Physiology of the Salivary Glands PDF

SECTION 2 Salivary Glands 81 81 Physiology of the Salivary Glands Ravindhra G. Elluru KEY POINTS...

SECTION 2 Salivary Glands 81 81 Physiology of the Salivary Glands Ravindhra G. Elluru KEY POINTS to be advanced.1 Along with a new generation of scientists, recent technologic advances have further expanded our knowledge of Importantly, our current understanding of salivary gland the mechanisms of salivary gland function, disease processes that physiology is largely derived from the study of impede normal gland function, and methods by which to restore nonhuman salivary glands. homeostasis in a diseased gland. Importantly, our current under- standing of salivary gland physiology is largely derived from the Saliva is a complex mixture of electrolytes and study of nonhuman salivary glands. macromolecules secreted from three pairs of major Saliva is a complex mixture of electrolytes and macromolecules salivary glands and numerous minor salivary glands. secreted from three pairs of major salivary glands and numerous The basic unit of the salivary gland consists of an acinus, minor salivary glands. The major salivary glands consist of the a secretory duct, and a collecting duct. parotid, submandibular, and sublingual glands; the minor glands Saliva is formed via active transport processes that occur line the mucosa of the lip, tongue, palate, and pharynx. The throughout the secretory unit; these processes are under secretion of saliva is tightly modulated by a multitude of factors the control of complex neuronal and hormonal signals. that include the autonomic nervous system, humoral factors, and disease states. Saliva performs a number of diverse and crucial The innervation patterns of the major salivary glands roles: (1) it provides lubrication, which aids in swallowing; (2) it differ considerably from species to species, subject to is an emulgent that aids in enzymatic cleavage and the digestion subject, and cell type to cell type. of food; (3) it produces hormones, hormone-like substances, and The neurotransmitter acetylcholine mediates the effects other metabolically active compounds; (4) it assists in excretion of the parasympathetic nervous system, whereas of endogenous and exogenous materials such as antibodies, blood norepinephrine mediates the effects of the sympathetic group–reactive substances, iodine, and viruses; (5) it mediates taste nervous system. sensations; and (6) it provides defense against bacterial pathogens. Salivary flow rates are highly variable but stabilize after Relative to size, the salivary glands produce a large volume of the age of 15 years; therefore they should be interpreted saliva. The maximal rate of saliva production in humans is about in a clinical context. 1 mL/min/g of glandular tissue. The rate of metabolism and blood flow to the salivary glands is also high and proportional to the Salivary secretion is controlled by a salivary center in rate of saliva secreted. To put this in perspective, the flow of blood the medulla, which is triggered by specific stimuli that to a maximally secreting salivary gland is approximately 10 times include the mechanical act of chewing and gustatory and greater than the flow of blood to an equal mass of actively contract- olfactory stimuli. ing skeletal muscle.2 This chapter provides a detailed discussion Salivary function can be organized into five major of the various aspects of salivary gland function and physiology. categories that serve to maintain oral health and homeostasis: (1) lubrication and protection, (2) buffering and clearance, (3) maintenance of tooth integrity, PRINCIPLES OF SALIVARY GLAND SECRETION (4) antibacterial activity, and (5) taste and digestion. Anatomy of the Secretory Unit Dry mouth is a common complaint in the geriatric population and is commonly believed to arise from The basic unit of the salivary gland consists of an acinus, a secretory age-associated intrinsic salivary gland dysfunction. duct, and a collecting duct (Fig. 81.1A and B). In general, the area of the acinus and proximal secretory duct is called the secretory end piece. The secretory duct is composed of the intercalated and striated ducts, which are intralobular; the excretory and collecting ducts are extralobular. The structural relationships and secretory Throughout the history of science, the salivary glands have been capabilities of secretory units within different salivary glands differ a topic of keen biologic interest, and questions regarding their widely. The parotid and submandibular glands have a single mechanisms of action have spurred numerous research endeavors. elongated large-caliber collecting duct with only a few major As early as 160 AD, Galen described the position of the major and branching interlobular ducts. These interlobular ducts, in turn, are minor salivary glands and their respective ductal openings. In connected to many intralobular ducts, each of which transports 1543, Vesalius published a more detailed anatomic description of saliva from several acini. In contrast to the parotid and subman- the salivary glands in a monograph titled De Humani Corporis dibular glands, the secretions of the sublingual gland are discharged Fabrica. Interestingly, however, before the 17th century, the salivary through 10 to 12 separate collecting ducts. The minor salivary glands were thought to serve only as emunctories, whose function glands, which are essentially groups of individual secretory units, was to strain excrementitious substances, such as the “evil spirits are distributed throughout the submucosa of the oral cavity and of the brain,” from the blood. Fortunately, the fortitude and have short convoluted collecting ducts.2 dedication of scientists such as Boredu, Ludwig, Langley, Haller, The acinus comprises a central lumen surrounded by pyramid- Heidenhain, Mueller, Baylis, Bernard, and Pavlov allowed this shaped cells (see Fig. 81.1A and B). These acinar cells are highly notion to be dispelled and the field of salivary gland physiology polarized and are bounded by a plasma membrane with two distinct 1139 Descargado para Diana Salgado ([email protected]) en Pontifical Catholic University of Ecuador de ClinicalKey.es por Elsevier en septiembre 18, 2024. Para uso personal exclusivamente. No se permiten otros usos sin autorización. Copyright ©2024. Elsevier Inc. Todos los derechos reservados.  CHAPTER 81 Physiology of the Salivary Glands1139.e1 Abstract Keywords 81 Throughout the history of science, the salivary glands have been saliva a topic of keen biologic interest, and questions regarding their glands mechanisms of action have spurred numerous research endeavors. parotid Importantly, our current understanding of salivary gland physiology submandibular is largely derived from the study of nonhuman salivary glands. regulation Saliva is a complex mixture of electrolytes and macromolecules digestion secreted from three pairs of major salivary glands and numerous minor salivary glands. The major salivary glands consist of the parotid, submandibular, and sublingual glands; the minor glands line the mucosa of the lip, tongue, palate, and pharynx. The secretion of saliva is tightly modulated by a multitude of factors that include the autonomic nervous system, humoral factors, and disease states. Saliva performs a number of diverse and crucial roles: (1) it provides lubrication that aids in swallowing; (2) it is an emulgent that aids in enzymatic cleavage and the digestion of food; (3) it produces hormones, hormone-like substances, and other metabolically active compounds; (4) it assists excretion of endogenous and exogenous materials such as antibodies, blood group–reactive substances, iodine, and viruses; (5) it mediates taste sensations; and (6) it provides defense against bacterial pathogens. Relative to size, the salivary glands produce a large volume of saliva. Descargado para Diana Salgado ([email protected]) en Pontifical Catholic University of Ecuador de ClinicalKey.es por Elsevier en septiembre 18, 2024. Para uso personal exclusivamente. No se permiten otros usos sin autorización. Copyright ©2024. Elsevier Inc. Todos los derechos reservados. 1140 PART VI Head and Neck Surgery and Oncology Serous demilune Myoepithelial cells Serous acinus Mucous acinus Intercalated duct Intercellular secretory canaliculi B Striated A duct Fig. 81.1 (A) Schematic representation of a normal secretory unit. (B) Histologic section of a normal salivary gland. Normal appearance of the ducts (arrowhead) and acini (arrow) under low-power magnification (×10). (A, From Ganong WF: Review of Medical Physiology, New York, 1999, McGraw-Hill, p 473.) TABLE 81.1 Contribution to and Relative Viscosities of Saliva by as striated ducts, which are lined by columnar cells and have a Salivary Glands brush border composed of microvilli on their luminal surface. Striated ductal cells also have prominent basal striations formed Whole Unstimulated by infoldings of the plasma membrane that enclose columns of Gland Acinar Type Viscosity Daily Saliva (%) rod-shaped mitochondria. The high-energy characteristics of these cells suggest that they are involved with the transport of ions and Parotid Serous Watery 25 water. The striated ducts lead into excretory ducts lined by two Submandibular Mixed Semiviscous 71 Sublingual Mucous Viscous 3–4 layers of epithelium, a layer of flat cells that surround the ductal Minor Mucous Viscous Trace lumen and an outer layer of columnar cells.6,7 From Mandel ID: Sialochemistry in diseases and clinical situations affecting salivary glands. Crit Rev Clin Lab Sci 12(4):321–366, 1980. Secretory Process Saliva consists of a complex mixture of electrolytes and macro- molecules. It is now known that saliva is formed via active transport processes that occur throughout the secretory unit and that these domains, a basolateral domain and an apical domain. These two processes are under the control of complex neuronal and hormonal domains are functionally and physically separated by tight junctions signals. The secretory unit consists of two anatomically and that link adjacent cells just below the luminal area. Each acinus functionally distinct regions: the acinus and the secretory duct. is surrounded by a layer of myoepithelial cells, which in turn is The acinus is the site of all fluid generation and most (approximately delimited by a distinct basement membrane layer. Myoepithelial 85%) of the exocrine protein secretion.7 The fluid component is cells are elongated or star-shaped nonsecreting cells with long derived from the local vascular bed in the form of an isotonic branching processes that surround the acinus and proximal ducts. solution and is secreted into the acinar lumen. This primary The observation that myoepithelial cells possess adenosine tri- secretion traverses the ductal system before emptying into the phosphate (ATP) activity, have intercellular gap junctions, and mouth. In contrast to the water-permeable cells of the acinus, contain myofilaments has led to the hypothesis that these cells ductal cells are water impermeable. Most of the sodium (Na+) and have contractile properties and play a role in expelling preformed chloride (Cl−) in the primary secretion is reabsorbed in the duct, secretions.3–5 and a small amount of potassium (K+) and bicarbonate (HCO3− ) Acini are classified as serous, mucous, or mixed (Table 81.1). is secreted. In addition, some proteins are added to the salivary Serous acini contain pyramid-shaped cells with round basal nuclei fluid as it traverses the secretory duct. By the time the saliva enters surrounding the lumen. The cytoplasm of the serous cells is densely the mouth, it has generally been rendered hypotonic (approximately packed with basophilic secretory granules poised to discharge 25 mEq/L NaCl). The electrolyte composition of saliva, however, their contents into the acinar lumen. The number of these granules can be influenced by salivary flow rates. The reabsorption of salivary varies with the phase of secretory activity, decreasing after a period sodium and chloride is directly related to these rates, with decreased of secretion and reaccumulating after a period of synthesis. Mucous reabsorption and increased salivary concentrations of electrolytes, acini have a larger lumen than serous acini, and the cells that along with increasing salivary flow rates. Potassium reabsorption surround the lumen have a clear cytoplasm, flattened basal nuclei, is independent of flow rates.8,9 and numerous droplets of mucigen, which is the precursor of mucin. Mixed acini are composed of both serous and mucinous cells; serous cells are found near the fundus of the acini and form Mechanisms of Primary Fluid Secretion a cap-like structure, called a serous demilune, whereas mucinous Fluid transport in salivary glands is thought to be driven osmotically cells are found surrounding the lumen of the acini.6 in response to transepithelial salt gradients. These gradients are The acinus is contiguous with the intercalated duct, a hollow generated by ion transport systems localized to the luminal and structure lined by a single layer of small cuboidal cells (see Fig. basolateral membranes of the acinar cell. On the basis of studies 81.1A and B). A layer of myoepithelial cells surrounds these cuboidal in rabbit and rat salivary glands, three mechanisms for primary cell–lined ducts, similar to acini. The intercalated ducts continue fluid secretion by the acini have been proposed. These mechanisms Descargado para Diana Salgado ([email protected]) en Pontifical Catholic University of Ecuador de ClinicalKey.es por Elsevier en septiembre 18, 2024. Para uso personal exclusivamente. No se permiten otros usos sin autorización. Copyright ©2024. Elsevier Inc. Todos los derechos reservados.  CHAPTER 81 Physiology of the Salivary Glands 1141 81 5K 2K 2K 2K 2K 2K 3Na 3Na 3Na  3Na 3Na 3HCO3 3Na 6CI 3CI H 3H 3H 6CI  Lumen 3N Lumen Ca Lumen HCO3 H CO2 CO2 Ca HCO3 3CI CO2 3HCO3 Interstitium Interstitium Interstitium Mechanism 1 Mechanism 2 Mechanism 3 Fig. 81.2 Schematic representation of three mechanisms of primary fluid secretion in acinar cells. (From Turner RJ: Mechanisms of fluid secretion by salivary glands. Ann N Y Acad Sci 694:24–35, 1993.) (Fig. 81.2) appear to operate concurrently in the same gland bicarbonate loss is buffered by the Na+/H+ exchanger, which uses and possibly in the same acinar cell. The relative importance of the extracellular-to-intracellular sodium gradient generated by each of these mechanisms varies from species to species, gland the Na+/K+-ATPase to drive protons out of the cell. The net result type to gland type, and possibly from physiologic status to is the movement of NaCl into the cell in exchange for H2CO3, physiologic status. which in turn is recycled across the basolateral membrane as CO2 Fluid secretion in the acini is the result of the combined action after hydrolysis by carbonic anhydrase. In this model, three chloride of four membrane transport systems: (1) a Na+/K+/2Cl− cotrans- ions are translocated from the interstitium to the acinar lumen porter located in the basolateral membrane of the acinar cell; (2) for every ATP molecule hydrolyzed. Sodium and water follow the a calcium (Ca2+)-activated K+ channel in the basolateral membrane; chloride into the acinar lumen from the interstitium.9 (3) a calcium-activated Cl− channel localized to the apical mem- In contrast to mechanisms 1 and 2, in which chloride is the brane; and (4) an adenosine triphosphatase (ATPase)-driven Na+/K+ secreted anion, mechanism 3 (see Fig. 81.2C) involves apical pump in the basolateral membrane. In the resting or unstimulated bicarbonate secretion. In this model, carbon dioxide (CO2) enters state, both K+ and Cl− are concentrated in the acinar cell above the acinar cell across the basolateral membrane and is converted the electrochemical equilibrium, the former by the Na+/K+-ATPase to HCO3− plus a proton by carbonic anhydrase. The bicarbonate and the latter via the Na+/K+/2Cl− cotransporter.9,10 is lost across the apical membrane via an anion channel, possibly In the first mechanism of saliva secretion (see Fig. 81.2A), the same channel involved in chloride secretion, and the protein stimulation by the autonomic nervous system, leads to a rise in is extruded by the basolateral Na+/H+ exchanger. In this model, intracellular calcium concentration, which results in the opening three bicarbonate ions are secreted for every ATP molecule of the basolateral Ca2+-activated K+ channels and the apical calcium- hydrolyzed. Sodium and water follow the secreted bicarbonate activated Cl− channels. This increase in K+ and Cl− conductance ions into the acinar lumen.9 allows KCl to flow out of the cell, which results in an accumulation of Cl− ions and their associated negative electrical charge in the acinar lumen. Sodium in the interstitium then follows Cl− as a Mechanisms of Primary Macromolecule Secretion result of electrical attraction, by leaking through the tight junctions The protein subcomponent of saliva is derived primarily from between the cells into the acinar lumen. The resulting osmotic secretory granules of the acinar and ductal cells. Secretory proteins gradient for NaCl causes a transepithelial movement of water are discharged into the lumen of the secretory unit by a process from the interstitium into the acinar lumen. In the continued of exocytosis, wherein fusion of secretory granules with a delimited presence of the agonist, a net transepithelial chloride flux and a portion of the plasmalemma of the apical membrane occurs. The concomitant secretion of fluid are sustained because of Cl− entry membrane fusion is the last of a series of steps required for the via the Na+/K+/2Cl− cotransporter and exit via the apical Cl− channel. transfer of export proteins from their synthesis in the rough When the stimulus is removed, the intracellular calcium concentra- endoplasmic reticulum (RER) to the extracellular environment. tions fall to resting levels, the K+ and Cl− channels close, and the According to the model offered by Palade,11 the secretory process cell returns to its resting state. For this model to operate continu- can be divided into six steps: (1) synthesis, (2) segregation, (3) ously, it must satisfy the constraints of mass and charge balance; intracellular transport, (4) concentration, (5) intracellular storage, in other words, in the steady state, ion transport must be such and (6) discharge. that neither mass nor charge is continually accumulated in or The synthesis of secretory proteins requires the uptake of amino depleted from the cell. These constraints, along with the known acids by the cell, which is accomplished via an active transport stoichiometries of the Na+/K+/2Cl− cotransporter (1Na+: K+: 2Cl−) mechanism in the basolateral surface of the cell. Transfer ribonucleic and the Na+/K+-ATPase (3Na+: 2K+: 1ATP), determine the relative acids then deliver the amino acids to the ribosomes of the RER, fluxes of ions per cycle: six chloride ions are translocated from where messenger ribonucleic acids are translated into polypeptides. the interstitium to the acinar lumen for each ATP molecule Before transport of these polypeptides from the RER to the Golgi hydrolyzed by the Na+/K+-ATPase.9 apparatus, they undergo some posttranslational modifications and The second mechanism (see Fig. 81.2B) is similar to the first are segregated in the cisternal space of the RER. Segregation is mechanism except that in this model, a basolateral Cl − HCO3− regarded as an irreversible step. From the RER, polypeptides are exchanger, in parallel with an Na+/H+ exchanger, replaces the transported to the Golgi apparatus via an ATP-dependent mecha- Na+/K+/2Cl− cotransporter. Decreases in intracellular chloride nism. In this apparatus, polypeptides undergo further posttrans- concentrations resulting from secretagogue-induced KCl loss lead lational modifications, such as terminal glycosylation, and are to increased Cl− entry in exchange for HCO3− via the Cl − HCO3− concentrated. At this step the polypeptides are transferred from exchanger. The cytoplasmic acidification that results from this a high-permeability membrane to a membrane with characteristics Descargado para Diana Salgado ([email protected]) en Pontifical Catholic University of Ecuador de ClinicalKey.es por Elsevier en septiembre 18, 2024. Para uso personal exclusivamente. No se permiten otros usos sin autorización. Copyright ©2024. Elsevier Inc. Todos los derechos reservados. 1142 PART VI Head and Neck Surgery and Oncology similar to those of the plasmalemma, forming secretory granules. innervated, whereas the collecting ducts are sparsely innervated. On appropriate stimulation from the autonomic nervous system, In contrast to other organ systems such as skeletal muscles, which the secretory granules discharge their contents into the glandular contain a well-defined neuronal synapse at the axon–effector organ lumen by the process of exocytosis. The membrane of the secretory interface, secretory cells have unmyelinated fibers of the para- granule fuses with the plasmalemma, bringing into continuity the sympathetic and sympathetic systems that lie in close proximity contents of the secretory granule and the extracellular lumen and to the effector cell. These axonal fibers can lie either outside at the same time maintaining a diffusion barrier between the (epilemmal fibers) or inside (hypolemmal fibers) the basement interior of the cell and the extracellular medium. The mechanism membrane of the effector cell.16 Neurotransmitters released from by which the cell recycles the apical membrane is not completely the axon presumably reach the secretory cell by diffusion. These understood but likely involves the process of endocytosis and the neurotransmitters, as well as other hormones and regulatory selective degradation of endocytic vesicles.12 molecules, affect the function of salivary cells in a complex manner that is poorly understood. Mechanisms of Ductal Secretion Neurotransmitters and Receptors. Cell surface receptors are Ductal secretion is not constant, and the underlying mechanisms macromolecular moieties within the cell membrane that bind are only partially understood. Microperfusion studies of excretory ligands such as neurotransmitters in the extracellular milieu. Ligand ducts have confirmed the ability of ductal cells to modify saliva binding activates the receptor, which then transmits a signal across by reabsorbing sodium and chloride and secreting potassium and the cell membrane and triggers a biologic response within the bicarbonate to produce the final hypotonic solution.13 In addition, target cell (Fig. 81.3). The biologic response can be initiated directly ductal cells have the ability to secrete some protein into the ductal by the receptor or, more commonly, it is mediated through a lumen. In general, when the salivary flow rate is slow, more time second-messenger system activated by the receptor-ligand complex. is available in which ion transfer can occur across the tubular cells, The specific biologic response initiated and the magnitude of that which results in greater modification of the secretory fluid. When response is a function of the receptor itself and not of the ligand the flow rate is high, however, the contact period is shortened, with which it binds. Receptors for neurotransmitters are typically and this diminishes the influence of the tubular cells on solute located on the basal and lateral surfaces of the secretory cells of concentration. The exception to this rule is that conditions the salivary gland. stimulating increased flow rates also stimulate increased bicarbonate The neurotransmitter acetylcholine mediates the effects of the secretion.2,6 parasympathetic nervous system, whereas norepinephrine mediates the effects of the sympathetic nervous system. Adrenergic receptors, receptors for norepinephrine, are divided into two major classes, Neuronal Control of Secretion α and β, which are further subdivided into two subtypes, yielding In general, significant secretion from the human salivary glands α1 and α2 and β1 and β2 receptors (Table 81.2).17 The best-studied occurs only in response to stimulation by the autonomic nervous acinar cells, those of the rat parotid gland, appear to have all four system or the action of substances that can mimic the effects of subtypes of adrenergic receptors, although, in general, the function- such stimulation.14 Both sympathetic and parasympathetic nerves ally important receptors appear to be the α1 and β1 subtypes. The innervate the salivary glands, although the effects of the parasym- β1 and β2 receptors are linked to the adenylate cyclase second- pathetic nerves predominate. Nevertheless, it is likely that the messenger system, and binding of ligand to this receptor activates two components of the autonomic nervous system have a synergistic adenylate cyclase. The α2 receptors are also linked to the adenylate effect on salivary gland function. Parasympathetic stimulation is cyclase system; however, binding of ligand to this receptor leads the principal impetus for salivary gland fluid secretion. In addition, to the inhibition of adenylate cyclase. The α1 receptors are linked parasympathetic stimulation leads to some exocytosis and protein to a yet uncharacterized second-messenger system that does not secretion, myoepithelial contraction, and vasodilation. Sympathetic regulate adenylate cyclase but instead modulates calcium influx.7 stimulation is a weak mobilizer of salivary fluid, although its effect may be additive to that of the parasympathetic system. On the other hand, sympathetic stimulation causes high levels of protein Protein secretion, myoepithelial contraction, and maintenance of vascular tone. In general, parasympathetic stimulation leads to the output of saliva that has a large volume and low protein content, whereas A eC CI kinase sympathetic stimulation leads to the secretion of low volumes of s saliva with high protein content.2,6,12 a  Na n Ca++ ki The innervation patterns of the major salivary glands differ Protein n i te considerably among species, subjects, and cell types. The para- K K Pro sympathetic supply to the parotid gland originates in the inferior IP3 Ca2 salivatory nucleus and travels with the glossopharyngeal nerve cAMP ATP PLC and then with the Jacobson nerve to the otic ganglion, where it Adenylate Cyclase DAG synapses. The postganglionic fibers are carried by the auriculo- PIP2 Gs Gi Gq temporal branch of the trigeminal nerve to the parotid gland. The ? parasympathetic supply to the submandibular gland originates in 1 2 2 1 MUSC PEPT the superior salivatory nucleus and travels via the nervus intermedius and chorda tympani to the submandibular ganglion. Some of these Ca++ fibers synapse in the ganglion, whereas others synapse in the gland Fig. 81.3 Schematic representation of acinar cell receptors itself. The sympathetic supply to the parotid and submandibular and second messenger systems. ATP, Adenosine triphosphate; glands originates from the superior cervical ganglion and follows cAMP, cyclic adenosine monophosphate; DAG, diacyl-glycerol; major arterial blood vessels to reach the various salivary glands. Gi, G protein inhibitory; Gs, G protein stimulatory; Gq, G protein Nerve fibers of the parasympathetic and sympathetic nervous other; IP3, 1,4,5-inositol triphosphate; MUSC, muscarinic receptor; systems are distributed in a similar fashion around the acini and PEPT, peptide receptor; PIP2, phosphoinositol diphosphate; intercalated ducts and are striated, although the parasympathetic PLC, phospholipase C. (From Baum BJ: Principles of saliva secretion. fibers predominate.15 Myoepithelial cells are similarly liberally Ann N Y Acad Sci 694:17, 1993.) Descargado para Diana Salgado ([email protected]) en Pontifical Catholic University of Ecuador de ClinicalKey.es por Elsevier en septiembre 18, 2024. Para uso personal exclusivamente. No se permiten otros usos sin autorización. Copyright ©2024. Elsevier Inc. Todos los derechos reservados.  CHAPTER 81 Physiology of the Salivary Glands 1143 TABLE 81.2 Localization and Mechanism of Action of Salivary Adrenergic Receptors 81 α1 α2 β1 β2 Physiologic Smooth muscle contraction in Smooth muscle contraction in Stimulates amylase Smooth muscle relaxation response blood vessels selected vascular bed secretion Assists release of Inhibits release of norepinephrine norepinephrine Stimulates secretion of K+ and H2O Location Postsynaptic Presynaptic, postsynaptic, and Postsynaptic Presynaptic, postsynaptic, without synapse and without synapse Mechanism Changes of cellular Ca2+ fluxes Inhibition of adenylate cyclase Stimulation of adenylate Stimulation of adenylate cyclase cyclase Data from Lefkowitz RJ, Stadel JM, Cerione RA, et al: Structure and function of beta-adrenergic receptors: regulation at the molecular level. Adv Cyclic Nucleotide Protein Phosphorylation Res 17:19, 1984. Cholinergic receptors, receptors for acetylcholine, are divided the receptor–G protein complex leads to replacement of the guanine into two categories: muscarinic and nicotinic. Acinar cells contain diphosphate (GDP), which is bound to the α subunit with a guanine only muscarinic receptors, specifically the muscarinic receptor M3 triphosphate (GTP), and to dissociation of the heterotrimeric G subtype. Binding of acetylcholine to the M3 receptor leads to the protein into a free α subunit and a free β-γ complex. The α subunit activation of the phospholipase C pathway and ultimately leads is then available to activate a specific second-messenger system. to intracellular calcium mobilization. Recent evidence suggests The activation continues until the GTP is degraded to GDP by the presence of two additional subtypes of muscarinic receptors GTPase activity endogenous to the α subunit. The GDP-associated in the rat submandibular and sublingual glands” M1 and M5.18 α subunit then reassociates with the β-γ complex to generate the The effect of these two receptors on acinar cell function and the inactive heterotrimeric G protein. The two best-studied second- mechanism by which these effects are mediated are unclear at this messenger systems in the salivary gland are (1) the generation of point. Some of the effects of the M1 receptor on salivary gland cyclic adenosine monophosphate (cAMP) following β-adrenergic function may occur indirectly, via nitric oxide.7 receptor stimulation, which leads to protein exocytosis, and (2) Parasympathetic-mediated nonadrenergic, noncholinergic the formation of 1,4,5-inositol triphosphate (IP3) after muscarinic secretory response and vasodilation are well-known phenomena acetylcholine receptor stimulation, which leads to calcium mobiliza- in salivary glands, and a number of polypeptides—including neuro- tion and fluid secretion. Other more speculative second-messenger peptide Y, vasoactive intestinal peptide, galanin, substance P (SP), systems involve nitric oxide, cyclic guanine monophosphate, and calcitonin gene-related peptide (CGRP)—have been implicated phospholipids, cytosol pH, and membrane depolarization. in mediating this pathway.19 Neuropeptide Y–, vasoactive intestinal peptide–, and galanin-immunoreactive nerve fibers are densely distributed around acini and ducts. CGRP- and SP-immunoreactive Adenylate Cyclase System fibers are also found around these structures but to a lesser extent. Stimulation of β adrenergic receptors on acinar cells leads to Interestingly, the density of SP- and CGRP-immunoreactive fibers protein exocytosis. The role of cAMP in protein secretion from around the mucous acini was significantly higher than that of those acinar cells has been well documented for nearly 30 years, although around the serous acini. The vasoactive intestinal peptide (VIP) some of the initial steps in this pathway have only recently been system is the best studied of these polypeptide neurotransmitters elucidated.20,21 Binding of norepinephrine to β1 and β2 adrenergic in salivary glands and is similar to what has been described in the receptors leads to activation of the G protein, Gs. Activation of gut and pancreas.8 Currently, the role of these different polypeptide Gs, in turn, leads to the activation of adenylate cyclase, which then neurotransmitters in salivary gland function is speculative; however, converts ATP into cAMP. Increasing concentration of cAMP then in view of their potential therapeutic roles, intense efforts are leads to the activation of cAMP-dependent protein kinase A. Both under way to better understand them.19 type 1 and type 2 cAMP-dependent protein kinase A are thought to be involved in this pathway.22 Cyclic AMP-dependent protein kinase A phosphorylates several cellular proteins, the most important Signal Transduction of which is considered to be a 26-kDa integral membrane protein.23 The formation of a receptor-ligand complex is only the first step As yet it is unclear how the activation of cAMP and cAMP- toward initiating a biologic response within the target cell. The dependent protein kinase A leads to protein exocytosis. Also, second step entails transmission of the ligand-receptor binding although ligand binding to β1 and β2 receptors activates the adenyl- signal across the cell membrane and activation of a second- ate cyclase system, ligand binding to α2 receptors inhibits adenylate messenger system. The second-messenger system then activates cyclase via the G protein, Gi.24 an effector system to bring about a specific biologic response (see Fig. 81.3). Phospholipase C System Researchers have long known that stimulation of acinar cell G Proteins muscarinic acetylcholine receptors leads to high levels of fluid A family of heterotrimeric guanine nucleotide-binding proteins secretion and that calcium plays a key role in this process.7,25 In (G proteins) has a well-defined role in transmitting receptor-ligand the past 25 years, efforts by several investigators have led to the signals across the cell membrane by linking the receptor with a characterization of the specific mechanisms involved in muscarinic second-messenger system.7 G proteins consist of three distinct acetylcholine receptor–mediated fluid secretion.7 Ligand binding subunits, termed α, β, and γ. The α subunit is the site of guanine to the muscarinic acetylcholine receptor activates a pertussis nucleotide binding and has generally been considered to be the toxin–insensitive G protein thought to belong to the Gq family.26 subunit that conveys the functional and receptor specificity of the Activation of this G protein activates the enzyme phospholipase G protein. When a neurotransmitter binds to a receptor, the affinity C, which hydrolyzes a minor membrane phospholipid phospha- of the receptor for a specific G protein increases. Formation of tidylinositol 4,5-bisphosphate. This leads to the formation of two Descargado para Diana Salgado ([email protected]) en Pontifical Catholic University of Ecuador de ClinicalKey.es por Elsevier en septiembre 18, 2024. Para uso personal exclusivamente. No se permiten otros usos sin autorización. Copyright ©2024. Elsevier Inc. Todos los derechos reservados. 1144 PART VI Head and Neck Surgery and Oncology second-messenger molecules IP3 and diacylglycerol. Diacylglycerol The stimulation of salivary flow with mastication is thought to is capable of activating protein kinase C, which leads to protein be a reflexive response mediated by receptors in the oral mucosa, exocytosis, although this is thought to represent a minor pathway muscles of mastication, and temporomandibular joint. These for protein secretion in acinar cells. receptors stimulate the salivary nucleus, which in turn increases The other product of hydrolysis, IP3, binds to a membrane the parasympathetic stimulation to the salivary glands, resulting receptor on intracellular calcium stores and causes the release of in increased salivary flow.37 Interestingly, the increase in salivary calcium into the cytoplasm. These intracellular calcium storage flow is thought to be directly proportional to the applied chewing units are derivatives of the endoplasmic reticulum. The IP3 receptor force.38 Gustatory stimuli are the most potent stimuli to the salivary itself is thought to function as a calcium channel; on ligand binding, center and elicit as much as a 10-fold increase in salivary flow. it allows calcium to move down a concentration gradient into the Acidic tastes lead to the greatest increases in saliva flow, whereas cytoplasm. Cytoplasmic calcium concentrations can increase 10-fold sweet tastes are the least stimulating. Olfaction is the weakest of within 5 seconds of muscarinic acetylcholine receptor activation the salivary center triggers. Furthermore, habituation is thought and can lead to a cascade of events that include a sustained influx to occur with repeated presentation of the same food cues, of extracellular calcium into the cytoplasm and the activation of which leads to a decrease in stimulation of the saliva center and specific ion transport pathways, leading to fluid secretion. Currently, saliva flow. Dishabituation occurs with the presentation of novel there is little understanding of the cell membrane channels that food cues.39–42 allow calcium to move into the cytoplasm in response to increased Many other factors can also influence salivary flow. These factors cytoplasmic calcium concentration in nonexcitable cells such as include (1) circadian rhythm; (2) psychic factors such as pain, acinar cells.7 depression, and anticipation of food; (3) medications; (4) local or systemic diseases; and (5) hormones. Isolating and studying the effect of a specific factor is often difficult because many of these SALIVA stimuli work in concert to affect salivary flow. Diurnal variation in salivary flow has been reported, with maximal flow rates in Flow Rate of Saliva the late afternoon and minimal flow rates at night. Decreased Salivary flow rates are highly variable and stabilize after the age salivary output at night may be secondary to a decrease in ambient of 15 years; therefore they should be interpreted in a clinical light and/or arousal state, both of which affect salivary gland context.27,28 The numbers depicted in this section are averages function.43 Medications with anticholinergic properties decrease projected from studies on the general population. The range of salivary flow; this includes most antidepressants. Dehydration can normal unstimulated salivary flow is 0.1 mL/min and above; in influence salivary gland output: with losses of 8% of body water; the stimulated state, it is 0.2 mL/min and above. On average the the result is cessation of salivary flow. Decreased salivary output unstimulated flow rate is 0.3 mL/min, and the stimulated flow is also noted during the “fight or flight” response, which results rate is 7 mL/min at maximum. Stimulated saliva is thought to from an increased sympathetic response and/or central inhibition contribute as much as 80% to 90% of the average daily salivary of parasympathetic output. The sympathetic nervous system has production. This leads to an average daily saliva secretion of around also been proposed to play a role in the reduction of saliva flow 1000 to 1500 mL or an average flow of 1 mL/min.29,30 Salivary after exercise via the constriction of blood vessels that supply the flow in the unstimulated state is produced primarily by the sub- salivary glands.44 mandibular glands (71%); the parotid and sublingual glands produce Salivary flow is uneven throughout the mouth secondary to 25% and 3% to 4% of the flow, respectively.30 The minor salivary the location of the ducts that empty the parotid and salivary glands. glands account for trace amounts of saliva. Once stimulated, the Intraoral flow volume is the highest in the mandibular lingual relative contributions of the parotid and submandibular glands area and the lowest in the area of the maxillary incisors and are reversed, and the parotid gland supplies two-thirds of the interproximals.45 These areas of higher- and lower-volume flow salivary flow.27,31 regions have been referred to as “salivary highways and byways.” Studies that have specifically addressed hypofunction of the The regional clearance rate of acid produced from bacteria is salivary gland have defined the critical range that separates a person directly influenced by regional variations in flow within the mouth.46 with normal gland function from someone with salivary gland Consequently, salivary byways are areas in which acid byproducts hypofunction as unstimulated whole salivary flow rates between may remain in longer contact with oral structures unless mechanical 0.12 and 0.16 mL/min.32 The diagnosis of salivary hypofunction means of cleansing are used. Furthermore, with varying amounts is often difficult to make, given the wide range of salivary flow of saliva and salivary constituents coming from different glands, rates that are accepted as normal. A more reliable means of it is suggested that saliva provides different types of protection diagnosing hypofunction is possible if an individual base record in different intraoral locations. of saliva flow has been established. Salivary gland hypofunction can then be defined as a 50% reduction in the individual base saliva flow rate. About 30% of the population reports some degree Composition of Saliva of dry mouth. In general, oral-related effects of salivary hypofunc- Saliva comprises a variety of organic and inorganic compounds tion are reduced preparation of food for digestion and taste and (Table 81.3) that enable its varied functional properties. The an increased susceptibility of oral structures to disease.33 Although inorganic component is composed mostly of electrolytes such as decreased concentrations of salivary mucins and decreased resting sodium, potassium, calcium, magnesium, bicarbonates, phosphates, salivary flow rates have been associated with increasing age, in and nitrogenous products such as urea and ammonia. The organic general, no substantial age-related changes in the secretory component includes several classes of proteins such as immuno- responsiveness of salivary cells are apparent.34,35 Furthermore, globulins, enzymes, and mucins. Because the final saliva product factors endemic to the geriatric population—such as polypharmacy, is an aggregate of the saliva produced by several glands, each with poor nutritional status, and systemic diseases—also contribute to different secretory characteristics, the composition of whole saliva salivary gland hypofunction.36 At present, the exact role of advancing at any particular time can be highly variable. This variability is age on the average daily production of saliva and xerostomia is further enhanced by the fact that the secretory characteristics of unknown. each gland will change with the type of stimulus that drives the Salivary secretion is controlled by a salivary center in the saliva production. Furthermore, the electrolyte composition of medulla, which is triggered by specific stimuli that include the saliva will change depending on flow rates secondary to changes mechanical act of chewing and gustatory and olfactory stimuli. in the amount of inorganic compounds secreted or reabsorbed in Descargado para Diana Salgado ([email protected]) en Pontifical Catholic University of Ecuador de ClinicalKey.es por Elsevier en septiembre 18, 2024. Para uso personal exclusivamente. No se permiten otros usos sin autorización. Copyright ©2024. Elsevier Inc. Todos los derechos reservados.  CHAPTER 81 Physiology of the Salivary Glands 1145 TABLE 81.3 Flow Rates and Composition of Saliva in Normal Adults TABLE 81.4 Major Salivary Macromolecules 81 Parotid Gland Submandibular Gland Protein Family Molecular Weight (kDa) Stimulated flow rate 0.7 0.6 Histatins 2–4 (mL/min/gland) Statherins 4–5 INORGANIC CONSTITUENTS (mEq/L) Lysozyme 14 Cystatins 14 K+ 20 17 Proline-rich proteins 10–30 Na+ 23 21 Carbonic anhydrases 42–45 Cl− 23 20 Amylase 55–60 HCO3 20 18 2+ Peroxidase 75–78 Ca 2 3.6 Lactoferrin 75–78 Mg2+ 0.2 0.3 Mucin 2 130 HPO4−2 6 4.5 Secretory immunoglobulin A 380 ORGANIC CONSTITUENTS (mg/dL) Mucin 1 >1000 Urea 15 7 From Levine MJ: Salivary macromolecules: a structure/function Ammonia 0.3 0.2 synopsis. Ann N Y Acad Sci 694:11, 1993. Uric acid 3 2 Glucose