Physiology and Pathology of Salivary Glands: History
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Subjects: Physiology
Contributor:
Thimios Mitsiadis

Salivary glands are essential structures in the oral cavity. A variety of diseases, such as cancer, autoimmune diseases, infections and physical traumas, can alter the functionality of these glands, greatly impacting the quality of life of patients. Understanding the cellular and molecular control of salivary glands function is highly relevant for therapeutic purposes. Three major salivary glands account for more than 90% of salivary secretion: the parotid gland (PG) is mainly composed of serous acini-secreting α-amylase-rich saliva; the sublingual gland (SL) secretes mucous, a viscous solution rich in mucins; the submandibular gland (SMG) is composed by a mixed population of acini with a mucous and serous function. 

  • salivary glands
  • cells
  • oral cavity
  • saliva
  • physiology

1. Morphogenesis of the Salivary Glands

Salivary glands originate from an epithelial placode during embryonic development (from E11 to E16 in mice and between the 4th and the 12th embryonic weeks in humans). The initial placode grows and extends into the underlying mesenchyme, acquiring a bud shape. The growing epithelial bud progressively stratifies with concentric layers each formed by a specialized cell type. During branching morphogenesis, the initial salivary bud divides into additional, independent buds that grow and cleave again, until the formation of an extensive arborization typical for the mature salivary gland [1].
A portion of the cells forming the outer epithelial layer of the buds differentiates into myoepithelial cells. They will then acquire smooth muscle characteristics and locate in direct contact with the acinar structure to regulate the release of secretion [2]. Inner epithelial cells differentiate further to acquire a distal (tips) or proximal (stalk) identity, which, in turn, evolves into acini or ducts, respectively [3].
Both epithelial and mesenchymal cells produce the basement membrane and stromal extracellular matrix. The composition of the extracellular matrix varies from region to region during branching, and bundles of collagen I, IV and fibronectin are thought to directly control the maturation process. Low concentrations of fibronectin and glycosaminoglycans facilitate the area of bud growth, while accumulation of fibronectin, collagen IV and glycosaminoglycans limit epithelial activity of the peripheral nervous system also participates in directing salivary growth and stabilizing the basal lamina, determining sites where branching and clefting occurs [4][5]. The peripheral nervous system participates in directing salivary gland maturation. The primordial epithelial structure is innervated by cholinergic neurons, whose axonal growth follows the ramified pattern of the developing gland [6]. Local release of acetylcholine induces proliferation of epithelial progenitor which positively regulate epithelial branching [7][8][9].
A network of capillaries derived from terminal arterioles develops in parallel with the acini-duct systems and has an instructive role in the establishment of the epithelial patterning [10].

2. Histological and Anatomical Features

The three major salivary glands have a similar anatomical structure, with a main secretory duct extending from the main body of the gland to the oral cavity. The secretory duct of the SMG is the Wharton’s duct, which reaches the oral cavity under the tongue at the sublingual caruncula. The Bartholin duct is the major duct of the SL and it connects with the Warthon’s duct at its extremity before the opening in the oral mucosa. SL also have smaller ducts called Rivinus’s ducts that release secretion beneath the tongue onto the floor of the mouth. Finally, the PG has an independent duct called Stensen’s duct, opening on the upper portion of the oral cavity.
The secretory duct branches up into striated ducts, composed of columnar epithelial cells whose appearance is due to infoldings of the basal membrane. Striated ducts extend further into progressively smaller intercalated duct, characterized by a wall of flat cuboidal epithelial cells. Finally, the structure ends into a secretory unit of acinar cells grouped as end-pieces specialized in producing and releasing the primary secretion.

3. Innervation and Trophic Support

Salivary glands are densely innervated by the autonomic nervous system.
The parasympathetic nerves release acetylcholine, which activates the muscarinic receptors stimulating fluid secretion. The sympathetic nerves, on the other hand, control salivation through release of noradrenaline and activation of α-and β-adrenoreceptors, the first stimulating fluid-rich secretion and the latter protein-rich secretion [11][12]. This suggests that the serous population of cells is innervated by the parasympathetic system, while the mucous population mainly depends on the sympathetic stimulation [13][14][15]. The distribution of the secretory nerves highly depends on species, age and type of gland [16].
Innervation of the salivary glands starts during embryonic development and progress in parallel with the organ definition. Neural crest-derived cells migrate to their appropriate location in the oral epithelium to instruct the thickening for the placode formation. The neural crest-derived precursors differentiate to form the parasympathetic submandibular ganglion (PSG) surrounding the epithelial primordia of the major secretory duct. As branching proceeds further with the developmental process, axons from the PSG extend along the epithelium to envelop the secretory end-pieces. By E14 in the mouse, the gland is highly branched and fully innervated [17]. The instructive role of the PSG is currently gathering interest, as ablation of the PSG reduces expression of epithelial progenitor markers such as Krt5 and Krt15, and might, therefore, be implicated in the maintenance of endogenous stem cells [18]. Similarly, acetylcholine induces proliferation of Krt5-expressing progenitor cells via regulation of the EGF pathway, suggesting that the parasympathetic activity coordinates the maintenance of the undifferentiated pool and their balance during organogenesis [18].
The development of the sympathetic innervation proceeds conjointly with acinar and ductal maturation, which suggests a role in the final specification of the salivary gland.
The primary sympathetic salivary centres are located in the upper thoracic spinal cord, and reach the salivary gland via the superior cervical ganglion. Sympathetic axons enter the SMG in parallel with the vascular system, and vascular-derived guidance cues are needed for sympathetic neurons to grow. Mice lacking endothelin3 or endothelin-receptor type-A have reduced sympathetic innervation of the salivary glands and defects in SMG secretion [19][20].
Despite developing with a similar timing and being surrounded by the same mesenchymal cap, the SL gland contains only a few sympathetic nerves, while the SMG has rich innervation. This dichotomy is probably to be associated with the different levels of NGF (high in the SMG and low in SL) [21]. After submandibular gland removal, the NGF levels drop dramatically in the plasma, to then go back to a normal level after several weeks. It has, therefore, been postulated that the submandibular gland in mice might work as source of NGF [22]. Nevertheless, removal of the SMG in mice has no deleterious systemic effect, indicating more of an accessory role in NGF secretion rather than a primary one [23].
Once reaching the salivary gland, the independent innervation of parasympathetic and sympathetic efference bundles up together surrounded by Schwann myelinating cells [24]. Dual innervation can be found in myoepithelial cells, acinar end-pieces and local blood vessels, all of which plays a functional role in salivary gland secretion [25].

4. Salivary Gland Disorders

4.1. Tumours

Tumours originating in salivary gland tissue are often benign. In minor salivary glands, the most common clinical complication is the formation of mucus retention cysts, a non-malignant evolution of the altered tissue [26].
Major salivary glands mainly display epithelial malignancies (carcinomas), with very heterogeneous features and occasional neuroendocrine differentiation. Malignant salivary gland tumours represent about 5% of all head and neck cancers, with a slight predominance in men [27][28].
The aetiology of the salivary gland tumour is mainly described by the multicellular theory, by which each cell type can give rise to a specific type of tumour [29][30][31][32][33].
In addition to being a site for primary tumours, salivary glands are also a site for tumorigenic cells to establish metastases, originating from other primary cancers, mainly skin malignancies.
The most common malignant tumour is mucoepidermoid carcinoma, potentially arising in any salivary tissue, but mostly affecting the PG. Mucoepidermoid carcinoma is associated with a specific genetic translocation between chromosomes 11 and 19, which produces a fusion gene (MECT1) involved in the Notch-pathway and cAMP-responsive element binding (CREB) activation. The product of gene fusion was detected in genomic screenings together with alteration of the EGF-receptor pathway and aberrant activation of p53 regulator of apoptosis [34][35]. The specificity of the novel gene-fusion for mucoepidermoid carcinoma cells has improved diagnostic capacity and brought increased focus on the study of the molecular mechanisms supporting the disease. Identification of the fusion product (CRTC1-MAML2) or constitutive activation of the Notch pathway via high levels of the Notch target Hes1 are indicative of cancer progression [36][37].
Similarly, in adenoid cystic carcinoma, mutations in NOTCH1 and NOTCH2 have been identified as altered targets in various genomic screenings [38][39], and knock-down of Notch1 or Notch2 inhibits proliferation of adenoid cystic carcinomas in models of the disease [40][41]. These findings suggest that this pathway has a central role in the initiation of the most common neoplasms affecting salivary glands.

4.2. Primary Sjögren’s Syndrome

Primary Sjögren’s syndrome (pSS) is a systemic autoimmune disease affecting salivary and lacrimal glands. Often accompanying other immune system disorders (such as lupus and rheumatoid arthritis), its main effect is the loss of mucous membrane and moisture-secreting gland cells, resulting in xerostomia and xerophthalmia. Although the pathogenesis of the disease remains largely unknown, the role of the B-lymphocytes appears to be essential in the initiation of the disease. Members of the TNF superfamily (such as BAFF/APRIL) are produced not only by patrolling immune cells but also by the epithelial cells of the salivary glands. Through these pathways, B-cells are activated and start to proliferate in an uncontrolled manner [42][43][44]. Their pivotal role includes infiltration of the salivary glands to produce an ectopic germinal centre and local secretion of autoantibodies. The centre can grow independently from the surrounding tissue and can evolve in more complex diseases such as non-Hodgkin lymphoma [44].
To date, there is no efficient treatment available for pSS, and symptoms may only be attenuated. Specific antibodies for BAFF (Belimumab) show limited relief [45], but combination with other immune-therapies might prove to be more efficient [46]. Promising approaches using monoclonal antibodies anti-CD20 (Rituximab) or anti-CD22 (Epratuzumab), are currently under examination [46][47][48][49].

4.3. Post-Irradiation Syndrome

Radiotherapy is an important main or complementary treatment in a variety of cancers, including head and neck tumours. One of the most significant side effects of local irradiation is an alteration of salivary glands functionality, resulting in hyposalivation and xerostomia [50]. Exposure to radioactive sources causes DNA damage, leading to cell death or cell senescence in proliferating cells. Specifically, irradiated salivary glands rapidly lose acinar cells, with dramatic functional impairment [51]. Hyposalivation results in chronic dryness of the oral cavity, which, in turn, leads to ulceration, infections, increase exposure to caries, periodontal diseases and hampered speech and mastication [52]. The only treatment available to cope with xerostomia is the topic application of substituting agents, such as saliva substitute and mucosa lubricant [53][54]. Pharmacologically, pilocarpine and cevimeline administration are systemic drugs for the treatment of dry-mouth conditions, but their efficiency requires the presence of functional tissue. All therapies currently available for the treatment of xerostomia provide only temporary relief, and require multiple applications for a long period of time [55].

4.4. Infections

Several viruses and bacteria infect the tissue of salivary glands in a specific manner. Endemic parotitis is due to infection of the mumps virus and lead to PG swelling and systemic symptoms. It is mainly affecting children in pre-scholar age and treatment is primarily symptomatic. The HIV virus can infect the PG and induce the formation of cystic lesions with surgical resection being the most common treatment procedure. Hepatitis C and coxsackievirus are RNA-bound viruses, able to infect salivary glands and damage the host tissue, leading to xerostomia. One of the main routes of viral spreading is the gland secretion itself and thus transmission through saliva exchange is the major infection mode.
Bacterial infection is very rare and mainly affects the PG in patients already debilitated by other conditions, such as diabetes, recovery after surgery or immunodeficiency. Therapeutic treatments reducing saliva flow help the establishment of bacterial colonies in the mucosa and increase the risk of infection, mainly from Streptococcus strains and Staphylococcus aureus. Mycobacter infection is more common in infants where it locally grows masses that might break the skin of the patient leaving scarring of the tissue. Non-controlled bacterial infection might spread beyond the gland borders and invade the deep space of the neck with possible serious complications including septicaemia. Chronic inflammation might also lead to sialadenitis, an accumulation of lymphocyte infiltrate in the duct system with consequent obstruction and hampering of the secretory system. Clinically, this results in xerostomia and local painful swelling [56].

5. Conclusions

Salivary glands represent a major player in the maintenance of oral homeostasis and their study might shed light in more general disorders such as cancer, inflammation and healing upon mechanical traumas. Overall, their accessibility and heterogeneous histology provide an ideal structure to improve our understanding of tissue remodelling and interaction between cells and surrounding microenvironment. In addition to studies on the molecular control of the exocrine function, salivary glands can be used as a platform to study the physiology of epithelial tissue, the dynamic of the stem cell niche and basic developmental processes. Thus, future studies on salivary glands might be impactful to a variety of subjects and application in biomedicine.

This entry is adapted from the peer-reviewed paper 10.3390/cells8090976

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