The oral cavity is kept moist by a film of fluid called saliva that coats the teeth and the mucosa. Saliva is a complex fluid, produced by the salivary glands. Individuals with a deficiency of salivary secretion experience difficulty eating, speaking, and swallowing and become prone to mucosal infections and rampant caries.
In human beings, three pairs of major salivary glands—the parotid, submandibular, and sublingual—are located outside the oral cavity, with extended duct systems through which the gland secretions reach the mouth. Numerous smaller minor salivary glands are located in various parts of the oral cavity—the labial, lingual, palatal, buccal, glossopalatine, and retromolar glands—typically located in the submucosal layer (Figure 11-1), with short ducts opening directly onto the mucosal surface.
The composition of saliva is summarized in Table 11-1. The saliva produced by each major salivary gland, however, differs in amount and composition. The parotid glands secrete a watery saliva rich in enzymes such as amylase, proteins such as the proline-rich proteins, and glycoproteins. Submandibular saliva, in addition to the components already listed, contains highly glycosylated substances called mucins. The sublingual gland produces viscous saliva also rich in mucins. Oral fluid, which is referred to as mixed, or whole, saliva, includes the secretions of the major glands, the minor glands, desquamated oral epithelial cells, microorganisms and their products, food debris, and serum components and inflammatory cells that gain access through the gingival crevice. Moreover, whole saliva is not the simple sum of all of these components because many of the proteins are removed as they adhere to the surfaces of the teeth and oral mucosa, bind to microorganisms, or are degraded.
|Electrolytes||Na+, K+, Cl–, , Ca2+, Mg2+, , SCN–, and F–|
|Secretory proteins/peptides||Amylase, proline-rich proteins, mucins, histatin, cystatin, peroxidase, lysozyme, lactoferrin, defensins, and cathelicidin-LL37|
|Immunoglobulins||Secretory immunoglobulin A; immunoglobulins G and M|
|Small organic||Glucose, amino acids, urea, uric acid, and lipid molecules|
|Other components||Epidermal growth factor, insulin, cyclic adenosine monophosphate–binding proteins, and serum albumin|
|FLOW RATE (ml/min)||WHOLE||PAROTID||SUBMANDIBULAR|
|Pellicle formation||Proteins, glycoproteins, mucins|
|Tannin binding||Basic proline-rich proteins, histatins|
|Buffering||pH maintenance||Bicarbonate, phosphate, basic proteins, urea, ammonia|
|Neutralization of acids|
|Tooth integrity||Enamel maturation, repair||Calcium, phosphate, fluoride, statherin, acidic proline-rich proteins|
|Antimicrobial activity||Physical barrier||Mucins|
|Immune defense||Secretory immunoglobulin A|
|Nonimmune defense||Peroxidase, lysozyme, lactoferrin, histatin, mucins, agglutinins, secretory leukocyte protease inhibitor, defensins, and cathelicidin-LL 37|
|Tissue repair||Wound healing, epithelial||Growth factors, trefoil proteins, regeneration|
|Digestion||Bolus formation||Water, mucins|
|Starch, triglyceride digestion||Amylase, lipase|
|Taste||Solution of molecules||Water and lipocalins|
|Maintenance of taste buds||Epidermal growth factor and carbonic anhydrase VI|
Saliva protects the oral cavity in many ways. The fluid nature of saliva provides a washing action that flushes away nonadherent bacteria and other debris. In particular, the clearance of sugars from the mouth limits their availability to acidogenic plaque microorganisms. The mucins and other glycoproteins provide lubrication, preventing the oral tissues from adhering to one another and allowing them to slide easily over one another. The mucins also form a barrier against noxious stimuli, microbial toxins, and minor trauma.
The bicarbonate and, to some extent, phosphate, ions in saliva provide a buffering action that helps to protect the teeth from demineralization caused by bacterial acids produced during sugar metabolism. Some basic salivary proteins also may contribute to the buffering action of saliva. Additionally, the metabolism of salivary proteins and peptides by bacteria produces urea and ammonia, which help to increase the pH.
Many of the salivary proteins bind to the surfaces of the teeth and oral mucosa, forming a thin film, the salivary pellicle. Several proteins bind calcium and help to protect the tooth surface. Others have binding sites for oral bacteria, providing the initial attachment for organisms that form plaque.
Saliva is supersaturated with calcium and phosphate ions. The solubility of these ions is maintained by several calcium-binding proteins, especially the acidic proline-rich proteins and statherin. At the tooth surface the high concentration of calcium and phosphate results in a posteruptive maturation of the enamel, increasing surface hardness and resistance to demineralization. Remineralization of initial caries lesions also can occur; this is enhanced by the presence of fluoride ions in saliva.
Saliva has a major ecologic influence on the microorganisms that colonize oral tissues. In addition to the barrier effect provided by mucins, saliva contains a spectrum of proteins with antimicrobial activity such as the lysozyme, lactoferrin, peroxidase, and secretory leukocyte protease inhibitor. A number of small peptides that function by inserting into membranes and disrupting cellular or mitochondrial functions are present in saliva. These include α-defensins and β-defensins, cathelicidin-LL37, and the histatins. In addition to antibacterial and antifungal activities, several of these proteins and peptides also exhibit antiviral activity. The major salivary immunoglobulin, secretory immunoglobulin A (IgA), causes agglutination of specific microorganisms, preventing their adherence to oral tissues and forming clumps that are swallowed. Mucins, as well as specific agglutinins, also aggregate microorganisms.
A variety of growth factors and other biologically active peptides and proteins are present in small quantities in saliva. Under experimental conditions, many of these substances promote tissue growth and differentiation, wound healing, and other beneficial effects. However, the role of most of these substances in protection of the oral cavity is presently unknown.
Saliva functions in taste by solubilizing food substances so that they can be sensed by taste receptors located in taste buds. Saliva produced by minor glands in the vicinity of the circumvallate papillae contains proteins that are believed to bind taste substances and present them to the taste receptors. Additionally, saliva contains proteins that have a trophic effect on taste receptors.
The parotid gland is the largest salivary gland. The superficial portion of the parotid gland is located subcutaneously, in front of the external ear, and its deeper portion lies behind the ramus of the mandible. The parotid gland is associated intimately with peripheral branches of the facial nerve (cranial nerve VII; Figure 11-2, A). The duct (Stensen’s duct) of the parotid gland runs forward across the masseter muscle, turns inward at the anterior border of the masseter, and opens into the oral cavity at a papilla opposite the maxillary second molar. A small amount of parotid tissue occasionally forms an accessory gland associated with Stensen’s duct, just anterior to the superficial portion. The parotid gland receives its blood supply from branches of the external carotid artery as they pass through the gland. The parasympathetic nerve supply to the parotid gland is mainly from the glossopharyngeal nerve (cranial nerve IX). The preganglionic fibers synapse in the otic ganglion; the postganglionic fibers reach the gland through the auriculotemporal nerve. The sympathetic innervation of all of the salivary glands is provided by postganglionic fibers from the superior cervical ganglion, traveling with the blood supply.
The submandibular gland is situated in the posterior part of the floor of the mouth, adjacent to the medial aspect of the mandible and wrapping around the posterior border of the mylohyoid muscle (Figure 11-2, B). The excretory duct (Wharton’s duct) of the submandibular gland runs forward above the mylohyoid muscle and opens into the mouth beneath the tongue at the sublingual caruncle, lateral to the lingual frenum. The submandibular gland receives its blood supply from the facial and lingual arteries. The parasympathetic nerve supply is derived mainly from the facial nerve (cranial nerve VII), reaching the gland through the lingual nerve and submandibular ganglion.
The sublingual gland is the smallest of the paired major salivary glands. The gland is located in the anterior part of the floor of the mouth between the mucosa and the mylohyoid muscle (see Figure 11-2, B). The secretions of the sublingual gland enter the oral cavity through a series of small ducts (ducts of Rivinus) opening along the sublingual fold and often through a larger duct (Bartholin’s duct) that opens with the submandibular duct at the sublingual caruncle. The sublingual gland receives its blood supply from the sublingual and submental arteries. The facial nerve (cranial nerve VII) provides the parasympathetic innervation of the sublingual gland, also via the lingual nerve and submandibular ganglion.
The minor salivary glands, estimated to number between 600 and 1000, exist as small, discrete aggregates of secretory tissue present in the submucosa throughout most of the oral cavity. The only places they are not found are the gingiva and the anterior part of the hard palate. They are predominantly mucous glands, except for the lingual serous glands (Ebner’s glands) that are located in the tongue and open into the troughs surrounding the circumvallate papillae on the dorsum of the tongue and at the foliate papillae on the sides of the tongue.
Just as for teeth, the individual salivary glands arise as a proliferation of oral epithelial cells, forming a focal thickening that grows into the underlying ectomesenchyme. Continued growth results in the formation of a small bud connected to the surface by a trailing cord of epithelial cells, with mesenchymal cells condensing around the bud (Figure 11-3). Clefts develop in the bud, forming two or more new buds; continuation of this process, called branching morphogenesis, produces successive generations of buds and a hierarchic ramification of the gland.
Studies of analogous processes in experimental animals and studies of salivary gland development in vitro have revealed that the process of branching morphogenesis requires interactions between the epithelium and mesenchyme. Several factors that control the location of the branch points and the overall structure of the gland have been identified. Signaling molecules, including members of the fibroblast growth factor protein family, sonic hedgehog, transforming growth factor β, and their receptors, play a major role in the development of branches. The differential contraction of actin filaments at the basal and apical ends of the epithelial cells is thought to provide the physical mechanism underlying cleft formation, and the deposition of extracellular matrix components within the clefts apparently serves to stabilize them. Finally, the specific mesenchyme associated with the salivary glands has been shown to provide the optimum environment for gland development.
The development of a lumen within the branched epithelium generally occurs in this order: (1) in the distal end of the main cord and in branch cords, (2) in the proximal end of the main cord, and (3) in the central portion of the main cord (Figure 11-4). The lumina form within the ducts before they develop within the terminal buds. Some studies have suggested that lumen formation may involve apoptosis of centrally located cells in the cell cords, but further research is required to establish definitively a role for cell death in this process.
Following development of the lumen in the terminal buds, the epithelium consists of two layers of cells. The cells of the inner layer eventually differentiate into the secretory cells of the mature gland, mucous or serous, depending on the specific gland. Some cells of the outer layer form the contractile myoepithelial cells that are present around the secretory end pieces and intercalated ducts. As the epithelial parenchymal components increase in size and number, the associated mesenchyme (connective tissue) is diminished, although a thin layer of connective tissue remains, surrounding each secretory end piece and duct of the adult gland. Thicker partitions of connective tissue (septa), continuous with the capsule and within which run the nerves and blood vessels supplying the gland, invest the excretory ducts and divide the gland into lobes and lobules (Figure 11-5).
The parotid glands begin to develop at 4 to 6 weeks of embryonic life, the submandibular glands at 6 weeks, and the sublingual and minor salivary glands at 8 to 12 weeks. The cells of the secretory end pieces and ducts attain maturity during the last 2 months of gestation. The glands continue to grow postnatally—with the volume proportion of acinar tissue increasing and the volume proportions of ducts, connective tissue, and vascular elements decreasing—up to 2 years of age.
As described in the previous section, a salivary gland consists of a series of branched ducts, terminating in spherical or tubular secretory end pieces or acini (Figure 11-6). An analogy can be made to a bunch of grapes, with the stems representing the ducts and the grapes corresponding to the secretory end pieces. The main excretory duct, which empties into the oral cavity, divides into progressively smaller interlobar and interlobular excretory ducts that enter the lobes and lobules of the gland. The predominant intralobular ductal component is the striated duct, which plays a major role in modification of the primary saliva produced by the secretory end pieces. Connecting the striated ducts to the secretory end pieces are intercalated ducts, which branch once or twice before joining individual end pieces. The lumen of the end piece is continuous with that of the intercalated duct. In some glands, small extensions of the lumen, intercellular canaliculi, are found between adjacent secretory cells (Figure 11-7). These intercellular canaliculi may extend almost to the base of the secretory cells and serve to increase the size of the secretory (luminal) surface of the cells.
The two main types of secretory cells present in salivary glands are serous cells and mucous cells. Serous and mucous cells differ in structure and in the types of macromolecular components that they produce and secrete. In general, serous cells produce proteins and glycoproteins (proteins modified by the addition of sugar residues [glycosylation]), many of which have well-defined enzymatic, antimicrobial, calcium-binding, or other activities. Typically, serous glycoproteins have N-linked (bound to the β-amide of asparagine) oligosaccharide side chains. The main products of mucous cells are mucins, which have a protein core (apomucin) that is organized into specific domains and is highly substituted with sugar residues. Mucins are therefore also glycoproteins, but they differ from most serous cell glycoproteins in the structure of the protein core, the nature (predominantly O-linked; i.e., to the hydroxyl groups of serine or threonine) and extent of glycosylation, and their function. Mucins function mainly to lubricate and form a barrier on surfaces and to bind and aggregate microorganisms. Mucous cells secrete few, if any, other macromolecular components.
In recent years the distinction between serous cells and mucous cells has become somewhat blurred. Serous cells of some salivary glands are known to produce certain type of mucins, and some mucous cells are thought to produce certain nonglycosylated proteins. Additionally, advances in tissue preservation procedures have demonstrated that the structure of mucous and serous cells is actually similar and that the typical morphology of swollen, fused, and empty-appearing mucous granules is likely a result of artifactual changes occurring during chemical fixation.
Secretory end pieces that are composed of serous cells are typically spherical and consist of 8 to 12 cells surrounding a central lumen (Figure 11-8). The cells are pyramidal, with a broad base adjacent to the connective tissue stroma and a narrow apex forming part of the lumen of the end piece. The lumen usually has fingerlike extensions located between adjacent cells called intercellular canaliculi that increase the size of the luminal surface of the cells. The spherical nuclei are located basally, and occasionally, binucleated cells are seen. Numerous secretory granules, in which the macromolecular components of saliva are stored, are present in the apical cytoplasm (Figures 11-9 and 11-10). The granules may have a variable appearance, ranging from homogeneously electron-dense to a combination of electron-dense and electron-lucent regions arranged in intricate patterns. The basal cytoplasm contains numerous cisternae of rough endoplasmic reticulum, which converge on a large Golgi complex located just apical or lateral to the nucleus (Figure 11-11). Forming secretory granules of variable size and density are present at the trans face of the Golgi complex. These granules increase in density as their content condenses, eventually forming the mature secretory granules. Serous cells also contain all of the typical organelles found in other cells, including cytoskeletal components, mitochondria, lysosomes, and peroxisomes.