This chapter should help you to:

· List the accessory glands attached, by their ducts, to the digestive tract. For each, name the primary exocrine products and their roles in digestion.
· Compare mucous and serous secretory cells in terms of their structure, staining properties, and secretory products.
· Compare the 3 major salivary gland types in terms of content and distribution of serous and mucous cells. · Relate the ultrastructure and function of the pancreatic acinar cell.
· Describe the liver's double blood supply.
· Relate the complex ultrastructure of the hepatocyte to its many functions.
· Describe the boundaries and contents of the classic liver lobule, the portal lobule, and the hepatic acinus (of Rappaport) and understand the liver functions that gave rise to these overlapping views of the functional organization of the liver.
· Describe the structure, function, and location of the gallbladder.
· Identify the gallbladder from a slide or photomicrograph and distinguish it from a similar section of small intestine.
· In a slide or photomicrograph of a digestive gland, identify the type of gland; distinguish between adenomeres and ducts; and identify the different types of ducts, cells, and other named substructures (eg, serous demilune, central vein, bile duct, sinusoid).

SYNOPSIS

I. GENERAL FEATURES OF THE GLANDS ASSOCIATED WITH THE DIGESTIVE TRACT

A. Components of the System: The salivary glands--parotid, submandibular, and sublingual-pancreas, and liver are digestive glands situated outside the digestive tract. The main function of the gall bladder, also discussed in this chapter, is to store bile.

B. Embryonic Origin and Association With the Tract: Each component arises as an out pocketing of the embryonic gut tube and retains its connection with the lumen of the tract through a duct. The duct-lining cells and exocrine secretory cells are epithelial and of endoder mal origin. The supporting connective tissue that forms the organ capsules and penetrates the glands to divide them into lobes and lobules derives from mesoderm.

C. Exocrineand Endocrine Functions: Thepresenceofducts indicatesthatthese areexocrine glands; however, the pancreas and liver also have important endocrine functions.

D. Serous and Mucous Exocrine Secretory Cells: In general, the secretory cells of the liver, pancreas, and parotid gland are exclusively serous, while the submandibular and sublingual glands contain a mixture of serous and mucous cells (see Chapter 4).

E, Glandular Subunits: Exocrine glands are structurally and functionally subdivided by septa, platelike invaginations of their connective tissue capsules. This arrangement applies mainly to the pancreas and salivary glands; the subdivision of the liver, which is more complex, is considered separately (IV.E).

1. Lobes are the largest of the subunits and are separated by connective tissue septa.
2. Lobules are subunits of the lobes and are separated by thin extensions of the septa.
3. Adenomeres are secretory subunits of lobules. They consist of all the secretory cells that release their products into a single intralobular duct.
4. Acini (or alveoli) are smaller secretory subunits. Each acinus is a spheric collection of secretory cells surrounding the blind-ended termination of a single intercalated duct (Fig 16 I). An adenomere may include one or several acini.

F. Exocrine Ducts: Digestive gland ducts (Fig 16-1) are classified by their location and identi fied by their location, size, and epithelial lining.

1. Intralobular ducts. Several of these small ducts may be found within each lobule. They are generally lined by simple cuboidal epithelial cells with central or basal nuclei and surrounded by only a thin layer of connective tissue. They transport the secretory products from the adenomeres to the interlobular excretory ducts. There are also 2 special types of intralobular ducts. a. Intercalated ducts are the smallest ducts in a gland, with a narrow lumen that is continuous with the lumen of the acini. These ducts usually have a simple squamous or low cuboidal epithelial lining. They transport secretory products from the adenomeres to the larger intralobular ducts. b. Striated ducts differ from standard intralobular ducts mainly in the appearance of their lining epithelial cells. The nucleus is displaced toward the cell apex by extensive infold ings of the basal plasma membrane, giving the cell's base a radially striped (striated) appearance at high magnification. With the electron microscope, these infoldings can be seen to interdigitate with numerous mitochondria. This arrangement of the epithelial basal surface is characteristic of sites of energy-dependent ion transport activity, such as that performed by Na+/K+-ATPase (see Chapter 4). Striated ducts, which are typical of salivary glands, are seldom (if ever) found in the pancreas.
2. In surrounding them. Their lining is typically simple tall cuboidal to simple columnar to stratified columnar epithelium. Generally, the larger the duct, the taller the epithelial lining. These ducts include the large ducts within the glands and the still larger excretory ducts that exit the gland. They transport secretory products from the intralobular ducts to the lumen of the digestive tract.

II. SALIVARY GLANDS

A. General Structure and Function: Three major pairs of glands, the parotid, submandibular, and sublingual, surround the oral cavity. The lobules of each gland contain numerous ade nomeres that empty their secretions (saliva) through a series of intercalated, striated, and interlobular ducts into the oral cavity. The saliva moistens the food, lubricates the digestive tract, and begins the enzymatic digestion of carbohydrates. The glands also excrete certain salts; they protect against bacterial invasion through the mouth by releasing lysozyme and IgA into the saliva.

B. Cell Types:

1. Serous and mucous cells are the predominant secretory cells of salivary adenomeres. The key to identifying the 3 types of salivary glands in tissue sections lies in knowing the differences in the staining properties of the cells, their organization, and the proportion of each type found in each gland. a. Serous cells. These relatively small basophilic cells produce a protein-rich, watery secretion and usually form acinar (spheric) adenomeres. b. Mucous cells. Larger and more acidophilic than the serous cells, these may have a foamy appearance. They produce a thick glycosaminoglycan-rich secretion (mucus) and usually form tubular adenomeres.
2. Myoepithelial cells are contractile cells between the basal lamina and the epithelial cells of adenomeres and ducts. Those surrounding the serous acini are often called basket cells because of their stellate shape and long cell processes that embrace the acinus. In the duct, the myoepithelial cells are spindle-shaped and lie parallel to its length. Both types contain abundant actin microfilaments and myosin and help propel secretory products toward the oral cavity.
3. Other cells. IgA-secreting plasma cells and other cells typically found in areolar tissue are scattered in the connective tissue surrounding the adenomeres.

C. Parotid Glands: These branched acinar glands contain almost exclusively serous secretory cells. The granules in these cells are PAS-positive (owing to their polysaccharide content) and are rich in protein. Parotid secretions, about 25% of the total salivary volume, contain amylase, maltase, sialomucin, and enzyme-resistant secretory IgA (see Chapter 14).

D. Submandibular (Submaxillary) Glands: These branched tubuloacinar glands, which pro duce about 70% of the salivary volume, contain both serous and mucous adenomeres (mostly serous). The serous acini are composed of small basophilic cells with PAS-positive cytoplasm and basal membrane infoldings. Their serous secretions contain sialomucin and have weak amylase activity. The mucous adenomeres may be capped by serous demilunes (Fig 16-1) composed of several serous cells that secrete lysozyme.

E. Sublingual Glands: These are also branched tubuloalveolar glands containing both mucous and serous cells (mostly mucous). While only mucous adenomeres are present, many are capped by serous demilunes. These glands produce about 5% of the salivary volume.

F. Modulation of Salivary Composition by Duct Epithelium: The saliva produced by the secretory cells (primary saliva) is isosmotic with blood; that reaching the oral cavity, however, is typically hypotonic and contains less sodium and more potassium than does blood. This is the result of the absorption of sodium and the addition of potassium and water by the cells lining the striated and excretory ducts. The ion-transporting cells lining the striated ducts, like those lining the distal tubules of the kidney (see Chapter 19), respond to aldosterone and help regulate electrolyte balance.

G. Modulation of Salivary Volume by Autonomic Innervation: Parasympathetic stimula tion leg, sitting down to a meal) provokes high-volume secretion of watery saliva containing less than average amounts of organic material. Sympathetic stimulation leg, fear and stress) yields low-volume viscous saliva, rich in organic material (sometimes known as cotton mouth).

III. PANCREAS

A. General Structure and Function: The pancreas is a serous, compound acinar gland that resembles the parotid gland in its microscopic appearance. It differs in that it lacks striated ducts (Fig 16-1) and contains islets of Langerhans. (These clusters of endocrine cells, discussed in Chapter 21, constitute the endocrine pancreas; only the exocrine pancreas will be considered here.) The lobules of the pancreas contain serous adenomeres that secrete a variety of digestive enzymes into a branched duct system that empties into the duodenum.

B. CellTypes:

1. Pancreatic acinar cells. Each acinus consists of several pyramid-shaped, enzyme secreting cells whose apices border on a small lumen and whose bases abut a basal lamina. The base of each cell is basophilic owing to the ribosomes of the enzyme-synthesizing RER found here. Acinar cells synthesize a wide variety of enzymes that can hydrolyze proteins (proteases, such as trypsin, chymotrypsin, and elastase), lipids (lipases, such as triacylglycerol lipase and phospholipase A,), carbohydrates (amylase), and nucleic acids (ribonuclease and deoxy ribonuclease). Nascent enzymes are packaged and concentrated by the juxtanuclear Golgi complex and stored in the acidophilic apical region as membrane-bound zymogen granules. Here they await exocytosis in response to stimulation by cholecystokinin, which is produced by enteroendocrine cells in the small intestine, or parasympathetic stimulation via the vagus nerve. The enzymes in the granules are zymogens, which are inactive before the release. One such zymogen, trypsinogen, is enzymatically converted to the active protease trypsin in the small intestine by enterokinase, an enzyme that is secreted by enterocytes.
2. Centroacinar cells. Unique to the exocrine pancreas, each centroacinar cell has a condensed nucleus and a clear cytoplasm. One or 2 can be found in the lumen of each acinus at the origin of the intercalated duct (Fig 16-1). These and other duct-lining cells produce a watery, bicarbonate-rich fluid in response to stimulation by secretin, an enteroendocrine product of the small intestine mucosa. This fluid helps to adjust the acidic chyme to neutral pH and thus to optimize pancreatic enzyme activity.

IV. LIVER

A. General Structure: The liver is the body's largest gland. It is partly covered by a thin capsule (Glisson's capsule) and has a sparse, delicate, reticular connective tissue stroma accompanying the blood vessels as they penetrate the parenchyma. Its predominant cell type is the hepatocyte. These cells are arranged in one- or 2-cell-thick plates that are separated by the hepatic sinusoids (Fig 16-2). The liver has a dual blood supply, the portal vein and the hepatic artery; it also has 3 drainage systems, the hepatic veins, lymphatic vessels, and bile ducts.

B. General Functions: The liver has several important functions, most of which are carried out by hepatocytes. Its main role in digestion involves the enzymatic processing (metabolism) of nutrients absorbed by the intestines to provide the body with the chemical building blocks and fuel needed to support life. Some hepatocyte enzymes aid in detoxification by modifying potentially dangerous chemicals and drugs and rendering them harmless. Hepatocytes synthe size many important proteins leg, albumin, prothrombin, fibrinogen, lipoproteins) and secrete them into the blood, thus acting as an endocrine gland. They also synthesize bile from the wastes of erythrocyte destruction and secrete it into the biliary tract (IV.F.2), acting as an exocrine gland. The liver also serves as a storage site for glucose, fats, and vitamin A. Since the hepatocytes carry out most of the liver's functions, knowledge of their structure and functions (detailed in IV.D.I) is a prerequisite for understanding liver function.

C. Blood Supply: Because the liver's complex structure is organized around its many vessels and sinusoids, it is helpful to begin more detailed studies of liver structure by examining its unusual double blood supply.

1. Hepatic portal vein. This large vein is formed by the junction of mesenteric and splenic veins. Mesenteric veins deliver oxygen-poor, nutrient-rich blood from capillaries in the intestinal walls. The splenic vein delivers byproducts of red blood cell destruction from the splenic sinusoids (see Chapter 14). The hepatic portal vein, which supplies about 75% of the liver's total blood volume, enters through the hilum on the liver's inferior surface. It branches repeatedly to form the portal venules that penetrate the liver parenchyma and empty their blood into the hepatic sinusoids.
2. Hepatic artery. This is a smaller vessel, a branch of the celiac artery, and enters the liver alongside the portal vein. It follows the latter's branching pattern and empties oxygen-rich blood into the same sinusoids. It supplies about 25% of the liver's blood volume.
3. Hepatic sinusoids. Serving as the liver's blood capillaries, these lie between the radially oriented hepatocyte plates and receive blood from branches of both the portal vein and the hepatic artery (Fig 16-2). The mixed arterial and venous blood flows through the sinusoids and directly into the central veins. The sinusoid lumen is separated from the free surface of the hepatocyte plates by a discontinuous endothelial wall composed of typical endothelial cells and Kupffer's cells. Between the endothelium and the hepatocytes is the narrow space of Disse. Blood plasma enters this space through openings between the endothelial cells that are too small for blood cells to pass. Blood-borne substances thus directly contact the microvillus-covered free surface of the hepatocytes. In the space of Disse, hepatocytes absorb nutrients, oxygen, and toxins and release their endocrine secretory products. The spaces of Disse also serve as the liver's lymphatic capillaries, and the fluid in these spaces flows toward lymphatic vessels in the portal spaces, ie, in a direction opposite to the blood flow.
4. Central veins. So named because each lies at the center of a classic liver lobule, these veins receive blood from the sinusoids and deliver it to larger sublobular veins, which merge to form even larger hepatic veins. They can be distinguished from other hepatic vessels by their position at the hub of the radially arranged hepatocyte plates and sinusoids and by the paucity of surrounding connective tissue.
5. Hepatic veins. These collect oxygen- and nutrient-poor blood from the sublobular veins. They converge to form larger veins that exit the liver's upper surface and empty into the inferior vena cava.

D. Cell Types:

1. Hepatocytes. These are the primary structural and functional subunits of the liver. a. Structure and organization. Hepatocytes can have one or 2 nuclei; they contain every type of membrane-bound organelle (see Chapter 3) as well as numerous glycogen gran ules and lipid droplets. Organized into one- or 2-cell-thick plates that are separated by the sinusoids, the polygonal hepatocytes are essentially cubelike, with 6 major surfaces. Four of these typically abut on similar surfaces of adjacent hepatocytes. The abutting hepatocyte plasma membranes are attached by desmosomes and are closely apposed, except where they form the walls of a bile canaliculus. These small, tubular, plasma membrane-bound gaps between adjacent hepatocytes receive bile (IV.F.I). They are sealed around their periphery with continuous occluding junctions to prevent the bile from leaking out between the hepatocytes and into the sinusoids. Short microvilli project into each canaliculus. Each of the other 2 free surfaces generally faces the sinusoids on either side of the plate and is covered with short microvilli that project into the space of Disse. b. Function. The metabolism of absorbed nutrients may involve their further degradation, the storage of any excess as glycogen granules or lipid droplets, or the use of one type of nutrient to synthesize another leg, amino acids to make glucose). Unlike most endocrine glands, the liver's endocrine functions are not restricted to hormone leg, somatomedin) secretion, but also include the production of various processed nutrients (eg, glucose, lipoproteins) and the synthesis and secretion of plasma proteins leg, albumin, fibrinogen). The liver's main exocrine function is the production and secretion of bile. Metabolic wastes, byproducts of red blood cell destruction, and toxic substances re moved from the blood are enzymatically inactivated (detoxified) in the SER and released into the bile canaliculi.
2. Kupffer's cells. Monocyte-derived members of the mononuclear phagocyte system, these are interspersed among the sinusoidal endothelial cells and on their luminal surfaces. They contain ovoid nuclei, many mitochondria, a well-developed Golgi complex, scattered lyso somes, phagosomes, and RER. They are more easily distinguished from the endothelial cells in standard H&E preparations when they have phagocytosed colored particles leg, india ink) prior to fixation.
3. Fat-storing cells. These are stellate cells that are associated with the sinusoids but lie in the space of Disse. They accumulate fat and store vitamin A in the form of retinyl esters leg, retinyl acetate, retinyl palmitate). Their precise function is unclear.

E. Liver Lobules: The relationship between hepatic structure and function can best be demon strated through 3 models of liver subdivision: the classic lobule, the portal lobule, and the hepatic acinus (of Rappaport), as shown in Fig 16-3.

1. Classic liver lobule. This model is based on the direction of blood flow. In sections, liver substructure exhibits a pattern of interlocking hexagons; each of these is a classic lobuie. Whereas lobules in pigs are defined by a sheath of connective tissue, there is less connective tissue in humans and the lobule boundaries are indistinct. The boundaries of human lobules can be estimated, however, by noting the positions of the portal triads at the lobule periphery, the central vein at its center, and the alternating hepatocyte plates and sinusoids that lie between them. a. Portal triad. One triad occupies a potential space (portal space) at each of the 6 comers of the lobule. Each triad contains 3 main elements surrounded by connective tissue: a portal venule (a branch of the portal vein), a bepatic arteriole (a branch of the hepatic artery), and a bile ductule (a tributary of the larger bile ducts). A lymphatic vessel may also be seen. b. Central vein. A single vein marks the center of each lobule. This vessel is easily distinguished from those in the portal triad by its larger opening and lack of a connective tissue investment. c. Hepatocyte plates and hepatic sinusoids. Many such plates radiate from the central vein toward the lobule periphery (like the spokes of a wheel). The plates are separated by hepatic sinusoids, which receive blood from the vessels in the triads, converging on the lobule center to empty directly into the central vein.
2. Portal lobule. This model is based mainly on the direction of bile flow, which is opposite to that of blood. From this perspective, the liver parenchyma is divided into interlocking triangles, each of which has a portal triad at the center and a central vein at each of its 3 comers. Bile, produced by the hepatocytes, enters the membrane-bound bile canaliculi between them and flows within the hepatocyte plates toward the bile duct in the portal triad. Liver lymph in the spaces of Disse flows in the same direction as bile, toward lymphatic vessels in the triad. 3. Hepatic acinns (of Rappaport). This model is more abstract; it is based on changes in oxygen, nutrient, and toxin content as blood flowing through the sinusoids is acted on by hepatocytes. Each diamond-shaped acinus contains 2 central veins and 2 portal triads that define its 4 corners. The diamond is divided into 2 triangles by a line connecting the portal triads. Along this line run terminal branches of the portal and hepatic vessels that deliver blood to the sinusoids. Each triangle can be divided into 3 zones, according to their distance from the terminal distributing vessels. Zone I, for example, is closer to these vessels, while zone ill is closer to the central vein. Blood in zone I sinusoids has higher oxygen, nutrient, and toxin concentrations than in the other zones. As the blood flows toward the central vein, these substances are gradually removed by hepatocytes. Zone I hepatocytes thus have a higher metabolic rate and larger glycogen and lipid stores. They are also more susceptible to damage by blood-borne toxins, and their energy stores are the first to be depleted during fasting. This model helps explain regional histopathologic differences in patients with liver damage .

F. Biliary System: The synthesis and secretion of bile are the major exocrine functions of the liver.

1. Bile. Bile consists of bile acids, phospholipids, cholesterol, bilirubin, water, and elec trolytes. This composition gives it detergent properties that aid in digesting dietary fat. About 90% of the bile comes from recycled substances that were added to the intestinal contents in the duodenum and then reabsorbed into the portal circulation by the epithelial lining of the distal part of the intestine. Hepatocytes merely reabsorb them from the sinusoids and transport them back to the bile canaliculi. About 10% of the bile is synthesized de novo in the hepatocyte's SER. a. Bile acids. Cholic acid is synthesized from cholesterol and conjugated with glycine or taurine to form glycocholic and taurocholic acid, respectively. b. Bilirubin is a water-insoluble byproduct of the hemoglobin catabolism that accompanies the disposal of worn erythrocytes by cells of the mononuclear phagocyte system in the spleen, liver, and bone marrow. It is carried by the blood to the hepatocytes, which conjugate it with glucuronic acid to form bilirubin glucuronide. This now water-soluble substance is secreted, with other bile components, into the bile canaliculi.
2. Biliary tract. Bile in the canaliculi flows toward the portal triads tie, opposite to the blood flow in the sinusoids). At the lobule periphery, the canaliculi empty into short, narrow bile ductules (also called cbolangioles or Hering's canals), which are lined by cuboidal cells with clear cytoplasm. The ductules deliver the bile to bile ducts in the portal triads (in cross section, the nuclei of the duct-lining cells resemble strings of beads). The bile ducts empty into successively larger ducts, ending in a single hepatic duct that joins the cystic duct from the gallbladder to form the common bile duct (ductus cboledochus). This empties the bile into the duodenum. Where the common bile duct penetrates the duodenal wall, it is encircled by a thick layer of smooth muscle, the spbincter of Oddi. Although the liver produces bile continuously, the sphincter opens fully only when a particularly fatty meal enters the duo denum. When the sphincter is closed, bile backs up the common duct, through the cystic duct, and into the gallbladder.

V. GALLBLADDER

A small, blind-ending sac, the gallbladder is attached to the lower surface of the liver. Its function is to store and concentrate bile and to release stored bile in response to cbolecystokinin. It is a hollow organ with layered walls whose microscopic structure resembles the digestive tract; however, it lacks a definitive submucosa and therefore has only 3 of the 4 layers commonly present in the digestive tract wall.

A. Mucosa: This consists of simple columnar epithelium overlying a typical lamina propria. The epithelial cells have abundant apical microvilli. They secrete some mucus and contain a sodium pump in their basal membranes to facilitate water absorption from stored bile. The many mucosal folds are branched, thus differing from intestinal villi. Near the cystic duct, the mucosa invaginates deeply into the lamina propria and often into the underlying muscularis. These invaginations form glands with large lumens whose continuity with the principal lumen of the organ may not be apparent in cross section. These large sinuses also help to distinguish gallblad der tissue from that of the intestines. The cells lining these sinuses contribute most of the mucus to the stored bile.

B. Muscularis: This is a layer of interwoven smooth muscle fibers underlying the lamina pro pria. These contract and empty the gallbladder in response to the release of cholecystokinin by enteroendocrine cells in the intestinal mucosa. This is triggered by the entry of dietary fat into the intestinal lumen.

C. Adventitia and Serosa: Like the retroperitoneal organs of the tract, the outer layer of the gallbladder consists of both an adventitia that attaches it to the liver and a typical serosa that covers its free (peritoneal) surface.

This chapter should help you to:

· List the skin's functions and relate them to its structure.
· Name the 2 major layers of skin and, for each of these, name the basic tissue type that predominates and describe the arrangement and distinguishing features of its constituent layers.
· Name the 4 cell types typical of the epidermis and describe their structure, function, and location.
· Relate the steps in cell renewal and keratinization to the epidermal layers.
· Compare thick and thin skin.
· Describe melanin granule synthesis and turnover.
· Identify and describe the components of hair follicles and nail complexes. Briefly describe nail and hair growth.
· Describe the blood and nerve supply to the skin in terms of structure, location, and specialized functions.
· Name and compare the 3 main types of glands associated with the skin in terms of structure, function, and location.
· Identify skin type, the named layers, cell types, hair follicles, and the gland types present in a slide of photomicrograph of a section of skin.

SYNOPSIS

I. GENERAL FEATURES OF THE SKIN

A. General Functions: The skin is the largest and heaviest organ. It protects against microor ganisms, toxic substances, dehydration, ultraviolet radiation, impact, and friction. It also acts as a sensory receptor and has a role in excretion, vitamin D metabolism, and regulation of blood pressure and body temperature.

B, General Organization: Human skin (the integument) is of 2 types. Thick skin, restricted to the palms of the hands and soles of the feet, lacks hairs and has abundant sweat glands. Thin skin, which has hairs, covers the rest of the body (Table is-i). Thick or thin, the skin consists of 2 distinct but tightly attached layers, the epidermis and dermis, which are underlain by the hypodermis (Fig 18-1).

1. Epidermis. This outer (superficial) layer of skin, composed of keratinized stratified squamous epithelium, derives from embryonic surface ectoderm. It is avascular, receiving nourishment from vessels in the underlying dermis. Its only innervation is by unencapsulated (free) nerve endings. The epidermal layer is further divided into 5 strata; these layers, in order from superficial to deep, are the stratum corneum, stratum lucidum, stratum gran ulosum, stratum spinosum, and stratum basale (II.A.1-5). The thickness of these layers differs in thick and thin skin (Table 18-1).
2. Dermal-epidermal junction. The stratum basale is underlain by a basement membrane connecting the epidermis and dermis. The junction has the appearance of zigzagging inter digitations between upward projections of the dermis--dermal papillae--and downward projections of the epidermis--epidermal ridges.
3. Dermis, This inner (deeper) layer is a vascular connective tissue of mesodermal origin. It can be further divided into a superficial papillary layer and a deeper reticular layer. The papillary layer contains extensive capillary networks, which nourish the epidermis. The reticular layer contains many arteriovenous anastomoses that help regulate blood pressure and body temperature. It is richly supplied with free nerve endings, a variety of encapsulated sensory receptors, and autonomic fibers that control the vascular smooth muscle. Even in thick skin, the dermis is much thicker than the overlying epidermis.
4. Hypodermis, Although not a part of the skin, this layer of mesoderm-derived loose connec tive and adipose tissue underlying the dermis ffexibly binds the skin to deeper structures. Its thickness varies, depending on nutritional status, level of activity, body region, and gender. The hypodermis is also called the subcutaneous fascia and, where thick enough, the pan niculus adiposus,

C. Structures Associated With the Skin: Glands (sebaceous and sweat), hairs, and nails arise from epidermal downgrowths into the dermis during embryonic development. These structures, which are mainly of epithelial origin, require epitheliomesenchymal interactions between the epidermis and dermis for their formation and maintenance (V-VII).

II. EPIDERMIS

The epidermis contains 2 major and 2 minor cell populations specialized for specific functions. Major populations include the keratinocytes and melanocytes. Minor populations include Langerhans' and Merkel's cells.

A. Keratinizing System: The keratiuocytes make up most of the epidermis. They participate in the continuous turnover (renewal) of the skin surface by passing through 4 overlapping pro cesses: cell renewal, or mitosis; differentiation, or keratinization; cell death; and exfoliation (the sloughing of dead cells from the skin surface) (Fig 18-2). The entire process takes 15-30 days and occurs in waves. A cell layer produced by a mitotic wave in the basal layer undergoes keratinization in synchrony. Each wave pushes the cell layers produced in earlier waves toward the surface. The layers from several waves, each at a different depth and step in the process, give a stratified appearance to vertical sections of the epidermis. The 5 layers of the epidermis are distinguished by the shape, staining properties, contents, and orientation of the keratinocytes they contain.

1. Stratum basale (stratum germiuativum). This single layer of columnar basophilic ker- atinocytes rests on the basal lamina that separates epidermis from dermis. These cells divide continuously and give rise to the keratinocytes in all other layers. They attach to their neighbors by desmosomes and to the basal lamina by hemidesmosomes (4.IV.C.2). Cytokeratiu intermediate filaments (tonofilaments; 3.III.I.3.a, 4.IV.B.3) are important components of both junctions. The cytokeratin content increases as these cells approach the stratum corneum, where it constitutes about 50% of their total protein. The basophilia of the basal layer is caused by ribosomes.
2. Stratum spinosum. This comprises several layers of large keratinocytes overlying the stratum basale. The cells are cuboidal or polygonal in the deeper layers and slightly flattened in the upper layer. Touofibrils (tonofilament bundles) fill the cytoplasm, extend into the numerous cell processes that give these cells their spiny appearance, and insert into the desmosomes that attach the tips of these processes to those of adjacent cells. The mitotic rate here is lower than in the stratum basale. Mitosis occurs only in the malphighian layer, which includes the stratum basale and stratum spinosum.
3. Stratum granulosum. This lies above the stratum spinosum and, in thick skin, consists of 3-5 layers of flattened polygonal (often diamond-shaped) cells that contain numerous mem braneless keratohyalin granules. The intense basophilia of these granules is caused by their content of a phosphorylated histidine-rich precursor of the protein filaggrin. Cells in this layer also contain small ovoid or rodlike lamellar granules. These fuse with the plasma membrane and release their contents (glycosaminoglycans and phospholipids) into the inter cellular spaces. This material may be important in sealing the deeper layers of the skin from the external environment and in protection from dehydration.
4. Stratum lucidum, This layer overlies the stratum granulosum and is apparent only in thick skin. It is a narrow, acidophilic, translucent band of flattened keratinocytes whose nuclei, organelles, and intercellular borders are not visible. The cytoplasm contains dense cytokeratin aggregates embedded in an amorphous electron-dense matrix derived from the keratohyalin granules. This intracellular mixture of intermediate filaments and matrix con stitutes the immature keratin, sometimes called eleidin,
5. Stratum corneum, The outermost layer, this consists of many layers of dead, platelike enucleate keratinocytes with thickened plasma membranes. These cells represent the final stage of keratinization and are filled with mature keratin, a birefringent scleroprotein con sisting of at least 6 polypeptides. The molecular weights of the polypeptides of mature keratin in the stratum corneum is higher than those of immature keratin in deeper, less differentiated cells. Keratin's substructure includes tonofilament subunits formed by 3 coiled and intertwined polypeptide chains. Nine of these subunits coil together to form each IO-nm thick intermediate filament. As they aggregate end to end, the tonofilament increases in length. Tonofilaments are embedded in and bound together by the amorphous matrix first found in keratohyalin granules. Dead cells are continuously sloughed (exfoliated) from the surface and replaced, through successive waves of mitosis and differentiation, by cells from the deeper waves.

B, Pigmentation System: Skin color is conferred mainly by the pigments melanin and carotene, the thickness of the epidermis, the number of dermal blood vessels, and the color of the blood in those vessels.

1. Melanins contribute to skin, eye, and hair color. Synthesized by melanocytes, they include the dark brown pigment eumelanin, found in the epidermis, iris, and brown and black hair; and the cysteine-rich pigment pheomelanin, found in red hair.
2, Melanocytes derive from the neural crest and migrate into the epidermis during em bryogenesis. Although they are scattered among the keratinocytes of the stratum basale, they are not attached to them by desmosomes. They have round cell bodies, central nuclei, and long cytoplasmic processes that pass between the cells of the strata basale and spinosum and terminate in small indentations on the keratinocyte surfaces. Melanocytes make up 10-25% of this layer's cells but do not participate in keratinization. They cytoplasm contains many mitochondria, a well-developed Golgi complex, short cistemae of the RER, and special membrane-bound organelles, melanosomes, in which melanin is synthesized. There is no difference in the number of melanocytes per unit area in the skin of dark- and light-skinned races. Rather, differences in skin color reflect differences in the rates of melanin synthesis, accumulation, and degradation.
3. Melanin synthesis involves the tyrosinase-mediated enzymatic conversion of tyrosine to DOPA (3,4-dihydroxyphenylalanine) and of DOPA to dopaquinone. Additional steps are required to convert dopaquinone to melanin. In melanin granule formation, tyrosinase is synthesized on ribosomes of the RER and transported to the Golgi complex. Membrane limited tyrosinase-filled vesicles called melanosomes pinch off from the Golgi complex, accumulate in the Golgi region, and develop through 4 stages to become mature melanin granules. Stage I melanosomes are round vesicles with tyrosinase activity associated with fine-granular-to-filamentous material in the vesicle periphery. Melanin is not yet present. Stage II melanosomes are ovoid and contain parallel filaments. The associated tyrosinase activity triggers melanin deposition on the filaments. Stage III melanosomes have the same structure as in stage II, but continued melanin deposition has partly obscured the filaments. Stage IV melanosomes (mature melanin granules) are 1 um long, 0.4 um wide, and so completely filled with melanin that their ultrastructure is no longer visible.
4. Fate of mature melanin granules. Mature granules move from the Golgi region into the tips of the melanocytes' long processes. They are then "injected" into the keratinocytes of the strata basale and spinosum in a process termed cytocrine secretion. (Keratinocytes act as melanin depots and usually contain more melanin than do melanocytes). Melanin granules accumulate over the nuclei of the dividing keratinocytes, protecting the DNA from the damaging effects of the Sun's rays. Keratinocytes carry melanin with them to the skin surface. During keratinization, the granules, along with the keratinocytes' nuclei and organelles, are often digested by lysosomes. 5. Melanin function. Certain of the Sun's rays break apart molecules in the skin, forming highly reactive free radicals. The cleavage of DNA by ionizing radiation or the recombina tion of normal DNA with other free radicals can alter its structure, causing cell death or neoplastic transformation. The euchromatic DNA of dividing cells in the malpighian layer is most susceptible to these effects. Although melanin's dark color allows it to absorb some rays directly, its major protective effect is its ability to absorb free radicals. 6. Factors affecting melanin synthesis. Melanogenesis is known to increase or decrease in response to a variety of factors. Increased exposure to ultraviolet rays both darkens existing melanin and speeds tyrosinase synthesis, increasing the amount of melanin produced and the rate of production. Melanocyte-stimulating hormones (alpha- and P-MSH) from the pituitary (Chapter 20) markedly enhance pigmentation, but do not exist in free form in humans. Pituitary ACTH, however, contains a peptide sequence identical to (-w-MSH that is known to influence human pigmentation. Addison's disease involves underproduction of cortisol by the adrenal cortex (Chapter 21). The pituitaries release excess ACTH in an attempt to stimulate the adrenals. The resulting stimulation of tyrosinase activity in melano cytes causes the hyperpigmentation that accompanies Addison's disease. Albinism, in which no melanin pigment is produced, is most often caused by a genetic defect in tyrosinase synthesis and a consequent absence of tyrosinase activity. Melanocytes of affected individ uals typically contain melanosomes, but only to stage II. Hydroquinone, the active ingre dient in some over-the-counter treatments for "age spots," inhibits melanin synthesis.

C. Langerhans' cells: These star-shaped cells lack tonofilaments and occur mainly in the stra tum spinosum (400-1000 cells/mm2 of skin surface). They stain selectively with gold chloride and contain numerous rodlike or racket-shaped cytoplasmic granules (Birbeck's granules). They are thought to be antigen-presenting cells (I4.III.E) that process and present to the lymphocytes any antigenic material that penetrates the skin's surface. Of mesodermal origin, they arise in bone marrow and may belong to the mononuclear phagocyte system. Langerhans' cells also occur in oral and vaginal epithelia as well as in the thymus.

D. Merkel's cells: Scattered in the stratum basale, these cells are most numerous in thick skin (Table 18-1). They resemble basal keratinocytes but have a clearer cytoplasm containing many small dense granules. Free nerve endings form a disklike expansion (Merkel's disk) that covers the basal surface of each Merkel's cell. This arrangement suggest that the cells function as sensory mechanoreceptors, but other evidence suggests that they may have DNES-related functions .

III. DERMIS

The dermis, which contains the hair follicles (found only in thin skin; Table 18-1; V) and sebaceous and sweat glands (VIII; IX), consists of 2 layers of vascular connective tissue that blend at their common border.

A. Papillary Layer: This layer of loose connective tissue, rich in elastic fibers, lies directly beneath the epidermal basement membrane. Its projections--dermal papillae-interdigitate with the epidermal ridges, increasing the area of contact. Special collagen fibers, anchoring fihrils, extend from this layer into the epidermal basal lamina to reinforce the dermal-epidermal junction. The papillary layer contains immunoprotective cells (S.III.A. 1), a rich capillary net work (IV. B), and abundant free nerve endings, some of which penetrate the epidermis. The tips of many dermal papillae contain encapsulated touch receptors called Meissner's corpuscles (24.II.D).

B. Reticular Layer: Beneath the papillary layer is a thicker layer of dense irregular connective tissue. Also richly vascularized, this layer contains many arteriovenous anastomoses, or shunts (IV. D), that control the amount of blood reaching the papillary capillaries and thus aid in regulating heat loss and blood pressure. The reticular layer also contains a rich supply of nerves in both free and encapsulated endings leg, Pacinian corpuscles; 24.II.A-G).

IV. BLOOD SUPPLY TO THE SKIN

Although the epidermis is avascular, the skin still receives an extensive vascular supply through the dermal blood vessels (Fig 18-1), which can hold about 4.5% of the body's total blood volume.

A. Arterial Plexuses: One of the 2 arterial plexuses that provide the skin's blood supply lies at the border between the papillary and reticular layers of the dermis. The other lies at the border between the dermis and hypodermis. Both give rise to arterioles that feed the papillary capil laries.

B. Papillary Capillaries: The dermal papillae, which surround the epidermal ridges, contain a rich capillary network that provides oxygen and nutrients to the avascular epidermis.

C. Venous Plexuses: The capillary bed in each papilla drains, by a single venule, into one of 3 venous plexuses. Two of these lie in the same position as the arterial plexuses; the other lies between them in the middle of the reticular dermis.

D. Arteriovenous Anastomoses (Shunts): Within the dermal plexuses there are many anastomoses--direct connections--between the arteries and veins. Postganglionic autonomic fibers control the opening and closing of these shunts, helping to control blood pressure and body temperature by regulating the amount of blood in the papillary capillaries. When the shunts are closed, more blood flows through the papillary capillaries; when open, they direct blood away from the capillaries, increasing blood volume in the larger vessels and thus increasing the blood pressure. Opening the shunts also reduces the loss of body heat through the skin.

V. HAIR

Hair occurs only in thin skin; its color, size, shape, and distribution vary according to race, age, sex, and body region. The structures in skin that form hairs and maintain their growth are called hair follicles.

A. Follicle and Hair Development:

1. Follicles. Early in the third month of human development, local epidermal thickenings form at the sites of future hairs: first on the eyebrows, chin, and upper lip and then over the rest of the thin skin. Cells at the base of each thickening invade the dermis, and a small dermal papilla invades the leading edge of the epidermal downgrowth. Interactions between the papilla and the invaginating epidermis induce the differentiation of the hair follicle. Hair begins to form in the hair bulb at the base of the hair follicle as a result of the keratinization of the bulb's epithelial cells. These cells are pushed toward the surface by the mitosis in the germinal matrix (hair bulb epithelium). Some epithelial cells in the walls of the developing follicle divide, forming bulges that differentiate into sebaceous glands (VIII).
2. Hairs. By the fifth or sixth month of gestation, the fetus is covered by fine hairs (lanugo). Just before birth, most of the lanugo is shed, except for the scalp, eyebrows, and eyelashes. A few months after birth, the remaining lanugo has been replaced by coarser mature termi nal hairs; the rest of the body is covered with a coat of fine short hairs, called vellus. At puberty, coarse terminal hairs replace the vellus in specific body areas. In males, terminal hairs develop in the axilla and pubic region, on the face, and, to some extent, over the rest of the body. In females, they develop mainly in the axilla and pubic regions.

B. Follicle and Hair Structure: Hair follicles extend from the surface deep into the dermis or hypodermis. The follicle's broad base, or hair bulb, consists of a cap of rapidly dividing epithelial cells (the germinal matrix) overlying a dermal papilla that harbors the nerve and blood supply. Cells from the germinal matrix keratinize, forming the concentric layers of the hair shaft as they move toward the surface. Near the surface, distinct layers can be seen ensheathing the canal that contains the hair shaft.

1.Germinal matrix. This cluster of epithelial cells capping the dermal papilla can be divided into 4 indistinct zones that are arranged concentrically around the papilla. The zone closest to the papilla resembles the stratum basale of the epidermis in both structure and function. It contains both columnar epidermal cells and the melanocytes that give the hair its color. This germinal layer gives rise to the poorly keratinized cells of the medulla of the hair shaft and to the cells in the other 3 zones of the germinal matrix. Around the base of the bulb, this layer is continuous with the external root sheath that surrounds the entire bulb and shaft; near the surface, it is continuous with the stratum basale. Cells in the next layer form the cuticle. The most peripheral layer of the germinal matrix forms the poorly keratinized cells of the internal root sheath.
2. Hair shaft layers. These 3 concentric layers are formed by the germinal matrix (V.B. 1). The cell borders are indistinct, however, and cross sections through hair folticles near the skin surface often do not show the cellular nature of these layers. In addition, the hair itself may be dislodged from the canal during tissue processing, leaving only the open space (follicular canal) originally occupied by the shaft. The medulla forms the shaft's thin central core. It is composed of poorly keratinized and often vacuolated cells. The cortex surrounds the medulla and is composed of several layers of well-keratinized polygonal cells. The cuticle is the shaft's outermost layer. Within the bulb, its cells are cuboidal; farther up the shaft they become tall columnar, fill with keratin, and finally change their orientation to become a few layers of flattened, highly keratinized cells. These cells form the hard, shinglelike cuticle that covers the hair's outer surface.
3. Root sheaths. The concentric sheaths surrounding the hair shaft are more clearly distin- guished in the area between the bulb and the skin surface. a. Internal root sheath. The layer closest to the hair shaft, it extends only from the bulb to the level of the sebaceous gland ducts. At this point the soft keratin-filled cells are shed into the follicular canal. There are 3 component layers: the cuticle of the internal root sheath is a layer of flat cells separated from the hair shaft cuticle only by the follicular canal; the middle layer is Huxley's layer, comprising one to 3 layers of low cuboidal cells; the outermost layer is Henle's layer, a translucent layer of flattened to cuboidal cells resembling the epidermal stratum lucidum. b. External root sheath. This surrounds the internal root sheath and is continuous with the epidermis. Above the level of the sebaceous glands, it includes all the epidermal layers. Below this level, it retains only the granulosum, spinosum, and basale. The granulosum is also lost near the follicle's base, where the spinosum and basale become continuous with the layers of the germinal matrix. c. Glassy membrane. This is the thickened basal lamina underlying the stratum basale of the external root sheath and separating it from the surrounding connective tissue sheath. d. Connective tissue sheath. A layer of condensed connective tissue, this surrounds the entire follicle, including the bulb. It extends along the follicle to the surface, where it blends into the looser papillary dermis.

4. Associated structures. Found near the neck of the root sheath, sebaceous glands (VII) always accompany hairs. They empty their secretions via a short duct into the follicular canal. Arrector pill muscles are small bundles of smooth muscle fibers that originate in the papillary dermis and extend obliquely toward the hair follicle to insert into the follicle's connective tissue sheath below the sebaceous glands. When they contract, these muscles cause the hairs to stand upright, giving the appearance of gooseflesh. Their contraction also compresses the sebaceous glands, pushing their secretions into the neck of the follicular canal and out onto the surface of the skin.

C. Keratinization of Hair: Although both the hair and the epidermis contain keratin, there are differences in their keratinization. For example, the keratin of the hair's cortex and cuticle is harder than that of the epidermis; keratinized hair cells remain tightly attached to one another, whereas those of skin are continuously sloughed; keratinization of the hair is intermittent and is restricted to the bulb, whereas that of skin is continuous and occurs over the entire surface; and keratinized cells of the epidermis are identical, whereas those in hairs differ in structure and function depending on their position in the hair.

D. Hair Growth: Hair growth is not continuous but cycles through repeated growing and resting phases. In the growing phase, the proliferation and differentiation of cells in the germinal matrix cause the hair to elongate. In the resting phase, the germinal matrix becomes inactive and may atrophy. The hair detaches from the bulb, moving upward as the external root sheath retracts toward the surface. Eventually, the hair is shed. During the next growing phase, the lower part of the external root sheath grows downward again, either forming a new germinal matrix over the old papilla or stimulating formation of a new papilla. The bulb re-forms, and the next phase of the cycle--proliferation in the matrix and renewed hair growth--begins. Hair growth cycles do not occur synchronously over the entire body surface. Rather, they occur in patches, a pattern called growth in mosaic. Several hormones, especially androgens, influence the pattern of terminal hair distribution and growth rate.

VI. NAILS

These plates of highly keratinized cells are analogous to, but harder than, the stratum corneum.

A. Nail Development: The formation of the nails is similar to that of hair, but involves produc ing plates rather than cylinders. At the end of the third month of embryonic development, a narrow plate of epidermis on the dorsal surface of the terminal phalanges invades the underlying dermis of each finger and toe. This invasion continues proximally, forming a furrow called the nail groove. Epithelial cells beneath the groove proliferate to form the nail matrix, whose composition and function are similar to those of the hair's germinal matrix. Proliferation in the nail matrix pushes the upper cells toward the surface. These cells differentiate, becoming highly keratinized to form the nail plate. The plate is gradually pushed out of the groove by further cell proliferation and differentiation in the nail matrix. The growing plate slides distally on the dorsal surface of the digit. The epidermis over which it slides becomes the nail bed.

B. Nail Complex Structure: The nail plate (or nail) consists of 2 parts: the nail body (the visible part of the nail) and the nail root--(the part hidden in the nail groove). The nail and its supporting structure are surrounded by papillary dermis. The nail matrix is a thickened region of epidermis containing proliferating cells in the layer that directly contacts the dermis, and keratinizing cells between this basal layer and the nail plate. The nail matrix surrounds the root and extends beyond the nail groove. The nail bed lies beneath the nail body, distal to the nail matrix. It consists of only the deeper epidermal strata, for which the nail serves as a stratum corneum. The eponychium (or cuticle) is a thick keratinized layer extending from the upper surface of the nail groove over the most proximal part of the nail body. The hyponychium is a local thickening of the stratum corneum underlying the free (distal) end of the tail. The lunula is the whitish, opaque, crescent-shaped region on the proximal nail body, adjacent to the nail groove. Its distal border corresponds roughly to the underlying nail matrix.

VII. SEBACEOUS GLANDS

A. Structure and Location: These exocrine glands occur in all thin skin, most often in association with hair follicles into which their ducts empty, but are most numerous in the skin of the face, forehead, and scalp. In hairless skin, they open directly onto the surface. Their acinar secretory portions contain many large lipid-filled cells that appear pale-staining and foamy.

B. Function: The acinar cells of sebaceous glands fill with lipid droplets containing a mixture of triglycerides, waxes, squalene, and cholesterol and its esters. Their nuclei become pyknotic, and the cells eventually burst, releasing their contents and other cell debris (together termed sebum) into the ducts. The entire cell is shed, a type of secretion known as bolocrine secretion. The oily sebum moves through the ducts and into the hair follicle. It covers the hair and moves out onto the surface. Here, it lubricates the skin and may have some antibacterial or antifungal effects. The secretory activity of these glands, which begin functioning at puberty, is continuous and is increased by androgens.

VIII. SWEAT GLANDS

Two types of sweat glands, eccrine (or merocrine) and apocrine, occur in human skin. Both develop as epidermal invaginations into the dermis, and they differ mainly in their size, distribution, and secretory products.

A. Eccrine Sweat Glands:

1. Distribution. The most numerous sweat glands in humans, these average about 3 million per individual. They occur over most of the body, except for the glans penis, glans clitoridis, and the vermiliion border of the lips. They are most abundant in thick skin, such as the palms, where there are about 3000 per square inch.
2. Structure. They are simply coiled tubular glands. a. Ducts. The slightly coiled ducts are lined with simple to stratified cuboidal epithelium; their lining cells are smaller than those in the secretory portions and stain darker. Each duct opens directly onto the skin surface. b. Secretory portions. These highly coiled parts of the sweat glands are located in deep reticular dermis or shallow hypodermis. Surrounding connective tissue condenses to form a sheath around the basal lamina, and there are numerous myoepithelial cells between the basal lamina and the secretory cells. The secretions are released via ex ocytosis (merocrine secretion). Secretory cells are larger and stain lighter than the duct lining cells. Two secretory cell types are seen. Dark (mucoid) cells are pyramidal and line most of the gland's secretory portion; their bases do not reach the basal lamina. They contain rodlike mitochondria, a well-developed Golgi complex, RER, many free ribo somes, and dark glycoprotein-containing granules. Clear cells are also pyramidal. They lack secretory granules, contain abundant glycogen, and surround the inner layer of dark cells. Their basal plasma membranes, which do contact the basal lamina, are highly infolded, suggesting a role in ion and water transport.
3. Secretory product. Eccrine sweat is a watery secretion whose main components (besides water) include NaCI, urea, ammonia, and uric acid. The glands thus assist in excreting by-products of protein metabolism. In addition, evaporation of water from the skin surface reduces body temperature by cooling the blood in the papillary capillaries.

B. ApocrineSweat Glands

1. Distribution. Less numerous than the eccrine type, these glands occur mainly in the axilla, pubic and anal regions, and the areolae of the breasts.
2. Structure. Apocrine sweat glands are also simple coiled tubular glands, but are generally larger than eccrine glands. a. Ducts. These coiled ducts are lined with low cuboidal epithelium and open into hair follicles . b. Secretory portions. Coiled and embedded in the dermis, each has a wide lumen lined by cuboidal to columnar cells. Myoepithelial cells are present between the secretory cells and the basal lamina.

3. Secretory Product. Apocrine sweat is a viscous, odorless fluid that, once secreted, acquires a distinctive odor as a result ofbacterial degradation. The term apocrine derives from early evidence that the secretory cells of these glands released their apical cytoplasm along with the secretory product. Recent evidence, however, argues against apical shedding. Therefore, although the secretory products ofapocrine and eccnne sweat glands do differ, their mode of secretion-merocrine-is similar.

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