Introduction

Salivation plays a vital role in digestion, as digestion of food begins in the mouth. The salivary submandibular, parotid, sublingual, and submucosal glands produce saliva which is necessary for the moistening of food products, breakdown of carbohydrates by salivary amylase (formerly known as ptyalin), antimicrobial, and other protective mechanisms. This initial phase of digestion and lubrication is essential for the passage of food from the oropharynx to the esophagus and stomach. Certain disease states, drugs, and radiation therapy can affect the proper functioning of salivation. This article will review the associated anatomy, histology, innervation, cellular mechanisms, development, the physiologic and pathophysiologic basis of salvation.[1][2]

Issues of Concern

Anatomy

The glands responsible for the production of saliva include the parotid gland, the largest of the salivary glands, the submandibular glands, and the sublingual glands.

The structure of the salivary glands consists of a series of ducts that eventually end in either a spherical or tubular secretory acini or end piece. The main excretory duct is the one that empties into the oral cavity and divides into progressively smaller ductal units, the interlobar and interlobular excretory ducts. The main intralobular duct is the striated duct which is the main modifier of primary saliva. The striated ducts are connected to the secretory end pieces by intercalated ducts that branch several times before they join each end piece. The end piece and intercalated duct lumens are continuous. Some of the glands will contain intercellular canaliculi that extend to almost the level of the base of secretory cells as a means to increase the surface area of the cells.

The parotid glands are located on each side of the face anterior to the ears and are made up of two lobes, a superficial lobe, and a deep lobe. Between these two lobes, lies the facial nerve which is important for the function of the muscles of facial expression. The duct of the parotid gland, also termed the Stensen duct, runs across the masseter muscle and exits into the oral cavity at the level of the upper second molar. The parotid gland is supplied by the external carotid artery and its branches and drained by the external jugular vein.

The submandibular glands are approximately the size of a walnut and are located under and medial to the mandible of the jaw beneath the floor of the mouth. They, like the parotid glands, contain superficial and deep lobes. The excretory ducts of these glands, also known as Wharton’s ducts, run above the mylohyoid muscle and end at the sublingual caruncle beneath the tongue. Blood supply to the submandibular glands come from branches of the facial and lingual arteries and venous drainage by the submental veins to the facial vein. Nearby structures include the hypoglossal nerve which is important for motor function of the tongue, the lingual nerve which is necessary for the sensory function of the tongue, the marginal mandibular nerve which gives motor function to the muscles that assist in smiling, and the platysma muscle which supports in the movement of the lower lip.

The sublingual glands are the smallest in size of the three major salivary glands and are between the mylohyoid muscle and mucosa in the anterior portion of the floor of the mouth. There are a series of ducts, ducts of Rivinus, that secrete the saliva from the sublingual gland along the sublingual fold, but also through the Bartholin duct that opens with the submandibular duct at the sublingual caruncle. The sublingual and submental arteries supply these glands and drained by the corresponding veins.

The minor salivary glands are much smaller than the major salivary glands and range in number reaching up to 1000. They exist throughout the submucosa of the oral cavity, except for the gingiva and anterior portion of the hard palate, as discrete secretory tissue aggregates.[3][4]

Histology

Salivary glands are made up of lobules, and each lobule contains many secretory acinar cells, which are rounded secretory units with a central duct. There are two types of acinar cells, mucinous and serous, but there also can be a mixture of both with a serous demilune around the mucinous acini. Serous acini secrete an isotonic fluid that is protein-rich, and the mucous acini secrete the lubricant, mucin. The secretory units of the acini merge into intercalated ducts that are lined with cuboidal epithelium and are surrounded by myoepithelial cells that contract to assist with the secretions. The intercalated ducts lead into striated ducts which lead into the excretory columnar epithelium-lined interlobular ducts. The striated ducts are important because they allow for active transport of substances out of the duct, water resorption, and ion secretion to create hypotonic saliva with low sodium and chloride levels and increased carbonate and potassium levels. The parotid glands contain serous acini, the submandibular glands are a mix of serous and mucinous, and the sublingual glands are predominantly mucinous acini. The minor salivary glands are mainly mucinous glands except for the lingual serous glands known as Ebner glands.[3][4]

Innervation and Autonomics

The salivary glands are under autonomic control by both sympathetic and parasympathetic systems. Stimulation of either parasympathetic or sympathetic nervous systems will stimulate salivary gland secretion, but the effects of parasympathetic stimulation are stronger and longer lasting. Sympathetic innervation of all salivary glands derives from postganglionic fibers from the superior cervical ganglion which travels with the blood supply to each gland. Sympathetic nerves will stimulate adrenergic receptors on the salivary acinar cells through the release of norepinephrine. The parasympathetic system, involving the facial nerve (cranial nerve VII) and the glossopharyngeal nerve (cranial nerve IX), will stimulate the glands through muscarinic/cholinergic M3 receptors and also increase substance P which plays a role in amylase output. The parasympathetic innervation to the parotid gland preganglionic fibers of the glossopharyngeal nerve begins at the inferior salivatory nucleus and synapse on the otic ganglion. Postganglionic fibers reach the gland via the auriculotemporal nerve. The parasympathetic innervation to the submandibular and sublingual glands begins in the superior salivatory nucleus with preganglionic fibers of the facial nerve synapsing on the submandibular ganglion and postganglionic fibers reaching the submandibular and sublingual glands via the lingual nerve. Not only do the nerves stimulate salivary gland secretion, but they also may play a role in the ability of the salivary glands to regenerate, avoid atrophy, and maintain their function. This role of the autonomic nerves could help advance future therapies for chronic oral dryness or salivary gland atrophy.[3][4] 

Cellular Level

Acinar cells are the secretory cells of the salivary gland and are either serous or mucinous. These cells differ in their structure and the content that they produce and secrete. Serous acinar cells are spherical and consist of 8 to 12 cells surrounding a central lumen that produce glycoproteins and proteins which function to bind calcium, act as anti-microbial agents, and complete other enzymatic activities. Serous cells have a pyramidal shape with a broad base where the nuclei, rough endoplasmic reticulum, and Golgi apparatus are located and where the secretory granules with the secretory components are formed and stored. The cell units have fingerlike projections that extend into the lumen and increase cell surface area. Mucinous acinar cells contain apomucin, a protein core, with highly substituted sugar residues and acts primarily as a lubricant. The glycoproteins of serous cells are N-linked whereas the mucinous cells are O-linked.[3][4] 

Development

The larger salivary gland, the parotid gland, begins to form at 4 to 6 weeks in embryonic development. The submandibular gland begins forming at around 6 weeks and the smaller sublingual and minor glands at about 8 weeks. The parotid gland is ectodermal in origin, and the submandibular and sublingual glands are endodermal. The stages of development are bud formation, cord formation, branching of the cords, lobule formation, canalization, and cytodifferentiation. Initially, oral epithelial cells proliferate and form a focal thickening that grows into the ectomesenchyme and continues to grow until buds form. These buds are connected to the surface by a cord of epithelial cells and surrounded by mesenchymal cells. Eventually, the buds begin to form clefts that lead to more bud formation, a process of branching morphogenesis, which continues until the lobules and canalization of each gland is complete. Maturation of the ducts and secretory end pieces occurs in the last two months of gestation. The glands themselves will continue to grow after birth, primarily due to the volume expansion of the acinar cells.[3][4]

Organ Systems Involved

Salivary glands are part of the digestive system.[1]

Function

Saliva has many functions which include:

• Protection
• Buffering
• Maintenance of tooth integrity
• Antimicrobial activity
• Tissue repair
• Digestion
• Assistance with taste.

Saliva functions to protects the oral cavity by several mechanisms, including flushing away pathogens like bacteria, with the help of proteins that have antimicrobial activity like lysozyme, lactoferrin, peroxidase, and small peptides like alpha-defensins and beta-defensins which disrupt the integrity of the microorganisms cellular and mitochondrial functions. Saliva also protects the mucosae of the oral cavity from adhering to each other with the help of the mucinous secretions which provide a lubricating barrier, protecting the mucosa from toxins, trauma, and noxious stimuli. Saliva also acts as a buffer, increasing pH with the help of bicarbonate, phosphate, and other ions. It forms a film called the salivary pellicle which is a binding spot for calcium to help protect the surface of teeth but can also be a binding site for bacteria and increases plaque formation. Biologically active proteins and growth factors are found in saliva and work to regenerate tissue and promote wound healing. Digestion begins in the mouth; saliva contains the enzyme amylase which breaks down starches into maltose and dextrin. This function in itself also reduces the number of sugars available to microorganisms and helps inhibit their growth. Saliva assists with the sensation of taste by solubilizing food so that the taste receptors can interact with the molecules that cause receptor activation.[3][4]

Mechanism

The mechanism of salivary gland secretion involves primarily cholinergic signaling by the parasympathetic nerves and signaling by neuropeptides like substance P, but also adrenergic signaling by sympathetic nerves. Parasympathetic stimulation will activate acetylcholine receptors to activate protein kinase C (PKC), releasing diacylglycerol (DAG) and inositol triphosphate (IP3) which stimulate increased intracellular calcium levels. The rise in calcium mediates the increased volume of saliva and amylase output. Substance P will activate the neurokinin-1 (NK-1) receptor to similarly stimulate PKC to increase the formation of IP3 and DAG, which subsequently increase amylase output and volume flow. Sympathetic stimulation will increase alpha receptor stimulation by norepinephrine which causes smooth muscle contraction and increases volume flow and amylase output. Norepinephrine will also act on beta receptors and activate the cyclic adenosine monophosphate cascade, increasing protein kinase A (PKA) activity, amylase output, and transient saliva volume flow.

There are two main stages to the secretion of saliva. First, once stimulated, acinar cells secrete primary saliva which is isotonic and contains amylase, mucus, and extracellular fluid. This isotonic form of saliva is made by secreting sodium chloride. In the second stage, the primary saliva gets modified as it passes down the ductal tree. The sodium gets actively reabsorbed, potassium is actively secreted, chloride is passively absorbed, and bicarbonate secreted. Of note, the ductal epithelium has poor water permeability. The final saliva product will be hypotonic.[3][4][5]

Related Testing

Before testing, a good history and physical inspection of the mouth is necessary. Saliva collection can be used to detect many things like biomarkers derived from epithelial cells, neutrophils, and microbes. This non-invasive method of testing can be used to detect hormone levels like cortisol; it can be used to screen for human immunodeficiency virus (HIV), detect drugs and identify infections caused by viruses or bacteria. Sialometry is sometimes used to diagnose salivary gland hypofunction. In this test, drug-stimulated and unstimulated salivary flow rates are measured  Salivary gland imaging with computerized tomography or magnetic resonance imaging of the head and neck region may be necessary when one suspects a neoplasm of the salivary glands and will be followed by salivary gland biopsy if it reveals a suspicious lesion.[5][6][7]

Pathophysiology

Many different diseases, treatments, and medications can alter the secretion of saliva. The mechanisms through which this occurs vary greatly and may include the sensation of dry mouth (xerostomia) despite adequate salivary flow, decreased flow of saliva, or abnormal constituents of saliva. Auto-immune diseases such as Sjogren syndrome, systemic lupus erythematosus, and rheumatoid arthritis are examples of conditions commonly implicated as causes of xerostomia. Similarly, hyposecretory conditions (e.g., biliary cirrhosis, atrophic gastritis) may be implicated as causes of xerostomia. Irradiation of the head and neck and surgical trauma are treatment-related causes of salivary gland dysfunction. Medications are also a common cause of xerostomia, with drugs for urinary urge incontinence and antidepressant medications at the top of the list, presumably due to disruption of parasympathetic signaling pathways.[8] Interruptions in normal salivation result may interrupt the normal protective and digestive functions provided by saliva. Decreased saliva will result in reduced protection of the oral cavity mucosa and teeth, buffering, antimicrobial activity, altered taste, digestion, and tissue repair. Without the natural antimicrobial defenses, those with xerostomia are at increased risk of dental caries, bacterial, and fungal infections.  Conversely, sialorrhea is the production of excessive saliva.[3][4][5]

Clinical Significance

Salivary gland function can undergo alteration in many ways leading to undersecretion or oversecretion of saliva. Sialorrhea, excess salivation, is common and normal among babies between 15 months and 3 years of age, seen commonly in those with neurodegenerative disorders, and can be seen as a side effect of medication. Sialorrhea becomes pathologic among children after the of 4 years and is most common in children with cerebral palsy. It can be due to excess production and stimulation of the glands or due to decreased clearance of saliva from the oral cavity by lack of muscle strength and coordination with disruption of neuromuscular activity. Sialorrhea is also a side effect of some medications including the atypical antipsychotic drug clozapine used in the treatment of schizophrenia, direct acting muscarinic agents such as pilocarpine, and acetylcholinesterase inhibitors such as donepezil. [9] Excess salivation can be problematic because of the risk of aspiration and choking. Treatments for hypersalivation can include physical therapy focused on strengthening oral cavity musculature, removal of offending drugs, or adding an anti-muscarinic drug that will counteract the hypersalivation and result in decreased salivation.

Dry mouth, also known as xerostomia, can occur for many reasons and is ultimately due to decreased salivation. Some of the major causes include radiation therapy to the head and neck region, medication side effect, infections like mumps, autoimmune diseases like Sjogren syndrome, and many other reasons like hormonal changes, diabetes, or simply as normal age-related changes. Radiation therapy to the head and neck directly damages the integrity of the salivary glands and decreases their ability to make and secrete saliva. Medications like atropine, scopolamine, and others in the anticholinergic drug class can result in xerostomia by blocking the muscarinic receptors on the salivary glands. Other drug classes that may cause xerostomia include antidepressants, particularly the tricyclic antidepressants which include amitriptyline, doxepin, nortriptyline as they also have antagonistic effects at the muscarinic receptors. Some antihypertensive medications like terazosin, clonidine, atenolol, and propranolol can also cause dry mouth. Retinoids like tretinoin, and isotretinoin, which are commonly used in the dermatological setting to treat acne, and other dermatologic conditions can also cause xerostomia. Other drugs include antihistamines, proton pump inhibitors, opioids, cannabinoids, and neurokinin 1 receptor antagonists. Unvaccinated individuals are at risk of infection by the mumps virus, which targets the salivary glands, results in enlargement of the parotid gland due to inflammation and this inflammation restricts saliva production and secretion leading to dry mouth. Sjogren syndrome is an autoimmune condition that causes dry mouth and dry eyes. These individuals have autoantibodies, anti-Ro (SS-A) and anti-La (SS-B) which target the salivary and lacrimal glands. There is no cure for Sjogren syndrome, and treatment focuses on symptomatic relief with saliva substitutes, agonist drugs of the muscarinic receptors, lubricating eye drops, and good oral hygiene.[10][11][12][13][14]

The salivary glands themselves are susceptible to neoplastic changes, and an individual may develop a benign or malignant lesion. Depending on tumor location, the possibility of damage to the facial nerve after surgical removal can lead to the paralysis of one side of the face, decreased saliva production, or damage to the nearby vasculature and musculature.[15][16][17][18][19]