervous system (CNS) that se-crete many of the same hormones, signaling molecules, and regulatory agents, they are also called neuroendocrine cells. Most of these cells are not grouped as clusters in any specific part of the gastrointestinal tract. Rather, enteroen-docrine cells are distributed singly throughout the gastroin-testinal epithelium. For that reason, they are described as constituting part of a diffuse neuroendocrine


Histology_Ross

Histology_Ross. tract. Rather, enteroen-docrine cells are distributed singly throughout the gastroin-testinal epithelium. For that reason, they are described as constituting part of a diffuse neuroendocrine system (DNES). Figure 17.13 shows the parts of the gastrointesti-nal tract from which the gastrointestinal peptides are pro-duced. One notable exception to this distribution pattern is found in the pancreas. Here, enteroendocrine cells, derived from pancreatic buds that also arise from the em-bryonic foregut, form specialized accumulations called en-docrine islets of Langerhans (see page 649). In the current view, the DNES includes both neurons and endocrine cells that share common characteristics, including the expression of specific markers (e.g., neu-ropeptides, chromogranins, and neuropeptide processing enzymes) and the presence of dense-core secretory gran-ules. Secretory products of enteroendocrine cells derive from a variety of genes; they are expressed in different forms because of


Histology_Ross

Histology_Ross. processing enzymes) and the presence of dense-core secretory gran-ules. Secretory products of enteroendocrine cells derive from a variety of genes; they are expressed in different forms because of alternative splicing and differential pro-cessing. Secretion of enteroendocrine cells is regulated by G protein–coupled receptors and tyrosine-kinase activity. There is evidence that chromogranin-A regulates biosyn-thesis of dense-core secretory granules, whereas chromo-granin-B controls sorting and packaging of produced peptides into secretory vesicles. Table 17.1 lists important gastrointestinal hormones, their sites of origin, and their major functions. Neoplastic transformations of DNES cells are responsi-ble for development of gastroenteropancreatic (GEP) neuroendocrine tumors. These tumors represent rare neoplasms of the gastrointestinal tract and pancreas that often secrete hormonally active agents, causing distinct clinical syndromes. The appendix is the most common gastrointestinal


Histology_Ross

Histology_Ross. represent rare neoplasms of the gastrointestinal tract and pancreas that often secrete hormonally active agents, causing distinct clinical syndromes. The appendix is the most common gastrointestinal site of origin for neuroendocrine tumors. The classical example is the carcinoid syndrome caused by the release of a variety of hormonally active substances by tumor cells. Symptoms include diarrhea (case by sero-tonin), episodic flushing, bronchoconstriction, and right-sided cardiac valve disease. Some enteroendocrine cells may be classifiable func-tionally as amine precursor uptake and decarboxylation (APUD) cells. They should not, however, be confused with the APUD cells that are derived from the embryonic neural crest and migrate to other sites in the body. APUD cells se-crete a variety of regulator substances in tissues and or-gans including the respiratory epithelium, adrenal medulla, islets of Langerhans, thyroid gland (parafollicular cells), and pituitary gland. The enteroendocrine


Histology_Ross

Histology_Ross. regulator substances in tissues and or-gans including the respiratory epithelium, adrenal medulla, islets of Langerhans, thyroid gland (parafollicular cells), and pituitary gland. The enteroendocrine cells differentiate from the progeny of the same stem cells as all of the other epithelial cells of the digestive tract. The fact that two dif-ferent cells may produce similar products should not imply that they have the same origin. Enteroendocrine cells produce not only gastrointestinal hormones such as gastrin, ghrelin, secretin, cholecys-tokinin (CCK), gastric inhibitory peptide (GIP), and motilin, but also paracrine hormones. A paracrine hormone dif-fers from an endocrine hormone in that it diffuses locally to its target cell instead of being carried by the bloodstream to a target cell. A well-known substance that appears to act as a paracrine hormone within the gastrointestinal tract and pancreas is somatostatin, which inhibits other gas-trointestinal and pancreatic islet endocrine


Histology_Ross

Histology_Ross. A well-known substance that appears to act as a paracrine hormone within the gastrointestinal tract and pancreas is somatostatin, which inhibits other gas-trointestinal and pancreatic islet endocrine cells. In addition to the established gastrointestinal hormones, several gastrointestinal peptides have not been definitely classified as hormones or paracrine hormones. These pep-tides are designated candidate or putative hormones. Other locally active agents isolated from the gastroin-testinal mucosa are neurotransmitters. These agents are released from nerve endings close to the target cell, usu-ally the smooth muscle of the muscularis mucosae, the muscularis externa, or the tunica media of a blood vessel. Enteroendocrine cells can also secrete neurotransmitters that activate afferent neurons, sending signals to the CNS and enteric division of autonomic nervous system. In addi-tion to acetylcholine (not a peptide), peptides found in nerve fibers of the gastrointestinal tract are


Histology_Ross

Histology_Ross. neurons, sending signals to the CNS and enteric division of autonomic nervous system. In addi-tion to acetylcholine (not a peptide), peptides found in nerve fibers of the gastrointestinal tract are vasoactive in-testinal peptide (VIP), bombesin, and enkephalins. Thus, a particular peptide may be produced by endocrine and paracrine cells and also be localized in nerve fibers.


Histology_Ross

Histology_Ross. FIGURE 17.12 • Electron micrograph and diagrams of enteroendocrine cells. a. This electron micrograph shows an example of the “closed” enteroendocrine cell. Arrowheads mark the boundary between the enteroendocrine cell and the adjacent epithelial cells. At its base, the enteroendocrine cell rests on the basal lamina (BL). This cell does not extend to the epithelial or luminal surface. Numerous secretory vesicle (G) in the base of the cell are secreted in the direction of the arrows across the basal lamina and into the connective tissue (CT ). En, endothelium of capillary; M, mitochondria; rER, rough endoplasmic reticulum; sER, smooth endoplasmic reticulum. b. This diagram of an enteroendocrine “closed” cell is drawn to show that it does not reach the epithelial surface. The secretory vesicles are regularly lost during routine preparation. Because of the absence of other distinctive organelles, the nucleus appears to be surrounded by a small amount of clear cytoplasm in H&E–stained


Histology_Ross

Histology_Ross. are regularly lost during routine preparation. Because of the absence of other distinctive organelles, the nucleus appears to be surrounded by a small amount of clear cytoplasm in H&E–stained sections. c. The enteroendocrine “open” extend to the epithelial surface. Microvilli on the apical surface of these cells possess taste receptors and are able to detect sweet, bitter, and umami sensations. These cells serve as chemoreceptor cells, which monitor an environment on the surface of the epithelium. They are involved in a regulation of gastrointestinal hormones secretion.


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Histology_Ross. “open” cells. It is now known that open cells serve as primary chemoreceptors that sample the contents of the gland lumen and release hormones based on the information obtained from those samples. The taste receptors, similar to those found in taste buds of the specialized oral mucosa (page 530), detect sweet, bitter, and umami sensations and have now been characterized on the free surface of the open enteroendocrine cells. They belong to the T1R and T2R families of G protein–coupled receptors described in Chapter 16 (page 531). Secretion from closed cells, however, is regulated by luminal content indirectly through neural and paracrine mechanisms.


Histology_Ross

Histology_Ross. Electron micrographs reveal small membrane-bound secretory vesicles throughout the cytoplasm; however, the vesicles are typically lost in H&E preparations, and the cytoplasm appears clear because of the lack of sufficient stainable material. Although these cells are often difficult to identify because of their small size and lack of distinctive staining, the clear cytoplasm of the cell sometimes stands out in contrast to adjacent chief or parietal cells, thus allowing their easy recognition.


Histology_Ross

Histology_Ross. The names given to the enteroendocrine cells in the older literature were based on their staining with salts of silver and chromium (i.e., enterochromaffin cells, argentaffin cells, and argyrophil cells). Such cells are currently identified and characterized by immunochemical staining for the more than 20 peptide and polypeptide hormones and hormone-like regulating agents that they secrete (a list of many of these agents and their actions is given in Fig. 17.13 and in Tables 17.1 and 17.2). With the aid of the TEM, at least 17 different types of enteroendocrine cells have been described on the basis of size, shape, and density of their secretory vesicles. Cardiac Glands of the Gastric Mucosa Cardiac glands are composed of mucus-secreting cells.


Histology_Ross

Histology_Ross. Cardiac glands are limited to a narrow region of the stomach (the cardia) that surrounds the esophageal orifice. Their secretion, in combination with that of the esophageal cardiac glands, contributes to the gastric juice and helps protect the esophageal epithelium against gastric reflux. The glands are tubular, somewhat tortuous, and occasionally branched (Fig. 17.14 and Plate 56, page 610). They are composed mainly of mucus-secreting cells, with occasional interspersed enteroendocrine cells. The mucus-secreting cells are similar in appearance to the cells of the esophageal cardiac glands. They have a flattened basal nucleus, and the apical cytoplasm is typically filled with mucin granules. A short duct segment containing columnar cells with elongate nuclei is interposed between the secretory portion of the gland and the shallow pits into which the glands secrete. The duct segment is the site at which the surface mucous cells and the gland cells are produced.


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Histology_Ross. FIGURE 17.13 • Gastrointestinal hormones. This schematic diagram shows the distribution of gastrointestinal peptide hormones produced by enteroendocrine cells in the alimentary canal. CCK, cholecystokinin; VIP, vasoactive intestinal peptide; GIP, gastric inhibitory peptide. (Modified from Johnson LR, ed. Gastrointestinal Physiology. St. Louis: Mosby-Year Book, 1997.) Pyloric Glands of the Gastric Mucosa Pyloric gland cells are similar to surface mucous cells and help protect the pyloric mucosa. Pyloric glands are located in the pyloric antrum (the part of the stomach between the fundus and the pylorus). They are branched, coiled, tubular glands (Plate 58, page 614).


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Histology_Ross. 583 TABLE Physiologic Actions of Gastrointestinal Hormones 17.1 Major Action Hormone Site of Synthesis Stimulates Inhibits Gastrin G cells in stomach Gastric acid secretion Ghrelin Gr cells in stomach GH secretion Appetite and perception of hunger Lipid metabolism Fat utilization in adipose tissue Cholecystokinin (CCK) I cells in duodenum and jejunum Gallbladder contraction Pancreatic enzyme secretion Pancreatic bicarbonate ion secretion Pancreatic growth Gastric emptying Secretin S cells in duodenum Pancreatic enzyme secretion Pancreatic bicarbonate ion secretion Pancreatic growth Gastric acid secretion Gastric inhibitory peptide (GIP) K cells in duodenum and jejunum Insulin release Gastric acid secretion Motilin Mo cells in duodenum and jejunum Gastric motility Intestinal motility Modified from Johnson LR, ed. Essential Medical Physiology. Philadelphia: Lippincott-Raven, 1998. GH, growth hormone.


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Histology_Ross. TABLE Physiologic Actions of Other Hormones in the Gastrointestinal Tract 17.2 Modified from Johnson LR, ed. Essential Medical Physiology. Philadelphia: Lippincott-Raven, 1998. GI, gastrointestinal. Major Action Hormone Site of Synthesis Stimulates Inhibits Candidate hormones Pancreatic polypeptide PP cells in pancreas Gastric emptying and gut motility Pancreatic enzyme secretion Pancreatic bicarbonate secretion Peptide YY L cells in ileum and colon Electrolyte and water absorption in the colon Gastric acid secretion Gastric emptying Food intake Glucagon-like peptide-1 (GLP-1) L cells in ileum and colon Insulin release Gastric acid secretion Gastric emptying Paracrine hormones Somatostatin D cells in mucosa throughout GI tract Gastrin release Gastric acid secretion Release of other GI hormones Histamine Mucosa throughout GI tract Gastric acid secretion Neurocrine hormones Bombesin Stomach Gastrin release Enkephalins Mucosa and smooth muscle throughout GI tract Smooth muscle


Histology_Ross

Histology_Ross. GI hormones Histamine Mucosa throughout GI tract Gastric acid secretion Neurocrine hormones Bombesin Stomach Gastrin release Enkephalins Mucosa and smooth muscle throughout GI tract Smooth muscle contraction Intestinal secretion Vasoactive inhibitory peptide (VIP) Mucosa and smooth muscle throughout GI tract Pancreatic enzyme secretion Intestinal secretion Smooth muscle contraction Sphincter contraction


Histology_Ross

Histology_Ross. The lumen is relatively wide, and the secretory cells are similar in appearance to the surface mucous cells, suggesting a relatively viscous secretion. Enteroendocrine cells are found interspersed within the gland epithelium along with occasional parietal cells. The glands empty into deep gastric pits that occupy about half the thickness of the mucosa (Fig. 17.15). Epithelial Cell Renewal in the Stomach Surface mucous cells are renewed approximately every 3 to 5 days.


Histology_Ross

Histology_Ross. Epithelial Cell Renewal in the Stomach Surface mucous cells are renewed approximately every 3 to 5 days. The relatively short lifespan of the surface mucous cells, 3 to 5 days, is accommodated by mitotic activity in the isthmus, the narrow segment that lies between the gastric pit and the fundic gland (Fig. 17.16). The isthmus of the fundic gland contains a reservoir of tissue stem cells that undergo mitotic activity, providing for continuous cell renewal. Most of the newly produced cells at this site become surface mucous cells. They migrate upward along the wall of the pit to the luminal surface of the stomach and are ultimately shed into the stomach lumen. The cells of the fundic glands have a relatively long lifespan.


Histology_Ross

Histology_Ross. Other cells from the isthmus migrate down into the gastric glands to give rise to the parietal cells, chief cells, mucous gland cells, and enteroendocrine cells that constitute the gland epithelium. These cells have a relatively long lifespan. The parietal cells have the longest lifespan, approximately 150 to 200 days. Although parietal cells develop from the same undifferentiated stem cells, their lifespan is distinctly different. Recently, it has been hypothesized that parietal cells may have originated from a bacterium called Neurospora crassa that previously existed in a symbiotic relationship with the cells of the human stomach. The basis for this hypothesis is that the human proton pump (H/K-ATPase) found in parietal cells bears a strong genetic similarity to proton pumps found in this bacterium. The bacterial DNA is thought to have been translocated and subsequently incorporated into the nucleus of the stem cells, probably with the help of a virus.


Histology_Ross

Histology_Ross. The chief and enteroendocrine cells are estimated to live for about 60 to 90 days before they are replaced by new cells migrating downward from the isthmus. The mucous neck cell, in contrast, has a much shorter lifespan, approximately 6 days. The lamina propria of the stomach is relatively scant and restricted to the limited spaces surrounding the gastric pits and glands. The stroma is composed largely of reticular fibers with associated fibroblasts and smooth muscle cells. Other components include cells of the immune system, namely, lymphocytes, plasma cells, macrophages, and some eosinophils. When


Histology_Ross

Histology_Ross. FIGURE 17.14 • Photomicrograph of cardiac glands. This photomicrograph shows the esophagogastric junction. Note the presence of the stratified squamous epithelium of the esophagus in the upper right corner of the micrograph. The cardiac glands are tubular, somewhat tortuous, and occasionally branched. They are composed mainly of mucus-secreting cells similar in appearance to the cells of the esophageal glands. Mucous secretion reaches the lumen of the gastric pit via a short duct segment containing columnar cells. 240. inflammation occurs, as is often the case, neutrophils may also be prominent. Occasional lymphatic nodules are also present, usually intruding partially into the muscularis mucosae.


Histology_Ross

Histology_Ross. inflammation occurs, as is often the case, neutrophils may also be prominent. Occasional lymphatic nodules are also present, usually intruding partially into the muscularis mucosae. The muscularis mucosae is composed of two relatively thin layers, usually arranged as an inner circular and outer longitudinal layer. In some regions, a third layer may be present; its orientation tends to be in a circular pattern. Thin strands of smooth muscle cells extend toward the surface in the lamina propria from the inner layer of the muscularis mucosae. These smooth muscle cells in the lamina propria are thought to help outflow of the gastric gland secretions. The submucosa is composed of a dense connective tissue containing variable amounts of adipose tissue and blood vessels, as well as the nerve fibers and ganglion cells that compose the submucosal (Meissner’s) plexus. The latter innervates the vessels of the submucosa and the smooth muscle of the muscularis mucosae.


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Histology_Ross. FIGURE 17.15 • Photomicrograph of pyloric glands. This photomicrograph shows a section of the wall of the pylorus. The pyloric glands are relatively straight for most of their length but are slightly coiled near the muscularis mucosae. The lumen is relatively wide, and the secretory cells are similar in appearance to the surface mucous cells, suggesting a relatively viscous secretion. They are restricted to the mucosa and empty into the gastric pits. The boundary between the pits and glands is, however, hard to ascertain in routine H&E preparations. 120.


Histology_Ross

Histology_Ross. The muscularis externa of the stomach is traditionally described as consisting of an outer longitudinal layer, a middle circular layer, and an inner oblique layer. This description is somewhat misleading, as distinct layers may be difficult to discern. As with other hollow, spheroidal organs (e.g., gallbladder, urinary bladder, and uterus), the smooth muscle of the muscularis externa of the stomach is somewhat more randomly oriented than the term layer implies. Moreover, the longitudinal layer is absent from much of the anterior and posterior stomach surfaces, and the circular layer is poorly developed in the periesophageal region. The arrangement of the muscle layers is functionally important, as it relates to its role in mixing chyme during the digestive process as well as to its ability to force the partially digested contents into the small intestine. Groups of ganglion cells and bundles of unmyelinated nerve fibers are present between the muscle layers. Collectively, they


Histology_Ross

Histology_Ross. ability to force the partially digested contents into the small intestine. Groups of ganglion cells and bundles of unmyelinated nerve fibers are present between the muscle layers. Collectively, they represent the myenteric (Auerbach’s) plexus, which provides innervation of the muscle layers.


Histology_Ross

Histology_Ross. FIGURE 17.16 • Photomicrograph of a dividing cell in the isthmus of a pyloric gland. The gastric pits in this photomicrograph were sectioned in a plane that is oblique to the axis of the pit. Note that on this section, gastric pits (arrows) can be recognized as invaginations of surface epithelium that are surrounded by lamina propria. The lamina propria is highly cellular because of the presence of large numbers of lymphocytes. 240. Inset. This high magnification of the area indicated by the rectangle shows a dividing cell in the isthmus. 580. The serosa of the stomach is as described above for the alimentary canal in general. It is continuous with the parietal peritoneum of the abdominal cavity via the greater omentum and with visceral peritoneum of the liver at the lesser omen-tum. Otherwise, it exhibits no special features.


Histology_Ross

Histology_Ross. The small intestine is the longest component of the digestive tract, measuring over 6 m, and is divided into three anatomic portions:  Duodenum (25 cm long) is the first, shortest, and widest part of the small intestine. It begins at the pylorus of the stomach and ends at the duodenojejunal junction (Plate 59, page 616).  Jejunum (2.5 m long) begins at the duodenojejunal junction and constitutes the upper two fifths of the small intestine. It gradually changes its morphologic characteristics to become the ileum (Plate 60, page 618).  Ileum (3.5 m long) is a continuation of the jejunum and constitutes the lower three fifths of the small intestine. It ends at the ileocecal junction, the union of the distal ileum and cecum (Plate 61, page 620). The small intestine is the principal site for the digestion of food and absorption of the products of digestion.


Histology_Ross

Histology_Ross. The small intestine is the principal site for the digestion of food and absorption of the products of digestion. Chyme from the stomach enters the duodenum, where enzymes from the pancreas and bile from the liver are also delivered to continue the solubilization and digestion process. Enzymes, particularly disaccharidases and dipeptidases, are also located in the glycocalyx of the microvilli of the enterocytes, the intestinal absorptive cells. These enzymes contribute to the digestive process by completing the breakdown of most sugars and proteins to monosaccharides and amino acids, which are then absorbed (Folder 17.4). Water and electrolytes that reach the small intestine with the chyme and pancreatic and hepatic secretions are also reabsorbed in the small intestine, particularly in the distal portion. Plicae circulares, villi, and microvilli increase the absorptive surface area of the small intestine.


Histology_Ross

Histology_Ross. Plicae circulares, villi, and microvilli increase the absorptive surface area of the small intestine. The absorptive surface area of the small intestine is amplified by tissue and cell specializations of the submucosa and mucosa.  Plicae circulares (circular folds), also known as the valves of Kerckring, are permanent transverse folds that contain a core of submucosa. Each circular fold is circularly arranged and extends about one half to two thirds of the way around the circumference of the lumen (Fig. 17.17). The folds begin to appear about 5 to 6 cm beyond the pylorus. They are most numerous in the distal part of the duodenum and the beginning of the jejunum and become reduced in size and frequency in the middle of the ileum.


Histology_Ross

Histology_Ross.  Villi are unique, fingerlike and leaflike projections of the mucosa that extend from the theoretical mucosal surface for 0.5 to 1.5 mm into the lumen (Fig. 17.18). They completely cover the surface of the small intestine, giving it a velvety appearance when viewed with the unaided eye.  Microvilli of the enterocytes provide the major amplification of the luminal surface. Each cell possesses several thousand closely packed microvilli. They are visible in the light microscope and give the apical region of the cell a striated appearance, the so-called striated border. Enterocytes and their microvilli are described below. The villi and intestinal glands, along with the lamina propria, associated GALT, and muscularis mucosae, constitute the essential features of the small intestinal mucosa.


Histology_Ross

Histology_Ross. The villi and intestinal glands, along with the lamina propria, associated GALT, and muscularis mucosae, constitute the essential features of the small intestinal mucosa. Villi, as noted, are projections of the mucosa. They consist of a core of loose connective tissue covered by a simple columnar epithelium. The core of the villus is an extension of the lamina propria, which contains numerous fibroblasts, smooth muscle cells, lymphocytes, plasma cells,  FOLDER 17.4 Functional Considerations: Digestive and Absorptive Functions of Enterocytes


Histology_Ross

Histology_Ross. Carbohydrate final digestion is brought about by enzymes bound to the microvilli of the enterocytes (Fig. 17.4.2). Galactose, glucose, and fructose are absorbed directly into venous capillaries and conveyed to the liver by the vessels of the hepatic portal system. Some infants and a larger percentage of adults cannot tolerate milk and unfermented milk products because of the absence of lactase, the disaccharidase that splits lactose into galactose and


Histology_Ross

Histology_Ross. The plasma membrane of the microvilli of the enterocyte plays a role in digestion as well as absorption. Digestive enzymes are anchored in the plasma membrane, and their functional groups extend outward to become part of the glycocalyx. This arrangement brings the end products of digestion close to their site of absorption. Included among the enzymes are peptidases and disaccharidases. The plasma membrane of the apical microvilli also contains the enzyme enteropeptidase (enterokinase), which is particularly important in the duodenum, where it converts trypsinogen into trypsin. Trypsin can then continue to convert additional trypsinogen into trypsin, and trypsin converts several other pancreatic zymogens into active enzymes (Fig. F17.4.1). A summary of digestion and absorption of the three major nutrients is outlined in the following paragraphs.


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Histology_Ross. FIGURE F17.4.1 • Diagram showing events in the activation of the proteolytic enzymes of the pancreas. The majority of pancreatic enzymes (proteases) are secreted as inactive proenzymes. Their activation is triggered by the arrival of chyme into the duodenum. This stimulates the mucosal cells to release and to activate the enterokinase (blue box) within the glycocalyx. The enterokinase activates trypsinogen, converting it into its active form, trypsin (green box). In turn, trypsin activates other pancreatic proenzymes (red box) into their active forms (purple box). The active proteases hydrolyze peptide bonds of proteins or polypeptides and reduce them to small peptides and amino acids. FIGURE F17.4.2 • Diagram showing the digestion and absorption of carbohydrates by an enterocyte.


Histology_Ross

Histology_Ross. Carbohydrates are delivered to the alimentary canal as monosaccharides (e.g., glucose, fructose, and galactose), disaccharides (e.g., sucrose, lactose, and maltose), and polysaccharides (e.g., glycogen and starch). Enzymes involved in digestion of carbohydrates are classified as salivary and pancreatic amylases. Further digestion is performed at the striated border of the enterocytes by enzymes breaking down oligosaccharides and polysaccharides into three basic monosaccharides (glucose, galactose, and fructose). Glucose and galactose are absorbed by the enterocyte via an active transport using Na-dependent glucose transporters (SGLT1). These transporters are localized at the apical cell membrane (brown circles with G and Na labels). Fructose enters the cell via facilitated Na-independent transport using GLUT5 (gray circle with F label) and GLUT2 glucose transporters (orange octagon with G2 label). The three absorbed monosaccharides then pass through the basal membrane of the


Histology_Ross

Histology_Ross. transport using GLUT5 (gray circle with F label) and GLUT2 glucose transporters (orange octagon with G2 label). The three absorbed monosaccharides then pass through the basal membrane of the enterocyte, using GLUT2 glucose transporters, into the underlying capillaries of the portal circulation to reach their final destination in the liver.


Histology_Ross

Histology_Ross. eosinophils, macrophages, and a network of fenestrated blood capillaries located just beneath the epithelial basal lamina. In addition, the lamina propria of the villus contains a central, blind-ending lymphatic capillary, the lacteal (Fig. 17.19 and Plate 60, page 618). Smooth muscle cells derived from the muscularis mucosae extend into the villus and accompany the lacteal. These smooth muscle cells may account for reports that villi contract and shorten intermittently, an action that may force lymph from the lacteal into the lymphatic vessel network that surrounds the muscularis mucosae. The intestinal glands, or crypts of Lieberkn, are simple tubular structures that extend from the muscularis mucosae through the thickness of the lamina propria, where they open onto the luminal surface of the intestine at the base of the villi (see Fig. 17.18). The glands are composed of a simple columnar epithelium that is continuous with the epithelium of the villi.


Histology_Ross

Histology_Ross. FIGURE 17.17 • Photograph of the mucosal surface of the small intestine. This photograph of a segment of a human jejunum shows the mucosal surface. The circular folds (plicae circulares) appear as a series of transversely oriented ridges that extend partially around the lumen. Consequently, some of the circular folds appear to end (or begin) at various sites along the luminal surface (arrows). The entire mucosa has a velvety appearance because of the presence of villi.


Histology_Ross

Histology_Ross. As in the stomach, the lamina propria surrounds the intestinal glands and contains numerous cells of the immune system (lymphocytes, plasma cells, mast cells, macrophages, and eosinophils), particularly in the villi. The lamina propria also contains numerous nodules of lymphatic tissue that represent a major component of the GALT. The nodules are particularly large and numerous in the ileum, where they are preferentially located on the side of the intestine opposite the mesenteric attachment (Fig. 17.20). These nodular aggregations are known as aggregated nodules or Peyer’s patches. In gross specimens, they appear as aggregates of white specks. The muscularis mucosae consists of two thin layers of smooth muscle cells, an inner circular and an outer longitudinal layer. As noted above, strands of smooth muscle cells extend from the muscularis mucosae into the lamina propria of the villi. At least five types of cells are found in intestinal mucosal epithelium.


Histology_Ross

Histology_Ross. At least five types of cells are found in intestinal mucosal epithelium. The mature cells of the intestinal epithelium are found both in the intestinal glands and on the surface of the villi. They include the following:  Enterocytes, whose primary function is absorption  Goblet cells, unicellular mucin-secreting glands  Paneth cells, whose primary function is to maintain substances  Enteroendocrine cells, which produce various paracrine and endocrine hormones  M cells (microfold cells), modified enterocytes that cover enlarged lymphatic nodules in the lamina propria Enterocytes are absorptive cells specialized for the transport of substances from the lumen of the intestine to the circulatory system. Enterocytes are tall columnar cells with a basally positioned nucleus (see Figs. 17.18 and 17.21). Microvilli increase the apical surface area as much as 600 times; they are recognized in the light microscope as forming a striated border on the luminal surface.


Histology_Ross

Histology_Ross. Each microvillus has a core of vertically oriented actin microfilaments that are anchored to villin located in the tip of the microvillus and that also attach to the microvillus plasma membrane by myosin I molecules. The actin microfilaments extend into the apical cytoplasm and insert into the terminal web, a network of horizontally oriented contractile microfilaments that form a layer in the most apical cytoplasm and attach to the intracellular density associated with the zonula adherens. Contraction of the terminal web causes the microvilli to spread apart, thus increasing the space between them to allow more surface area exposure for absorption to take place. In addition, contraction of the terminal web may aid in “closing” the holes left in the epithelial sheet by exfoliation of aging cells. Enterocytes are bound to one another and to the goblet, enteroendocrine, and other cells of the epithelium by junctional complexes.


Histology_Ross

Histology_Ross. Tight junctions establish a barrier between the intestinal lumen and the epithelial intercellular compartment. The tight junctions between the intestinal lumen and the connective tissue compartment of the body allow selective retention of substances absorbed by the enterocytes. As noted in the section on occluding junctions, the “tightness” of these junctions can vary. In relatively impermeable tight junctions, as in the ileum and colon, active transport is required to move solutes across the barrier. In simplest terms, active transport systems, e.g., sodium pumps (Na/K-ATPase), located in the lateral plasma membrane transiently reduce the cytoplasmic concentration of Na by transporting it across the lateral plasma membrane into the extracellular space below the tight junction. This transport of Na creates a high intercellular Na concentration, causing water from the cell to enter the intercellular space, reducing both the water and Na concentrations in the


Histology_Ross

Histology_Ross. FIGURE 17.18 • Intestinal villi in the small intestine. a. Scanning electron micrograph of the intestinal mucosa showing its villi. Note the openings (arrows) located between the bases of the villi that lead into the intestinal glands (crypts of Lieberkn). 800. b. This three-dimensional diagram of the intestinal villi shows the continuity of the epithelium covering the villi with the epithelium lining the intestinal glands. Note blood vessels and the blind-ending lymphatic capillary, called a lacteal, in the core of the villus. Between the bases of the villi, the openings of the intestinal glands can be seen (arrows). Also, the small openings on the surface of the villi indicate the location of discharged goblet cells.


Histology_Ross

Histology_Ross. cell. Consequently, water and Na enter the cell at its apical surface, passing through the cell, and exiting at the lateral plasma membrane as long as the sodium pump continues to function. Increased osmolarity in the intercellular space draws water into this space, establishing a hydrostatic pressure that drives Na and water across the basal lamina into the connective tissue. In epithelia with more permeable tight junctions, such as those in the duodenum and jejunum, a sodium pump also creates low intracellular Na concentration. When the contents that pass into the duodenum and jejunum are hypotonic, however, considerable absorption of water, along with additional Na and other small solutes, takes place directly across the tight junctions of the enterocytes into the intercellular spaces. This mechanism of absorption is referred to as solvent drag.


Histology_Ross

Histology_Ross. Other transport mechanisms also increase the concentrations of specific substances, such as sugars, amino acids, and other solutes in the intercellular space. These substances then diffuse or flow down their concentration gradients within the intercellular space to cross the epithelial basal lamina and enter the fenestrated capillaries in the lamina propria located immediately beneath the epithelium. Substances that are too large to enter the blood vessels, such as lipoprotein particles, enter the lymphatic lacteal.


Histology_Ross

Histology_Ross. The lateral cell surface of the enterocytes exhibits elaborate, flattened cytoplasmic processes (plicae) that interdigitate with those of adjacent cells (see Fig. 5.000). These folds increase the lateral surface area of the cell, thus increasing the amount of plasma membrane containing transport enzymes. During active absorption, especially of solutes, water, and lipids, these lateral plications separate, enlarging the intercellular compartment. The increased hydrostatic pressure from the accumulated solutes and solvents causes a directional flow through the basal lamina into the lamina propria (see Fig. 5.1).


Histology_Ross

Histology_Ross. FIGURE 17.19 • Photomicrograph of an intestinal villus. The surface of the villus consists of columnar epithelial cells, chiefly enterocytes with a striated border. Also evident are goblet cells that can be readily identified by the presence of the apical mucous cup. Located beneath the epithelium is the highly cellular loose connective tissue, the lamina propria. The lamina propria contains large numbers of round cells, mostly lymphocytes. In addition, smooth muscle cells can be identified. A lymphatic capillary called a lacteal occupies the center of the villus. When the lacteal is dilated, as it is in this specimen, it is easily identified. 160.


Histology_Ross

Histology_Ross. In addition to the membrane specializations associated with absorption and transport, the enterocyte cytoplasm is also specialized for these functions. Elongated mitochondria that provide energy for transport are concentrated in the apical cytoplasm between the terminal web and the nucleus. Tubules and cisternae of the smooth endoplasmic reticulum (sER), which are involved in the absorption of fatty acids and glycerol and in the resynthesis of neutral fat, are found in the apical cytoplasm beneath the terminal web. Enterocytes are also secretory cells, producing enzymes needed for terminal digestion and absorption as well as secretion of water and electrolytes.


Histology_Ross

Histology_Ross. Enterocytes are also secretory cells, producing enzymes needed for terminal digestion and absorption as well as secretion of water and electrolytes. The secretory function of enterocytes, primarily the synthesis of glycoprotein enzymes that will be inserted into the apical plasma membrane, is represented morphologically by aligned stacks of Golgi cisternae in the immediate supranuclear region and by the presence of free ribosomes and rER lateral to the Golgi apparatus (see Fig. 17.21). Small secretory vesicles con-


Histology_Ross

Histology_Ross. FIGURE 17.20 • Photomicrograph of Peyer’s patches. This photomicrograph shows a longitudinal section through the wall of a human ileum. Note the extensive lymphatic nodules located in the mucosa and the section of a circular fold projecting into the lumen of the ileum. Lymphatic nodules within the Peyer’s patch are primarily located within the lamina propria, although many extend into the submucosa. They are covered by the intestinal epithelium, which contains enterocytes, occasional goblet cells, and specialized antigen-presenting M cells. 40. taining glycoproteins destined for the cell surface are located in the apical cytoplasm, just below the terminal web, and along the lateral plasma membrane. Histochemical or autoradiographic methods are needed, however, to distinguish these secretory vesicles from endocytotic vesicles or small lysosomes. The small intestine also secretes water and electrolytes. This activity occurs mainly in the cells within the intestinal


Histology_Ross

Histology_Ross. FIGURE 17.21 • Diagrams of an enterocyte in different phases of absorption. a. This cell has a striated border on its apical surface and junctional complexes that seal the lumen of the intestine from the lateral intercellular space. The characteristic complement of major organelles is depicted in the diagram. b. This cell shows the distribution of lipid during fat absorption as seen with the TEM. Initially, lipids are seen in association with the microvilli of the striated border. Lipids are internalized and seen in vesicles of the smooth endoplasmic reticulum (sER) in the apical portion of the cell. The membrane-bounded lipid can be traced to the center of the cell, where many of the lipid-containing vesicles fuse. The lipid is then discharged into the intercellular space. The extracellular lipids, recognized as chylomicrons, pass beyond the basal lamina for further transport into lymphatic (green) and/or blood vessels (red).


Histology_Ross

Histology_Ross. glands. The secretion that occurs in these glands is thought ination with the TEM reveals a large accumulation of mu-to assist the process of digestion and absorption by maintain-cinogen granules in the apical cytoplasm that distends the ing an appropriate liquid state of the intestinal chyme. apex of the cell and distorts the shape of neighboring cells Under normal conditions, the absorption of fluid by the vil-(Fig. 17.22). With the apex of the cell containing a large lus enterocyte is balanced by the secretion of fluid by the accumulation of mucinogen granules, the basal portion of the gland enterocyte. cell resembles a narrow stem. This basal portion is intensely basophilic in histologic preparations because it is occupied by Goblet cells represent unicellular glands that are inter- a heterochromatic nucleus, extensive rER, and free ribo spersed among the other cells of the intestinal epithelium.


Histology_Ross

Histology_Ross. Goblet cells represent unicellular glands that are inter- a heterochromatic nucleus, extensive rER, and free ribo spersed among the other cells of the intestinal epithelium. somes. Mitochondria are also concentrated in the basal cyto-As in other epithelia, goblet cells produce mucus. In the plasm. The characteristic shape, with the apical accumulation small intestine, goblet cells increase in number from the duo-of granules and the narrow basal stem, is responsible for the denum to the terminal part of the ileum. Also, as in other name of the cell, as in a glass “goblet.” An extensive array of epithelia, because water-soluble mucinogen is lost during flattened Golgi cisternae forms a wide cup around the newly preparation of routine H&E sections, the part of the cell that formed mucinogen granules adjacent to the basal part of the normally contains mucinogen granules appears empty. Exam-cell (see Fig. 17.22a). The microvilli of goblet cells are


Histology_Ross

Histology_Ross. FIGURE 17.22 • Electron micrograph and the diagram of a goblet cell. a. This electron micrograph shows the basal portion of a goblet cell depicted on the adjacent diagram. The cell rests on the basal lamina. The basal portion of the cell contains the nucleus, rough endoplasmic reticulum, and mitochondria. Just apical to the nucleus are extensive profiles of Golgi apparatus. As the mucous product accumulates in the Golgi cisternae, they become enlarged (asterisks). The large mucinogen granules fill most of the apical portion of the cell and collectively constitute the “mucous cup” seen in the light microscope. 15,000. b. This diagram shows the entire goblet cell. The boxed region on this diagram represents an area from which the adjacent electron micrograph was most likely obtained. The nucleus is located at the basal portion of the cell. The major portion of the cell is filled with mucinogen granules forming the mucous cup that is evident in the light microscope. At the base and lower


Histology_Ross

Histology_Ross. is located at the basal portion of the cell. The major portion of the cell is filled with mucinogen granules forming the mucous cup that is evident in the light microscope. At the base and lower sides of the mucous cup are flattened saccules of the large Golgi apparatus. Other organelles are distributed throughout the remaining cytoplasm, especially in the perinuclear cytoplasm in the base of the cell.


Histology_Ross

Histology_Ross. restricted to a thin rim of cytoplasm (the theca) that surrounds the apical-lateral portion of the mucinogen granules. Microvilli are more obvious on the immature goblet cells in the deep one half of the intestinal gland. Paneth cells play a role in regulation of normal bacterial flora of the small intestine. Paneth cells are found in the bases of the intestinal glands. (They are also occasionally found in the normal colon in small numbers; their number may increase in certain pathologic conditions.) They have a basophilic basal cytoplasm, a supranuclear Golgi apparatus, and large, intensely acidophilic, refractile apical secretory vesicles. These vesicles allow their easy identification in routine histologic sections (Fig. 17.23).


Histology_Ross

Histology_Ross. The secretory vesicles contain the antibacterial enzyme lysozyme, -defensins, other glycoproteins, an arginine-rich protein (probably responsible for the intense acidophilia), and zinc. Lysozyme digests the cell walls of certain groups of bacteria. -defensins are homologs of peptides that function as mediators in cytotoxic CD8 T lymphocytes. Their antibacterial action and ability to phagocytose certain bacteria and protozoa suggest that Paneth cells play a role in regulating the normal bacterial ﬂora of the small intestine. Enteroendocrine cells in the small intestine produce nearly all of the same peptide hormones as they do in the stomach.


Histology_Ross

Histology_Ross. Enteroendocrine cells in the small intestine produce nearly all of the same peptide hormones as they do in the stomach. Enteroendocrine cells in the small intestine resemble those that reside in the stomach (see Fig. 17.12). The “closed cells” are concentrated in the lower portion of the intestinal gland, whereas the “open cells” can be found at all levels of each villus. Activation of taste receptors found on the apical cell membrane of “open cells” activates G protein–signaling cascade, resulting in releasing of peptides that regulate a variety of gastrointestinal functions. These include regulating pancreatic secretion, inducing digestion and absorption, and controlling energy homeostasis by acting on neural pathways


Histology_Ross

Histology_Ross. FIGURE 17.23 • Photomicrograph of intestinal glands showing Paneth cells. This photomicrograph shows the base of intestinal (jejunal) glands in an H&E preparation. The gland on the right is sectioned longitudinally; the circular cross-sectional profile of another gland is seen on the left. Paneth cells are typically located in the base of the intestinal glands and are readily seen in the light microscope because of the intensive eosin staining of their vesicles. The lamina propria contains an abundance of plasma cells, lymphocytes, and other connective tissue cells. Note several lymphocytes in the epithelium of the gland (arrows). 240. Inset. This high magnification of the area indicated by the rectangle shows the characteristic basophilic cytoplasm in the basal portion of the cell and large accumulations of intensely staining, eosinophilic, refractile secretory vesicles in the apical portion of the cell. An arginine-rich protein found in the vesicles is probably responsible for the


Histology_Ross

Histology_Ross. accumulations of intensely staining, eosinophilic, refractile secretory vesicles in the apical portion of the cell. An arginine-rich protein found in the vesicles is probably responsible for the intense eosinophilic reaction. 680.


Histology_Ross

Histology_Ross. of brain-gut-adipose axis. Nearly all of the same peptide hormones identified in this cell type in the stomach can be demonstrated in the enteroendocrine cells of the intestine (see Table 17.1). Cholecystokinin (CCK), secretin, gastric inhibitory polypeptide (GIP), and motilin are the most active regulators of gastrointestinal physiology that are released in this portion of the gut (see Fig. 17.13). CCK and secretin increase pancreatic and gallbladder activity and inhibit gastric secretory function and motility. GIP stimulates insulin release in the pancreas, and motilin initiates gastric and intestinal motility. Although other peptides produced by enteroendocrine cells have been isolated, they are not considered hormones and are therefore called candidate hormones (page 584). Enteroendocrine cells also produce at least two hormones, somatostatin and histamine, which act as paracrine hormones (see page 584) (i.e., hormones that have a local effect and do not circulate in the


Histology_Ross

Histology_Ross. cells also produce at least two hormones, somatostatin and histamine, which act as paracrine hormones (see page 584) (i.e., hormones that have a local effect and do not circulate in the bloodstream). In addition, several peptides are secreted by the nerve cells located in the submucosa and muscularis externa. These peptides, called neurocrine hormones, are represented by VIP, bombesin, and the enkephalins. The functions of these peptides are listed in Table 17.2.


Histology_Ross

Histology_Ross. M cells convey microorganisms and other macromolecules from the intestinal lumen to Peyer’s patches. M cells are epithelial cells that overlie Peyer’s patches and other large lymphatic nodules; they differ significantly from the surrounding intestinal epithelial cells (Folder 17.5). M cells have microfolds rather than microvilli on their apical surface, and they take up microorganisms and macromolecules from the lumen in endocytotic vesicles. The M cell is an antigen-transporting cell. The vesicles are transported to the basolateral membrane where they discharge their contents into the epithelial intercellular space in the vicinity of CD4 T lymphocytes. Thus, substances that gain access to the body from the intestinal lumen via M cells come into contact with cells of the immune system as they reach the basolateral surface. Antigens that reach lymphocytes in this manner stimulate a response in the GALT that is described below.


Histology_Ross

Histology_Ross. Intermediate cells constitute the amplifying compartment of the intestinal stem cell niche.


Histology_Ross

Histology_Ross. Intermediate cells constitute most of the cells found within the intestinal stem cell niche that is located in the lower half of the intestinal gland. These cells constitute the amplifying compartment of the cells that are still capable of cell division and usually undergo one or two divisions before they become committed to differentiation into either absorptive or goblet cells. These cells have short, irregular microvilli with long core filaments extending deep into the apical cytoplasm and numerous macular (desmosomal) junctions with adjacent cells. Small mucin-like secretory granules form a column in the center of the supranuclear cytoplasm. Intermediate cells that are committed to becoming goblet cells develop a small, rounded collection of secretory granules just beneath the apical plasma membrane; those that are committed to becoming absorptive cells lose the secretory granules and begin to show concentrations of mitochondria, rER, and ribosomes in the apical cytoplasm.


Histology_Ross

Histology_Ross. GALT is prominent in the lamina propria of the small intestine. As noted above, the lamina propria of the digestive tract is heavily populated with elements of the immune system; approximately one-fourth of the mucosa consists of a loosely organized layer of lymphatic nodules, lymphocytes, macrophages, plasma cells, and eosinophils in the lamina propria (Plate 55, page 608). Lymphocytes are also located between epithelial cells. This GALT serves as an immunologic barrier throughout the length of the gastrointestinal tract. In cooperation with the overlying epithelial cells, particularly M cells, the lymphatic  FOLDER 17.5 Functional Considerations: Immune Functions of the Alimentary Canal


Histology_Ross

Histology_Ross. Immunologists have shown that the GALT not only re-sponds to antigenic stimuli but also functions in a monitor-ing capacity. This function has been partially clarified for the lymphatic nodules of the intestinal tract. The M cells that cover Peyer’s patches and lymphatic nodules have a distinctive surface that might be misinterpreted in sections as thick microvilli. The cells are readily identified with the scanning electron microscope because microfolds con-trast sharply with the microvilli that constitute the striated border of the adjacent enterocytes. It has been shown with horseradish peroxidase (an enzyme used as an experimental marker) that the M cells pinocytose protein, from the intestinal lumen, transport the pinocytotic vesicles through the cell and discharge the protein by exocytosis into deep recesses of the adjacent extracellular space (Fig. F17.5.1). Lymphocytes within the deeply recessed extracellular space sample the luminal protein, including antigens, and thus have