Structure and function of Salivary Features and Functions of the Salivary Glands

Main functions: - Produces and secretes saliva - Cleanses the mouth - Dissolves food chemicals so they can be tasted - Moistens food, compacting it into a bolus - Begins the chemical breakdown of food • Salivary amylase: starch Types salivary glands The major salivary glands are paired glands with long ducts that empty into the oral cavity. - The parotid is located subcutaneously, below and in front of the ear in the space between the ramus of the mandible and the styloid process of the temporal bone. - The is located under the floor of the mouth, in the submandibular triangle of the neck. - The is located in the floor of the mouth anterior to the submandibular gland. Saliva travels to oral orifice via ducts from all three glands The minor salivary glands are located in the submucosa of different parts of the oral cavity. - They include the lingual, labial, buccal, molar, and .

Common properties of the salivary glands Secretory Gland Acini Secretory acini are organized into lobules. - The major salivary glands are surrounded by a capsule of moderately dense connective tissue from which septa divide the secretory portions of the gland into lobes and lobules. Acini are of three types: serous, mucous, or mixed. - The basic secretory unit of salivary glands, the salivon, consists of the , intercalated , the striated duct and the excretory duct. - The acinus is a blind sac composed of secretory cells. - Three types of acini are described: . Serous acini, which contain only serous cells and are generally spherical. . Mucous acini, which contain only mucous cells and are usually more tubular. . Mixed acini, which contain both serous and mucous cells. Diagram comparing the components of the salivon in the three major salivary glands. The four major parts of the salivon the acinus, intercalated duct, striated duct, and excretory duct are color-coded. The three columns on the right of the salivon compare the length of the different ducts in the three salivary glands. The red-colored cells of the acinus represent serous-secreting cells, and the yellow-colored cells represent -secreting cells. The ratio of serous-secreting cells to mucus-secreting cells is depicted in the acini of the various glands. Serous demilunes are artifacts of the traditional fixation method. .

Relationship of serous-secreting cells and mucus-secreting cells in the mixed acinus. a. This drawing indicates the relationship of the mucous and serous cells as observed in the electron microscope after the rapid freezing method. The serous cells extend from the basal lamina to the lumen of the acinus. b. In this drawing, serous cells are shown occupying the periphery of the acinus to form the so-called . This feature is visible in routine preparations using immersion fixation. The swollen mucous cells have forced out the serous cells, leaving small remnants of the cytoplasm between the mucous cells. Types of acini in salivary glands Types of salivary glands Cells

- Serous cells are actually seromucous cells that produce proteins and polysaccharides - They are pyramidal and have basal spherical euchromatic nucleus - Cytoplasm is basophilic due to presence of a developed RER, Golgi apparatus - Apically located zymogen granules that are usually eosinophilic and rich in ptyalin (salivary amylase) - Many basal mitochondria - Intercellular plasmalemma processes - Organized as acinus or demilune that secrete proteins, polysaccharides and ptyalin.

Electron micrograph of the apical portion of parotid gland serous cells. As indicated by the box in the orientation photomicrograph, only the apical portions of parotid gland serous acinus are shown in this electron micrograph. The cells are polarized, with their product package within the secretory vesicles (SV) near the lumen (L) of the acinus. The cells display rough endoplasmic reticulum (rER) and several profiles of the Golgi apparatus (G). Immature secretory vesicles (IV) are present close to the Golgi apparatus. At the apical pole of the cells are junctional complexes (JC). The intercellular space (IC) is dilated, and profiles of sectioned lateral plications are seen. M, mitochondria. 15,000. Salivary Gland Cells

- Mucous cells are cuboidal or pyramidal - Mucous cells have a heterochromatic basal flattened nucleus - Apical cytoplasm is pale or blue/purple - Their structure is acinar or tubular - They have less RER, fewer mitochondria but greater GA Mucous acinus Low magnification electron micrograph of a mucous acinus. The mucous cells contain numerous mucinogen granules. Many of the granules have coalesced to form larger irregular masses that will ultimately discharge into the lumen (L) of the acinus. processes (MyC) are evident at the periphery of the acinus. 5,000.

Mixed salivary gland Mixed salivary gland Electron micrographs of mixed acini. a. Low magnification electron micrograph of the sublingual gland, prepared by the rapid freezing and freeze-substitution method, shows the arrangement of the cells within a single acinus. The mucous cells have well-preserved round mucinogen granules. The mucous and serous cells are aligned to surround the acinus lumen. Serous demilunes are not evident. 6,000. b. Electron micrograph of the sublingual gland prepared by traditional fixation in formaldehyde. Note the considerable expansion and coalescence of the mucinogen granules and the formation of a serous demilune. 15,000. (Courtesy of Dr. Shohei Yamashina.) Salivary Gland Cells

Myoepithelial cells (Basket cells) contractile cells, they have large processes which form desmosomal contact with acini and ducts cells. - Their processes are rich in actin and myosin - Basket cells have a common basal lamina with acinar cells - They attach to basal lamina by hemidesmosome Myoepithelial cells (Basket cells) Myoepithelial cells

(a) The TEM shows two salivary gland cells Containing secretory granules, with an Associated myoepithelial cell (M).X20,000. (b) A myoepithelial cell immunostained Brown with antibodies against actin show Its association with cells of acinus stained by H&E. X200. * Contraction of the myoepithelial cell compresses the acinus and aids in the expulsion of secretory products into the duct. Myoepithelial cells (Basket cells)

Stellate shaped cells which embrace acini and duct as an octopus Electron micrograph of the basal portion of an acinus. This electron micrograph shows the basal portion of two secretory cells from a submandibular gland. A myoepithelial cell process is also evident. Note the location of the myoepithelial cell process on the epithelial side of the basal lamina. The cytoplasm of the myoepithelial cell contains contractile filaments and densities (arrows) similar to those seen in smooth muscle cells. The cell on the left with the small nucleus is a lymphocyte. Having migrated through the basal lamina, it is also within the epithelial compartment. Arrowheads, cell boundaries; asterisks, basolateral folds. 15,000.

Introduction The primary function of the salivary glands is to moisten the mucous membranes of the upper aerodigestive tract . In humans , this function is fulfilled by the continuous exocrine secretion of numerous minor salivary glands. These glands are located in the submucosa throughout the oral cavity, pharynx, and upper airways. In developed species, most of the saliva is elaborated by three pairs of major glands, or salivary glands, named by their location: the parotid, the submaxillary or submandibular, and the sublingual glands. They are connected symmetrically to the oral cavity , where they empty their secretion only under specific stimuli. The saliva produced by these glands (750 “1000 mL/24 hours) plays an important role in preparing food for digestion , as well as in controlling the bacterial flora of the mouth. The quality of the saliva produced by the major glands is variable and depends on both the stimuli and the predominant participating gland. Salivary glands - The major salivary glands are paired glands with long ducts that empty into the oral cavity. * The major salivary glands, as noted above, consist of the paired parotid, submandibular, and sublingual glands. The parotid and the submandibular glands are actually located outside the oral cavity; their secretions reach the cavity by ducts. . The parotid gland is located subcutaneously, below and in front of the ear in the space between the ramus of the mandible and the styloid process of the temporal bone. . The submandibular gland is located under the floor of the mouth, in the submandibular triangle of the neck. . The sublingual gland is located in the floor of the mouth anterior to the submandibular gland. * The minor salivary glands are located in the submucosa of different parts of the oral cavity. They include the lingual, labial, buccal, molar, and palatine glands. Each salivary gland arises from the developing oral cavity . Initially, the gland takes the form of a solid cord of cells that enters the mesenchyme. The proliferation of epithelial cells eventually produces highly branched epithelial cords with bulbous ends. Degeneration of the innermost cells of the cords and bulbous ends leads to their canalization. The cords become ducts, and the bulbous ends become secretory acini. Secretory Gland Acini - Secretory acini are organized into lobules. The major salivary glands are surrounded by a capsule of moderately dense connective tissue from which septa divide the secretory portions of the gland into lobes and lobules. The septa contain the larger blood vessels and excretory ducts. The connective tissue associated with the groups of secretory acini blends imperceptibly into the surrounding loose connective tissue. The minor salivary glands do not have a capsule. Numerous lymphocytes and plasma cells populate the connective tissue surrounding the acini in both the major and minor salivary glands. Their significance in the secretion of salivary antibodies is described below.

- Acini are of three types: serous, mucous, or mixed. The basic secretory unit of salivary glands, the salivon, consists of the acinus, intercalated duct, and excretory duct. The acinus is a blind sac composed of secretory cells. The term acinus [L., berry or grape] refers to the secretory unit of the salivary glands. The acini of salivary glands contain either serous cells (protein secreting), mucous cells (mucin secreting), or both. The relative frequencies of the three types of acini are a prime characteristic by which the major salivary glands are distinguished. Thus, three types of acini are described: • Serous acini, which contain only serous cells and are generally spherical • Mucous acini, which contain only mucous cells and are usually more tubular • Mixed acini, which contain both serous and mucous cells. In routine H&E preparations, mucous acini have a cap of serous cells that are thought to secrete into the highly convoluted intercellular space between the mucous cells. Because of their appearance in histologic sections, such caps are called serous demilunes [Fr., half-moon]. - Serous demilunes are artifacts of the traditional fixation method. As noted above, each mixed acinus, such as those found in the sublingual and submandibular glands, contains serous and mucus-producing cells. In routine preparation for both light and electron microscopy, serous cells have traditionally been regarded as the structures that make up the demilune. Recent electron microscopic studies now challenge this classic interpretation of the demilune. Rapid freezing of the tissue in liquid nitrogen, followed by rapid freeze substitution with osmium tetroxide in cold acetone, reveals that both mucous and serous cells are aligned in the same row to surround the lumen of the secretory acinus. No serous demilune is found. Sections prepared from the same specimen by conventional methods show swollen mucous cells with enlarged secretory granules. The serous cells form typical demilunes and are positioned in the peripheral region of the acinus with slender cytoplasmic processes interposed between the mucous cells. These findings indicate that the demilune observed in light or electron microscopy is an artifact of the routine fixation method ..

Relationship of serous-secreting cells and mucus-secreting cells in the mixed acinus. - Serous cells are protein-secreting cells. Serous cells have a pyramidal shape, with a relatively wide basal surface facing the basal lamina and a small apical surface facing the lumen of the acinus. They contain large amounts of rER, free ribosomes, a prominent Golgi apparatus and numerous spherical secretory granules. As in most protein-secreting cells that store their secretions in zymogen granules, the granules are located in the apical cytoplasm. Most other organelles are located in the basal or perinuclear cytoplasm. In H&E sections, the basal cytoplasm of the serous cell stains with hematoxylin because of the rER and the free ribosomes, whereas the apical region stains with eosin, in large part because of the secretory granules. When examined with the transmission electron microscope (TEM), the base of the serous cell may display infoldings of the plasma membrane and basolateral folds in the form of processes that interdigitate with similar processes of adjacent cells. The serous cells are joined near their apical surface by junctional complexes to neighboring cells of the acinus. - Mucous cells are mucin-secreting cells. As in other mucus-secreting epithelia, the mucous cells of the mucous salivary acini undergo cyclic activity. During part of the cycle, mucus is synthesized and stored within the cell as mucinogen granules. When the product is discharged after hormonal or neural stimulation, the cell begins to resynthesize mucus. After discharge of most or all of the mucinogen granules, the cell is difficult to distinguish from an inactive serous cell. However, most mucous cells contain large numbers of mucinogen granules in their apical cytoplasm, and because the mucinogen is lost in H&E–stained paraffin sections, the apical portion of the cell usually appears empty. In TEM preparation, the rER, mitochondria, and other components are seen chiefly in the basal portion of the cell; this part of the cell also contains the nucleus, which is typically flattened against the base of the cell. In rapid-freeze preparations , cells are rounded and clearly isolated from each other. The nuclei are round and centrally located. The apical portion of the mucous cell contains numerous mucinogen granules and a large Golgi apparatus, in which large amounts of carbohydrate are added to a protein base to synthesize the glycoprotein of the mucin. Mucous cells possess apical junctional complexes, the same as those seen between serous cells. - Myoepithelial cells are contractile cells that embrace the basal aspect of the acinar secretory cells. Myoepithelial cells are contractile cells with numerous processes. They lie between the basal plasma membrane of the epithelial cells and the basal lamina of the epithelium. Myoepithelial cells also underlie the cells of the proximal portion of the duct system. In both locations, the myoepithelial cells are instrumental in moving secretory products toward the excretory duct. Myoepithelial cells are sometimes difficult to identify in H&E sections. The nucleus of the cell is often seen as a small round profile near the basement membrane. The contractile filaments stain with eosin and are sometimes recognized as a thin eosinophilic band adjacent to the basement membrane. Salivary Ducts The lumen of the salivary acinus is continuous with that of a duct system that may have as many as three sequential segments: • Intercalated duct, which leads from the acinus. • Striated duct, so-called because of the presence of “striations,” the infoldings of the basal plasma membrane of the columnar cells that form the duct • Excretory ducts, which are the larger ducts that empty into the oral cavity The degree of development of the intercalated ducts and striated ducts varies, depending on the nature of the acinar secretion . Serous glands have well-developed intercalated ducts and striated ducts that modify the serous secretion by both absorption of specific components from the secretion and secretion of additional components to form the final product. Mucous glands, in which the secretion is not modified, have very poorly developed intercalated ducts that may not be recognizable in H&E sections. Moreover, they do not display striated ducts.

- Intercalated ducts are located between a secretory acinus and a larger duct. Intercalated ducts are lined by low cuboidal epithelial cells that usually lack any distinctive feature to suggest a function other than that of a conduit. However, the cells of intercalated ducts possess carbonic anhydrase activity. In serous-secreting glands and mixed glands, they have been shown to • secrete HCO3 into the acinar product. • absorb Cl from the acinar product. As noted above, intercalated ducts are most prominent in those salivary glands that produce a watery serous secretion. In mucus-secreting salivary glands, the intercalated ducts, when present, are short and difficult to identify. - Striated duct cells have numerous infoldings of the basal plasma membrane. Striated ducts are lined by a simple cuboidal epithelium that gradually becomes columnar as it approaches the excretory duct. The infoldings of the basal plasma membrane are seen in histologic sections as “striations.” Longitudinally oriented, elongated mitochondria are enclosed in the infoldings, a morphologic specialization associated with reabsorption of fluid and electrolytes. The striated duct cells also have numerous basolateral folds that are interdigitated with those of adjacent cells. • reabsorption of Na from the primary secretion. • secretion of K and HCO3 into the secretion. More Na is resorbed than K is secreted, so the secretion becomes hypotonic. When secretion is very rapid, more Na and less K appear in the final saliva because the reabsorption and secondary secretion systems cannot keep up with the rate of primary secretion. Thus, the saliva may become isotonic to hypertonic. The diameter of striated ducts often exceeds that of the secretory acinus. Striated ducts are located in the parenchyma of the glands (they are intralobular ducts) but may be surrounded by small amounts of connective tissue in which blood vessels and nerves can be seen running in parallel with the duct.

- Excretory ducts travel in the interlobular and interlobar connective tissue. Excretory ducts constitute the principal ducts of each of the major glands. They ultimately connect to the oral cavity. The epithelium of small excretory ducts is simple cuboidal. It gradually changes to pseudostratified columnar or stratified cuboidal. As the diameter of the duct increases, stratified columnar epithelium is often seen, and as the ducts approach the oral epithelium, stratified squamous epithelium may be present. The parotid duct (Stensen’s duct) and the submandibular duct (Wharton’s duct) travel in the connective tissue of the face and neck, respectively, for some distance from the gland before penetrating the oral mucosa. Embryologic and Postnatal Developmental Changes Parotid Gland During embryologic life, the parotid is the first of the three major glands to appear and is seen by the sixth week. It derives from the ectoderm as an epithelial bud from the primitive oral epithelium, at the angle between the maxillary process and the mandibular arch. By the seventh week, the primitive gland moves in a dorsal and lateral direction and reaches the preauricular region. Development of the divides the gland by approximately the tenth week into superficial and deep portions. By the third month, the gland has attained its general pattern of organization. By the sixth month, the epithelial cordons are canalized and exhibit a double-cell ciliated cover. Cell differentiation begins in the excretory ducts with the progressive transformation of ciliated cells by columnar , squamous, and goblet cells. Intralobular duct and acinar differentiation, including myoepithelial cell formation, begins about the eighth month and myoepithelial cell differentation by the nineteenth- to twenty-fourth “week period. Between 25 and 32 weeks, the myoepithelial cells become flattened and show cytoplasmal prolongations. Saliva production starts as a mucinous liquid at this time; but several studies in rodents suggest that full maturation is completed only after birth. The definitive location of the parotid is behind the inferior facial nerve maxillary branch, below and in front of the external ear. It is enclosed within a fibroadipose capsule in a depression whose anterior limit is the masseter muscle. Its superior limit is the zygomatic arch; the posterior limit is the tragus, and the inferior limit is the anterior border of the sternocleidomastoid muscle The adult parotid is the largest of the three major salivary glands and weighs between 14 and 28 g. The gland is surrounded by a fine capsule and is divided into two portions by the facial nerve. The main portion, or superficial lobe, is flattened and quadrilateral; The rest of the gland, called the deep lobe. The parotid gland is covered by a superficial musculoaponeurosis and the skin. Accessory parotid tissue is found in approximately 20% of cases. Like all the exocrine glands, the parotid is composed of numerous tubuloacinar units connected through the excretory ducts to a main duct (Stensen's duct) located in the anterior portion of the gland. The parotid duct follows a twisted course of 7 cm, crossing the masseter muscle, the corpus adiposum of the cheek, and the buccinator muscle before opening into the oral vestibule. Blood supply is by arterial branches from the external carotid. The veins are tributaries of the external jugular, and the lymphatics join the superficial and deep cervical lymph nodes. Innervation is derived from the sympathetic and auriculotemporal nerves. Parotid Gland

- The parotid glands are the largest of the major salivary glands. - Branched acinar structure. - The secretory units in the parotid are serous. - The parotid duct travels from the gland, which is located below and in front of the ear, to enter the oral cavity opposite the second upper molar tooth. - Long, narrow intercalated ducts. Striated ducts are large and conspicuous - Large amounts of adipose tissue often occur in the parotid gland; this is one of its distinguishing features. - Plasma cells (produce IgA) and lymphocytes in connective tissue The facial nerve (cranial nerve VII) passes through the parotid gland; large cross sections of this nerve may be encountered in routine H&E sections of the gland and are useful in identifying the parotid. Mumps, a viral infection of the parotid gland, can damage the facial nerve. Submaxillary Gland

In the submaxillary gland, the primordia appear at the end of the sixth week and, unlike the parotid, are probably of endodermal derivation. However, a recent study suggests that the sublingual process of the submandibular gland originates from a lateral ectodermal bud of the anlage of the submandibular gland. The epithelial bud appears in the groove between the lower jaw and , at one side of the midplane. The submaxillary gland is finely encapsulated; it lies inside the submandibular triangle, an osteofibrous cavity from which it takes the form of a triangular prism. This gland weighs approximately 7 to 8 g and, like the other major salivary glands, is organized in lobules connected to a main excretory duct ”the submaxillary duct (Wharton's duct) ”which measures 5 cm in length and 2 to 3 mm in diameter. The duct originates near the surface; runs between the mylohyoideus, the genioglossus muscles ; and finally opens through a narrow orifice in a الذقنية اللسانية hyoglossus, and frenulum linguae. Aلجام اللسان caruncula sublingualis on each side of the لحيمة small papilla called the submandibular gland having three ducts that open separately into the oral cavity has also been reported. The blood supply is from branches of the facial and sublingual arteries. The secretomotor nerves are fibers from the cranial parasympathetic branch of the facial nerve; the vasomotor nerves are derived from the superior cervical ganglion. The lymph nodes are arranged in a row in the spaces between the mandible and the gland and are disposed in anterior, medial, and posterior groups. Submandibular Gland

- The submandibular glands are mixed glands that are mostly serous in humans. -The large, paired, mixed submandibular glands are located under either side of the floor of the mouth, close to the mandible. - Some mucous acini capped by serous demilunes are generally found among the predominant serous acini. - Intercalated ducts are less extensive than in the parotid gland. - A duct from each of the two glands runs forward and medially to a papilla located on the floor of the mouth just lateral to the frenulum of the tongue. Sublingual Gland The sublingual glands are the last of the three major salivary glands to appear. Their primordia are located immediately lateral to the submaxillary glands for the greater sublingual glands and in the linguogingival sulcus for the lesser sublingual glands. The epithelial buds grow downward from the groove between the lower jaw and the tongue. Parenchymal organization and differentiation are similar to those of the submaxillary gland and are also probably of endodermal derivation. The principal sublingual gland weighs 3 g. It lies in the sublingual fossa of the mandible and is surrounded by loose connective tissue. Its secretion is drained through a main duct called the Bartholin's duct, which opens into the submandibular duct, and various small ducts (Rivinus' ducts) that open separately into the mouth in the plica sublingualis or join the submandibular duct ( 16 , 17 ). Vascular supplies come from the sublingual and submental arteries; the veins are tributaries of the external jugular. Innervation is similar to that of the submaxillary gland. Sublingual Gland

The sublingual glands, the smallest of the paired major salivary glands, are located in the floor of the mouth anterior to the submandibular glands. - Branched tubuloacinar gland. -The small sublingual glands are mixed glands that are mostly mucous secreting in humans. - The mucous secretory units may be more tubular than purely acinar. - Mostly mucous cells in acini with some serous demilunes. - Their multiple small sublingual ducts empty into the submandibular duct as well as directly onto the floor of the mouth. - Intercalated ducts and striated ducts are short, difficult to locate, or sometimes absent. Saliva - Saliva includes the combined secretions of all the major and minor salivary glands. Most saliva is produced by the salivary glands. A smaller amount is derived from the gingival sulcus, tonsillar crypts, and general transudation from the epithelial lining of the oral cavity. One of the unique features of saliva is the large and variable volume produced. The volume (per weight of gland tissue) of saliva exceeds that of other digestive secretions by as much as 40 times. The large volume of saliva produced is undoubtedly related to its many functions, only some of which are concerned with digestion. - Saliva performs both protective and digestive functions. The salivary glands produce about 1,200 mL of saliva a day. Saliva has numerous functions relating to metabolic and nonmetabolic activities, including these: • Moistening the oral mucosa • Moistening dry foods to aid swallowing • Providing a medium for dissolved and suspended food materials that chemically stimulate taste buds • Buffering the contents of the oral cavity, because of its high concentration of bicarbonate ions • Digesting carbohydrates with the digestive enzyme -amylase, which breaks one to four glycosidic bonds and continues to act in the esophagus and . • Controlling the bacterial flora of the oral cavity by use of lysozyme (muramidase), an enzyme that lyses the muramic acid in certain bacteria (e.g., staphylococci). - Saliva is a source of calcium and phosphate ions essential for normal tooth development and maintenance. Calcium and phosphate in the saliva are essential for the mineralization of newly erupted teeth and for repair of precarious lesions of the enamel in erupted teeth. In addition, saliva serves several other roles in protecting the teeth. Proteins in saliva cover the teeth with a protective coat called the acquired pellicle. Antibodies and other antibacterial agents retard bacterial action that would otherwise lead to tooth decay. Patients whose salivary glands are irradiated, as in the treatment of salivary gland tumors, fail to produce normal amounts of saliva; these patients typically develop rampant caries. Anticholinergic drugs used to treat some forms of heart disease also significantly reduce salivary secretion, leading to dental caries. - Saliva performs immunologic functions. As noted, saliva contains antibodies, salivary immunoglobulin A (IgA). IgA is synthesized by plasma cells in the connective tissue surrounding the secretory acini of the salivary glands, and both dimeric and monomeric forms are released into the connective tissue matrix . A polymeric immunoglobulin receptor (pIgR) protein is synthesized by the salivary gland cells and inserted into the basal plasma membrane, where it serves as a receptor for dimeric IgA. When the dimeric IgA binds to the receptor, the pIgR-dIgA complex is internalized by receptor- mediated endocytosis and carried through the acinar cell to the apical plasma membrane. Here, pIgR is proteolytically cleaved and the extracellular part of the receptor that is bound to dIgA is released into the lumen as secretory IgA (sIgA). This process of synthesis and secretion of IgA is essentially identical to that which occurs in the more distal parts of the gastrointestinal tract, where sIgA is transported across the absorptive columnar epithelium of the small intestine and colon . - Saliva contains water, various proteins, and electrolytes. Saliva contains chiefly water, proteins and glycoproteins (enzymes and antibodies), and electrolytes. It has a high potassium concentration that is approximately seven times that of blood, a sodium concentration approximately one tenth that of blood, a bicarbonate concentration approximately three times that of blood, and significant amounts of calcium, phosphorus, chloride, thiocyanate, and urea. Lysozyme and amylase are the principal enzymes present. Interlobar (Excretory) ducts Electron micrograph of the apical portion of parotid gland serous cells Electron micrograph of the basal portion of an acinus Submandibular Gland: “Human” Mixed acini Embryologic and Postnatal Developmental Changes Parotid Gland *During embryologic life, the parotid is the first of the three major glands to appear and is seen by the 6 week. It derives from the ectoderm as an epithelial bud from the primitive oral epithelium.. *By the 7 week, the primitive gland . *By the 3 month, the gland has attained its general pattern of organization. *By the 6 month, the epithelial cordons are canalized and exhibit a double-cell ciliated cover. Cell differentiation begins in the excretory ducts with the progressive transformation of ciliated cells by columnar , squamous, and goblet cells. *Intralobular duct and acinar differentiation, including myoepithelial cell formation, begins about the 8 month. *Saliva production starts as a mucinous liquid at this time; but several studies in rodents suggest that full maturation is completed only after birth. The definitive location of the parotid is behind the inferior facial nerve maxillary branch, below and in front of the external ear. It is enclosed within a fibroadipose capsule in a depression whose anterior limit is the masseter muscle. The adult parotid is the largest of the three major salivary glands and weighs between 14 and 28 g.

-The gland is surrounded by a fine capsule and is divided into two portions by the facial nerve. The main portion, or superficial lobe, is flattened and quadrilateral; The rest of the gland, called the deep lobe. Salivary Gland Cells

- Serous cells are actually seromucous cells that produce proteins and polysaccharides. Serous cells have a pyramidal shape, with a relatively wide basal surface facing the basal lamina and a small apical surface facing the lumen of the acinus. They contain large amounts of rER, free ribosomes, a prominent Golgi apparatus and numerous spherical secretory granules. As in most protein-secreting cells that store their secretions, In zymogen granules, the granules are located in the apical cytoplasm.. - Mucous cells are mucin-secreting cells. As in other mucus-secreting epithelia, the mucous cells of the mucous salivary acini undergo cyclic activity. During part of the cycle, mucus is synthesized and stored within the cell as mucinogen granules. - Myoepithelial cells are contractile cells that embrace the basal aspect of the acinar secretory cells. Myoepithelial cells are contractile cells with numerous processes. They lie between the basal plasma membrane of the epithelial cells and the basal lamina of the epithelium. .

Parotid Gland

- The parotid glands are the largest of the major salivary glands. - Branched acinar structure. - The secretory units in the parotid are serous. - The parotid duct travels from the gland, which is located below and in front of the ear, to enter the oral cavity opposite the second upper molar tooth. - Long, narrow intercalated ducts. Striated ducts are large and conspicuous. - Large amounts of adipose tissue often occur in the parotid gland; this is one of its distinguishing features. - Plasma cells (produce IgA) and lymphocytes in connective tissue The facial nerve (cranial nerve VII) passes through the parotid gland; large cross sections of this nerve may be encountered in routine H&E sections of the gland and are useful in identifying the parotid. Mumps, a viral infection of the parotid gland, can damage the facial nerve. Excretory ducts Excretory ducts A. Intercalated duct, B. Striated ducts, C. Excretory ducts Interlobular (striated) duct Sublingual Gland Saliva

- Saliva includes the combined secretions of all the major and minor salivary glands.

- Saliva performs both protective and digestive functions. The salivary glands produce about 1-1.5 l / day. Saliva has numerous functions, including these: • Moistening the oral mucosa; • Moistening dry foods to aid swallowing; • Providing a medium for dissolved and suspended food materials that chemically stimulate taste buds; • Buffering the contents of the oral cavity, because of its high concentration of bicarbonate ions. • Digesting carbohydrates with the digestive enzyme -amylase, which breaks one to four glycosidic bonds and continues to act in the esophagus and stomach. • Controlling the bacterial flora of the oral cavity by use of lysozyme (muramidase), an enzyme that lyses the muramic acid in certain bacteria (e.g., staphylococci). Submandibular Gland

- Extensive connective tissue capsule and abundant septa - Branched tubuloacinar gland produce 60% of saliva - Mucous and serous acini; . mucous acini with limited number of serous demilunes - About 80% of cells are serous (basophilic) - Lysozyme, mucous and amylase - Striated ducts are much longer than the other two glands Salivary Ducts

The lumen of the salivary acinus is continuous with that of a duct system that may have as many as three sequential segments: - Intercalated ducts are smallest branches, located between a secretory acinus and a larger duct. • lined by short, cuboidal or squamous cells and myoepithelial cells. - They have been shown to: • Secrete HCO3 into the acinar product. • Absorb Cl from the acinar product. Salivary Ducts - Striated duct cells have large diameter and have numerous infoldings of the basal plasma membrane. • lined by a simple cuboidal to low columnar cells are eosinophilic, and secrete fluid and ions, basolateral membrane folded with Na – ATPase pump, elongated mitochondria. • Reabsorption of Na from the primary secretion. • Secretion of K and HCO3 into the secretion. • These ducts join each other and forming larger caliber ducts known as interlobular ducts (excretory ducts)

- Excretory ducts travel in the interlobular and interlobar connective tissue outside of lobules. • They ultimately connect to the oral cavity. • The epithelium of small excretory ducts is simple cuboidal columnar . • It gradually changes to pseudostratified columnar or stratified cuboidal. Intercalated ducts, striated duct

Striated and Excretory ducts

Excretory duct Major Salivary Glands Parotid Gland

Submandibular Gland

Sublingual Gland Major salivary glands of parotid glands Embryologic and Postnatal Developmental Changes of Parotid Gland The parotid is the first of the three major glands to appear and is seen by the 6 week. - It derives from the ectoderm as an epithelial bud from the primitive oral epithelium. - By the 7 week, the primitive gland . - By the 3 month, the gland has attained its general pattern of organization. - By the 6 month, the epithelial cordons are canalized and exhibit a double-cell ciliated cover. - Cell differentiation begins in the excretory ducts with the progressive transformation of ciliated cells by columnar , squamous, and goblet cells. - Intralobular duct and acinar differentiation, including myoepithelial cell formation, begins about the 8 month. - Saliva production and full maturation is completed only after birth. - The adult parotid is the largest of the three major salivary glands and weighs between 14 and 28 g - The gland is surrounded by a fine capsule and is divided into two portions by the facial nerve. - The main portion, or superficial lobe, is flattened and quadrilateral; . The rest of the gland, called the deep lobe. Light micrograph of developing salivary gland Development and histogenesis of the epithelial constituents of the salivary gland. A. Fetal parotid gland at 4 months; Parotid Gland

- The largest salivary gland but produce 30% of saliva - Connective tissue capsule is well developed forms many septa divided the glands into lobes and lobules - Branched acinar structure - All serous cells, but actually they are seromucous - Secrete amylase (Ptyalin) - Lymphocytes and plasma cells are located in connective tissue elements produce IgA - After 40 year of age adipose tissue invaded the gland Parotid gland (a) H&E (LP) (b) Serous acinus and intercalated duct, H&E (MP); lobules L; septa S; excretory ducts E; serous cells SC; intercalated duct ID. Parotid gland. Serous Cells CLINICAL POINT - Mumps, or epidemic parotiditis, is an acute viral infection caused by paramyxovirus and transmitted mainly via infected saliva. - Before the vaccine, it was a common childhood communicable disease affecting both sexes equally. - It causes swollen and painful parotid glands (both glands or one), plus headache, malaise, and fever. - The parenchyma of the gland is diffusely infiltrated by plasma cells and macrophages, followed by degeneration of acini and vacuolation of ductal epithelium. - Inflammation of the testes (orchitis) occurs in 25%-30% of infected males, but infertility is rare. - Serious complications, such as pancreatitis, encephalitis, and meningitis, may develop. Histology of mixed salivary (submandibular and sublingual) glands Submaxillary Gland In the submaxillary gland, the primordia appear at the end of the 6 week and, unlike the parotid, are probably of endodermal derivation. - The sublingual process of the submandibular gland originates from a lateral ectodermal bud.. - The submaxillary gland is finely encapsulated. - It weighs approximately 7 - 8 g. - The submaxillary duct (Wharton's duct) ”which measures 5 cm in length and 2 to 3 mm in diameter. - The blood supply is from branches of the facial and sublingual arteries. - The secretomotor nerves are parasympathetic branch of the facial nerve; t . he vasomotor nerves are derived from the superior cervical ganglion. - The lymph nodes are arranged in a row. Submandibular Gland The large, paired, mixed Seromucous glands are mostly serous in humans located under either side of the floor of the mouth, close to the mandible. - Extensive connective tissue capsule and abundant septa - Branched tubuloacinar gland produce 60% of saliva - In human 90% of its acini are serous and 10% are mucous and mucoserous. - Mucous and serous acini; . mucous acini with limited number of serous demilunes - Striated ducts are much longer than the other two glands - Lysozyme, mucous and amylase - Intercalated ducts are less extensive than in the parotid gland. - A duct (glands Warton’Duct) from each of the two runs forward and medially to a papilla(sublingual papilla) located on the floor of the mouth just lateral to the frenulum of the tongue. Submandibular : lobules, septa with interlobular ducts Ultrastructure of serous and mucous cells. Submandibular gland, wall of an excretory duct Sublingual Gland Their primordia are located immediately lateral to the submaxillary glands. - The epithelial buds grow downward from the groove between the lower jaw and the tongue. - Parenchymal organization and differentiation are similar to those of the submaxillary gland and are also probably of endodermal derivation. - The principal sublingual gland weighs 3 g. - It lies in the sublingual fossa. - Its secretion is drained through a main duct called the Bartholin's duct, which opens into the submandibular duct, and various small ducts (Rivinus' ducts) that open separately into the mouth in the plica sublingualis or join the submandibular duct - Vascular supplies come from the sublingual and submental arteries; . the veins are tributaries of the external jugular. - Innervation is similar to that of the submaxillary gland. Sublingual Gland

The sublingual glands, the smallest of the paired major salivary glands, are located in the floor of the mouth anterior to the submandibular glands, that produce 5% of total saliva. - Branched tubuloacinar gland. - Mostly mucous cells in acini with some serous demilunes - The mucous secretory units may be more tubular than purely acinar. - Produce mix saliva but mostly mucous saliva - Their multiple small sublingual ducts empty into the submandibular duct as well as directly onto the floor of the mouth. - Intercalated ducts and striated ducts are short, difficult to locate, or sometimes absent. Sublingual Gland

Low-magnification electron micrograph of a mucous acinus Sublingual Gland Sublingual Gland

1- lobules of the gland, 2 - interlobular connective tissue septa, 3 - interlobular excretory duct Sublingual salivary gland Excretory duct Photomicrographs of the three major salivary glands. a. The parotid gland in the human is composed entirely of serous acini and their ducts. Typically, adipose cells are also distributed throughout the gland. The lower portion of the figure reveals an excretory duct within a connective tissue septum. 120. Inset. Higher magnification of the serous acinar cells. 320. b. The submandibular glands contain both serous and mucous acini. In humans, the serous components predominate. The mucus-secreting acini are readily discernible at this low magnification because of their light staining. The remainder of the field is composed largely of serous acini. Various ducts—excretory, striated, and intercalated are evident in the field. 120. Left inset. Higher magnification of an acinus revealing a serous demilune surrounding mucus-secreting cells. 360. Right inset. Higher magnification of a striated duct. These ducts have columnar epithelium with visible basal striations. 320. c. The sublingual gland also contains both serous and mucous elements. Here, the mucous acini predominate. The mucous acini are conspicuous because of their light staining. Critical examination of the mucous acini at this relatively low magnification reveals that they are not spherical structures but, rather, elongate or tubular structures with branching out pockets. Thus, the acinus is rather large, and much of it is usually not seen within the plane of a single section. The ducts of the sublingual gland that are observed with the greatest frequency in a section are the interlobular ducts. 120. Inset. The serous component of the gland is composed largely of demilunes (asterisks), artifacts of conventional fixation. 320. Saliva Saliva performs immunologic functions. - Immunoglobulin A (IgA) is synthesized by plasma cells. - A polymeric immunoglobulin receptor (pIgR) protein is synthesized by the salivary gland cells. - IgA binds to the receptor, the pIgR- dIgA complex is internalized. - PIgR is proteolytically cleaved and the extracellular part of the receptor that is bound to dIgA is released into the lumen as secretory IgA (sIgA). Diagram of different forms of immunoglobulin A (IgA). This drawing shows the monomer of IgA (top). The dimer of IgA is a product of the plasma cell and contains a J chain (J ) connecting two monomers (middle). The secretory component (SC), a product of proteolytically cleaved pIgR, is added to the dimer to form secretory IgA (sIgA; bottom). Saliva Saliva contains water, various proteins, and electrolytes. - Saliva contains chiefly water, proteins and glycoproteins (enzymes and antibodies), and electrolytes. - It has a high potassium concentration that is approximately seven times that of blood, a sodium concentration approximately one tenth that of blood, a bicarbonate concentration approximately three times that of blood, and significant amounts of calcium, phosphorus, chloride, thiocyanate, and urea. - Lysozyme and amylase are the principal enzymes present. Saliva Saliva is a source of calcium and phosphate ions essential for normal tooth development and maintenance. - Proteins in saliva cover the teeth with a protective coat called the acquired pellicle. - Antibodies and other antibacterial agents retard bacterial action that would otherwise lead to tooth decay. - Patients whose salivary glands are irradiated, as in the treatment of salivary gland tumors, fail to produce normal amounts of saliva; . these patients typically develop rampant caries. - Anticholinergic drugs used to treat some forms of heart disease also significantly reduce salivary secretion, leading to dental caries. Saliva Saliva includes the combined secretions of all the major and minor salivary glands. - The salivary glands produce about 1-1.5 l / day, pH 6.75-7.0 - Saliva includes water, enzymes, IgA, mucous, ions - Primary saliva manufactured by acinar cells is isotonic with plasma - Secondary saliva is altered by striated duct cells - Moisten and lubricate food for swallowing - Enzymes like amylase and lipase to begin digestion - Saliva has protective effect on oral cavity tissues (Buffering). - Participate in taste sensation - IgA, lactoferrin, lysozyme ((muramidase) have different role against antigens and microorganisms (Controlling the bacterial flora) Salivation - Controlled by autonomic nervous system . Parasympathetic stimulation promotes secretion of moderate amount of saliva . Sympathetic stimulation decreases salivation. Composition of Unstimulated Saliva CLINICAL POINT - Xerostomia commonly known as dry mouth is a condition resulting from inadequat production of saliva. - Symptoms are dryness and discomfort of the oral cavity, cracked lips, and halitosis (bad breath). - By promoting bacterial growth, it may lead to tooth decay, increased plaque formation, gum disease, and oral candidiasis. - It may also cause difficulties in tasting, chewing, and swallowing. - It is most often a side effect of commonly prescribed medications (e.g., antihistamines, decongestants, tricyclic antidepressants, anticholinergics, antihypertensives). - In addition to radiation and chemotherapeutic agents for cancer treatment, disorders such as Parkinson disease and the autoimmune Sjögren syndrome may also cause it. - Use of oral moisturizers, lubricants, and mouthwashes may alleviate symptoms.