Medical Physiology, 3rd Edition

Composition, Function, and Control of Salivary Secretion

Depending on protein composition, salivary secretions can be serous, seromucous, or mucous

Most saliva (~90%) is produced by the major salivary glands: the parotid, the sublingual, and the submandibular glands (see Fig. 43-10A). The remaining 10% of saliva comes from numerous minor salivary glands that are scattered throughout the submucosa of the oral cavity. Each salivary gland produces either a serous, a seromucous, or a mucous secretion; the definition of these three types of saliva is based on the glycoprotein content of the gland's final secretory product. In humans and most other mammals, the parotids produce a serous secretion (i.e., low glycoprotein content), the sublingual and submandibular glands produce a seromucous secretion, and the minor salivary glands produce a mucous secretion.

Serous secretions are enriched in α-amylase, and mucous secretions are enriched in mucin. However, the most abundant proteins in parotid and submandibular saliva are members of the group of proline-rich proteins, in which one third of all amino acids are proline. These proteins exist in acidic, basic, and glycosylated forms. They have antimicrobial properties and may play an important role in neutralizing dietary tannins, which can damage epithelial cells. In addition to serving these protective functions, proline-rich salivary proteins contribute to the lubrication of ingested foods and may enhance tooth integrity through their interactions with Ca2+ and hydroxyapatite. Saliva also contains smaller amounts of lipase, nucleases, lysozyme, peroxidases, lactoferrin, secretory IgA, growth factors, regulatory peptides, and vasoactive proteases such as kallikrein and renin (Table 43-5).

TABLE 43-5

Major Organic Components of Mammalian Saliva

COMPONENTS

CELL TYPE

GLANDS

POSSIBLE FUNCTION

Proline-rich proteins

Acinar

P, SM

Enamel formation
Ca2+ binding
Antimicrobial
Lubrication

Mucin glycoproteins

Acinar

SL, SM

Lubrication

Enzymes

     

α-amylase

Acinar

P, SM

Starch digestion

Lipase

Acinar

SL

Fat digestion

Ribonuclease

Duct

SM

RNA digestion

Kallikrein

Duct

P, SM, SL

Unknown

Miscellaneous

     

Lactoperoxidase

Acinar

SM

Antimicrobial

Lactoferrin

Acinar

Unknown

Antimicrobial

Lysozyme

Duct

SM

Antimicrobial

IgA receptor

Duct

Unknown

Antimicrobial

IgA secretory piece

Duct

Unknown

Antimicrobial

Growth factors

Duct

SM

Unknown

P, parotid; SL, sublingual; SM, submandibular..

Saliva functions primarily to prevent dehydration of the oral mucosa and to provide lubrication for the mastication and swallowing of ingested food. The senses of taste and, to a lesser extent, smell depend on an adequate supply of saliva. Saliva plays a very important role in maintaining proper oral hygiene. It accomplishes this task by washing away food particles, killing bacteria (lysozyme and IgA activity), and contributing to overall dental integrity. Although α-amylase is a major constituent of saliva and digests a significant amount of the ingested starch, salivary amylase does not appear to be essential for effective carbohydrate digestion in the presence of a normally functioning pancreas. The same can be said for lingual lipase. However, in cases of pancreatic insufficiency, these salivary enzymes can partially compensate for the maldigestion that results from pancreatic dysfunction.

At low flow rates, the saliva is hypotonic and rich in K+, whereas at higher flow rates, its composition approaches that of plasma

The composition of saliva varies from gland to gland and from species to species. The primary secretion of the salivary acinar cell at rest is plasma-like in composition. Its osmolality, reflecting mainly Na+ and Cl, is ~300 mOsm. The only significant difference from plasma is that the [K+] of the salivary primary secretion is always slightly higher than that of plasma. In some species, acinar cells may help to generate a Cl-poor, image-rich primary secretion after salivary gland stimulation. In most species, however, salivary gland stimulation does not significantly alter acinar cell transport function or the composition of the primary secretion. The leakiness of the tight junctions (see p. 137) between acinar cells contributes to the formation of a plasma-like primary secretory product.

The composition of the primary salivary secretion is subsequently modified by the transport processes of the duct cell (see Fig. 43-11). At low (basal) flow rates, Na+ and Cl are absorbed from the lumen and K+ is secreted into the lumen by the duct cells of most salivary glands (Table 43-6). These transport processes generate a K+-rich, hypotonic salivary secretion at rest. The tightness of the ductal epithelium inhibits paracellular water movement and therefore contributes to the formation of a hypotonic secretory product.

TABLE 43-6

Electrolyte Components of Human Parotid Saliva

COMPONENT

UNSTIMULATED OR BASAL STATE (mM)

STIMULATED (CHOLINERGIC AGONISTS) (mM)

Na+

15

90

K+

30

15

Cl

15

50

Total CO2

15

60

From Thaysen JH, Thorn NA, Schwartz IL: Excretion of sodium, potassium, chloride and carbon dioxide in human parotid saliva. Am J Physiol 178:155–159, 1954.

At higher flow rates, the composition of the final secretory product begins to approach that of the plasma-like primary secretion (see Table 43-6). This observation suggests that, as in the case of the renal tubules, the ductular transport processes have limited capacity to handle the increased load that is presented to them as the flow rate accelerates. However, the extent to which the transporters are flow dependent varies from gland to gland and from species to species. Human saliva is always hypotonic, and salivary [K+] is always greater than plasma [K+]. In humans, increased salivary flow alkalinizes the saliva and increases its [image]. This salivary alkalinization and net image secretion in humans neutralize the gastric acid that normally refluxes into the esophagus (Box 43-3).

Box 43-3

Sjögren Syndrome

Sjögren syndrome is a chronic and progressive autoimmune disease that affects salivary secretion. Patients with Sjögren syndrome generate antibodies that react primarily with the salivary and lacrimal glands. Lymphocytes infiltrate the glands, and subsequent immunological injury to the acini leads to a decrease in net secretory function. Expression of the Cl-HCO3 exchanger is lost in the striated duct cells of the salivary gland. Sjögren syndrome can occur as a primary disease (salivary and lacrimal gland dysfunction only) or as a secondary manifestation of a systemic autoimmune disease, such as rheumatoid arthritis. The disease primarily affects women; systemic disease usually does not develop.

Individuals with Sjögren syndrome have xerostomia (dry mouth) and keratoconjunctivitis sicca (dry eyes). Loss of salivary function causes these patients to have difficulty tasting, as well as chewing and swallowing dry food. They also have difficulty with continuous speech and complain of a chronic burning sensation in the mouth. On physical examination, patients with Sjögren syndrome have dry, erythematous oral mucosa with superficial ulceration and poor dentition (dental caries, dental fractures, and loss of dentition). Parotid gland enlargement is commonly present.

One of the proteins that is the target of the immunological attack in Sjögren syndrome is the water channel AQP5. No specific therapy for the disorder is available. Until the underlying cause of Sjögren syndrome is discovered, patients will have to rely on instillation of eyedrops and frequent ingestion of fluid to compensate for their deficiencies in lacrimal and salivary secretion. Various stimulants of salivary secretion (sialogogues), such as methylcellulose and sour candy, can also be helpful. Patients with severe involvement and functional disability are sometimes treated with corticosteroids and immunosuppressants.

Parasympathetic stimulation increases salivary secretion

Humans produce ~1.5 L of saliva each day. Under basal conditions, the salivary glands produce saliva at a rate of ~0.5 mL/min, with a much slower flow rate during sleep. After stimulation, flow increases 10-fold over the basal rate. Although the salivary glands respond to both cholinergic and adrenergic agonists in vitro, the parasympathetic nervous system is the most important physiological regulator of salivary secretion in vivo.

Parasympathetic Control

Parasympathetic innervation to the salivary glands originates in the salivatory nuclei of the brainstem (see Fig. 14-5). Both local input and central input to the salivatory nuclei can regulate the parasympathetic signals transmitted to the glands. Taste and tactile stimuli from the tongue are transmitted to the brainstem, where their signals can excite the salivatory nuclei and stimulate salivary gland secretion. Central impulses triggered by the sight and smell of food also excite the salivatory nuclei and can induce salivation before food is ingested. These central effects were best illustrated by the classic experiments of Ivan Pavlov, who conditioned dogs to salivate at the sound of a bell. For his work on the physiology of digestion, Pavlov received the 1904 Nobel Prize in Physiology or Medicine. imageN43-8

N43-8

Ivan Petrovich Pavlov

Contributed by Emile Boulpaep, Walter Boron

The classical experiments demonstrating the cephalic phase of salivary and gastric secretion in dogs were the work of Ivan Petrovich Pavlov. For his contributions to digestive physiology, Pavlov received the 1904 Nobel Prize in Physiology or Medicine. For more information about Pavlov and the work that led to his Nobel Prize, visit http://www.nobel.se/medicine/laureates/1904/index.html (accessed September 2014).

References

Wood JD. The first Nobel Prize for integrative systems physiology: Ivan Petrovich Pavlov, 1904. Physiology. 2004;19:326–330.

Preganglionic parasympathetic fibers travel in cranial nerve (CN) VII to the submandibular ganglia, from which postganglionic fibers reach the sublingual and submandibular glands (see Fig. 14-4). Preganglionic parasympathetic fibers also travel in CN IX to the otic ganglia, from which postganglionic fibers reach the parotid glands. In addition, some parasympathetic fibers reach their final destination via the buccal branch of CN V to the parotid glands or via the lingual branches of CN V to the sublingual and submandibular glands. Postganglionic parasympathetic fibers from these ganglia directly stimulate the salivary glands through their release of ACh. The prominent role of the parasympathetic nervous system in salivary function can be readily appreciated by examining the consequences of cholinergic blockage. Disruption of the parasympathetic fibers to the salivary glands can lead to glandular atrophy. This observation suggests that parasympathetic innervation is necessary for maintaining the normal mass of salivary glands. Clinically, some medications (particularly psychiatric drugs) have “anticholinergic” properties that are most commonly manifested as “dry mouth.” For some medications, this effect is so uncomfortable for the patient that use of the medication must be discontinued. Conversely, excessive salivation is induced by some anticholinesterase agents that can be found in certain insecticides and nerve gases.

Sympathetic Control

The salivary glands are also innervated by postganglionic sympathetic fibers from the superior cervical ganglia that travel along blood vessels to the salivary glands (see Fig. 14-4). Although sympathetic (adrenergic) stimulation increases saliva flow, interruption of sympathetic nerves to the salivary glands has no major effect on salivary gland function in vivo. However, the sympathetic nervous system is the primary stimulator of the myoepithelial cells that are closely associated with cells of the acini and proximal (intercalated) ducts. These stellate cells have structural features of both epithelial and smooth-muscle cells. They support the acinar structures and decrease the flow resistance of the intercalated ducts during stimulated secretion. Thus, the net effect of myoepithelial-cell activation is to facilitate secretory flow in the proximal regions of the gland, thus minimizing the extravasation of secretory proteins that could otherwise occur during an acute increase in secretory flow.

The sympathetic division can also indirectly affect salivary gland function by modulating blood flow to the gland. However, the relative contribution of this vascular effect to the overall secretory function of the salivary glands is difficult to determine.

Not only is salivary secretion subject to cholinergic and adrenergic regulation, but some autonomic fibers that innervate the salivary glands contain VIP and substance P. Although acinar cells in vitro respond to stimulation by substance P, the physiological significance of these neurotransmitters in vivo has not been established. Salivary secretion is also regulated, in part, by mineralocorticoids. Stimulation by the adrenal hormone aldosterone produces saliva that contains relatively less Na+ and more K+. The opposite effect on saliva is seen in patients with adrenal insufficiency caused by Addison disease (see p. 1019). The mineralocorticoid effect represents the only well-established example of regulation of salivary secretion by a hormone.