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Physiological Reviews Jul 2022Salivary glands produce and secrete saliva, which is essential for maintaining oral health and overall health. Understanding both the unique structure and physiological... (Review)
Review
Salivary glands produce and secrete saliva, which is essential for maintaining oral health and overall health. Understanding both the unique structure and physiological function of salivary glands, as well as how they are affected by disease and injury, will direct the development of therapy to repair and regenerate them. Significant recent advances, particularly in the OMICS field, increase our understanding of how salivary glands develop at the cellular, molecular, and genetic levels: the signaling pathways involved, the dynamics of progenitor cell lineages in development, homeostasis, and regeneration, and the role of the extracellular matrix microenvironment. These provide a template for cell and gene therapies as well as bioengineering approaches to repair or regenerate salivary function.
Topics: Cell Lineage; Humans; Oral Health; Regeneration; Salivary Glands; Signal Transduction
PubMed: 35343828
DOI: 10.1152/physrev.00015.2021 -
Head and Neck Pathology Mar 2022The salivary gland section in the 5th edition of the World Health Organization Classification of Head and Neck Tumours features a description and inclusion of several...
The salivary gland section in the 5th edition of the World Health Organization Classification of Head and Neck Tumours features a description and inclusion of several new entities, including sclerosing polycystic adenoma, keratocystoma, intercalated duct adenoma, and striated duct adenoma among the benign neoplasms; and microsecretory adenocarcinoma and sclerosing microcystic adenocarcinoma as the new malignant entities. The new entry also includes mucinous adenocarcinoma subdivided into papillary, colloid, signet ring, and mixed subtypes with recurrent AKT1 E17K mutations across patterns suggesting that mucin-producing salivary adenocarcinomas represent a histologically diverse single entity that may be related to salivary intraductal papillary mucinous neoplasm (IPMN). Importantly, the number of entities in the salivary chapter has been reduced by omitting tumors or lesions if they do not occur exclusively or predominantly in salivary glands, including hemangioma, lipoma, nodular fasciitis and hematolymphoid tumors. They are now discussed in detail elsewhere in the book. Cribriform adenocarcinoma of salivary gland origin (CASG) now represents a distinctive subtype of polymorphous adenocarcinoma (PAC). PAC is defined as a clinically, histologically and molecularly heterogeneous disease group. Whether CASG is a different diagnostic category or a variant of PAC is still controversial. Poorly differentiated carcinomas and oncocytic carcinomas are discussed in the category "Salivary carcinoma not otherwise specified (NOS) and emerging entities". New defining genomic alterations have been characterized in many salivary gland tumors. In particular, they include gene fusions, which have shown to be tightly tumor-type specific, and thus valuable for use in diagnostically challenging cases. The recurrent molecular alterations were included in the definition of mucoepidermoid carcinoma, adenoid cystic carcinoma, secretory carcinoma, polymorphous adenocarcinoma, hyalinizing clear cell carcinoma, mucinous adenocarcinoma, and microsecretory adenocarcinoma.
Topics: Adenocarcinoma; Adenocarcinoma, Mucinous; Adenoma; Biomarkers, Tumor; Humans; Salivary Gland Neoplasms; Salivary Glands; World Health Organization
PubMed: 35312980
DOI: 10.1007/s12105-022-01420-1 -
Journal of Dental Research Oct 2021Although the physiological control of salivary secretion has been well studied, the impact of disease on salivary gland function and how this changes the composition and... (Review)
Review
Although the physiological control of salivary secretion has been well studied, the impact of disease on salivary gland function and how this changes the composition and function of saliva is less well understood and is considered in this review. Secretion of saliva is dependent upon nerve-mediated stimuli, which activate glandular fluid and protein secretory mechanisms. The volume of saliva secreted by salivary glands depends upon the frequency and intensity of nerve-mediated stimuli, which increase dramatically with food intake and are subject to facilitatory or inhibitory influences within the central nervous system. Longer-term changes in saliva secretion have been found to occur in response to dietary change and aging, and these physiological influences can alter the composition and function of saliva in the mouth. Salivary gland dysfunction is associated with different diseases, including Sjögren syndrome, sialadenitis, and iatrogenic disease, due to radiotherapy and medications and is usually reported as a loss of secretory volume, which can range in severity. Defining salivary gland dysfunction by measuring salivary flow rates can be difficult since these vary widely in the healthy population. However, saliva can be sampled noninvasively and repeatedly, which facilitates longitudinal studies of subjects, providing a clearer picture of altered function. The application of omics technologies has revealed changes in saliva composition in many systemic diseases, offering disease biomarkers, but these compositional changes may not be related to salivary gland dysfunction. In Sjögren syndrome, there appears to be a change in the rheology of saliva due to altered mucin glycosylation. Analysis of glandular saliva in diseases or therapeutic interventions causing salivary gland inflammation frequently shows increased electrolyte concentrations and increased presence of innate immune proteins, most notably lactoferrin. Altering nerve-mediated signaling of salivary gland secretion contributes to medication-induced dysfunction and may also contribute to altered saliva composition in neurodegenerative disease.
Topics: Humans; Mouth; Neurodegenerative Diseases; Saliva; Salivary Glands; Salivation
PubMed: 33870742
DOI: 10.1177/00220345211004842 -
Cells Aug 2019Salivary glands are essential structures in the oral cavity. A variety of diseases, such as cancer, autoimmune diseases, infections and physical traumas, can alter the... (Review)
Review
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. To date, no definitive therapeutic approach can compensate the impairment of salivary glands, and treatment are purely symptomatic. Understanding the cellular and molecular control of salivary glands function is, therefore, highly relevant for therapeutic purposes. In this review, we provide a starting platform for future studies in basic biology and clinical research, reporting classical ideas on salivary gland physiology and recently developed technology to guide regeneration, reconstruction and substitution of the functional organs.
Topics: Animals; Female; Gene Regulatory Networks; Humans; Male; Mice; Regeneration; Salivary Glands; Sex Characteristics; Species Specificity
PubMed: 31455013
DOI: 10.3390/cells8090976 -
Clinical and Experimental Rheumatology 2018The formation of lymphomononuclear cell infiltrates organising as periductal infiltrates in the salivary glands of patients with primary Sjögren's syndrome (pSS) is one... (Review)
Review
The formation of lymphomononuclear cell infiltrates organising as periductal infiltrates in the salivary glands of patients with primary Sjögren's syndrome (pSS) is one of the hallmarks of the disease. Historically, the clinical role of salivary gland histopathology, most commonly performed on labial salivary gland biopsies, has been confined to the clinical classification and diagnosis of pSS whereby according to the ACR-EULAR a positive histopathology finding is a requirement for the diagnosis of pSS in the absence of anti-Ro/SSA antibodies. In recent years, further understanding of the heterogeneity of the immune cell infiltration and organisation within the salivary glands of pSS patients and its correlation with clinical manifestations of the disease has led to propose salivary gland histopathology as a novel tool able to identify patients at higher risk of developing more severe extraglandular manifestations and lymphoma. Furthermore, recent clinical developments in ongoing randomised clinical trials with novel biologics in pSS have focused on salivary glands histopathology to inform on patients stratification based on target validation, proof of drug efficacy and mechanisms of response/resistance to therapy. However, lack of standardisation of methodology and analysis has hindered the reproducibility of data from different groups and no definitive evidence in support of the use of salivary glands histopathology to inform clinical management of patients with pSS has been provided. In this review, we summarise recent evidence highlighting the promises and pitfalls of salivary glands histopathology in pSS emphasising the need for an international consensus on standardisation of methodology with validation in large prospective multicentre initiatives.
Topics: Antirheumatic Agents; Biomarkers; Biopsy; Decision Support Techniques; Immunohistochemistry; Lymphoid Tissue; Predictive Value of Tests; Reproducibility of Results; Risk Assessment; Risk Factors; Salivary Glands; Severity of Illness Index; Sjogren's Syndrome; Treatment Outcome
PubMed: 30156550
DOI: No ID Found -
Nature Reviews. Rheumatology Jun 2021In primary Sjögren syndrome (pSS), the function of the salivary glands is often considerably reduced. Multiple innate immune pathways are likely dysregulated in the... (Review)
Review
In primary Sjögren syndrome (pSS), the function of the salivary glands is often considerably reduced. Multiple innate immune pathways are likely dysregulated in the salivary gland epithelium in pSS, including the nuclear factor-κB pathway, the inflammasome and interferon signalling. The ductal cells of the salivary gland in pSS are characteristically surrounded by a CD4 T cell-rich and B cell-rich infiltrate, implying a degree of communication between epithelial cells and immune cells. B cell infiltrates within the ducts can initiate the development of lymphoepithelial lesions, including basal ductal cell hyperplasia. Vice versa, the epithelium provides chronic activation signals to the glandular B cell fraction. This continuous stimulation might ultimately drive the development of mucosa-associated lymphoid tissue lymphoma. This Review discusses changes in the cells of the salivary gland epithelium in pSS (including acinar, ductal and progenitor cells), and the proposed interplay of these cells with environmental stimuli and the immune system. Current therapeutic options are insufficient to address both lymphocytic infiltration and salivary gland dysfunction. Successful rescue of salivary gland function in pSS will probably demand a multimodal therapeutic approach and an appreciation of the complicity of the salivary gland epithelium in the development of pSS.
Topics: B-Lymphocytes; CD4-Positive T-Lymphocytes; Epithelial Cells; Humans; Immune Checkpoint Inhibitors; Inflammasomes; Interferons; Lymphoma, B-Cell, Marginal Zone; NF-kappa B; Salivary Glands; Sjogren's Syndrome
PubMed: 33911236
DOI: 10.1038/s41584-021-00605-2 -
Clinical and Experimental Rheumatology Dec 2023Primary Sjögren's syndrome (pSS) is a systemic autoimmune disorder characterised by the T-cell-mediated hyperactivation of B-cells and cytokine production. The... (Review)
Review
Primary Sjögren's syndrome (pSS) is a systemic autoimmune disorder characterised by the T-cell-mediated hyperactivation of B-cells and cytokine production. The condition may evolve from an asymptomatic, indolent course, with glandular involvement, to extra-glandular systemic manifestations up to lymphoma development. On tissue level, the typical feature is the lymphocytic infiltration of the salivary gland by B-, T- and antigen presenting cells, as mirrored by the diagnostic cornerstone role of minor salivary gland (MSG) biopsy. Recently, increasing research focused on the investigation of mechanisms underlying the complex pathogenesis of the disease and highlighted the multi-factorial nature of SS consisting of concomitant involvement of environmental, genetic, neuroendocrine and immune factors. In particular, many aspects have been investigated regarding genetic and epigenetics, the role of specific B- and T-cell phenotypes and the investigation of disease-specific biomarkers as predictors of disease development, activity, and lymphomagenesis. Surely, a deeper understanding of these multiple mechanisms may facilitate earlier diagnosis, enable subphenotyping of patients and open novel therapeutic possibilities to address the unmet needs of the disease in the upcoming years.In this review, following the others of this series, we will summarise the most recent literature on pSS pathogenesis and clinical features focusing in particular on new insights into pSS molecular stratification and therapeutic advances in the era of precision medicine.
Topics: Humans; Sjogren's Syndrome; Salivary Glands; Salivary Glands, Minor; B-Lymphocytes; Lymphoma
PubMed: 38149515
DOI: 10.55563/clinexprheumatol/255qsx -
Cell Jul 2021Many embryonic organs undergo epithelial morphogenesis to form tree-like hierarchical structures. However, it remains unclear what drives the budding and branching of...
Many embryonic organs undergo epithelial morphogenesis to form tree-like hierarchical structures. However, it remains unclear what drives the budding and branching of stratified epithelia, such as in the embryonic salivary gland and pancreas. Here, we performed live-organ imaging of mouse embryonic salivary glands at single-cell resolution to reveal that budding morphogenesis is driven by expansion and folding of a distinct epithelial surface cell sheet characterized by strong cell-matrix adhesions and weak cell-cell adhesions. Profiling of single-cell transcriptomes of this epithelium revealed spatial patterns of transcription underlying these cell adhesion differences. We then synthetically reconstituted budding morphogenesis by experimentally suppressing E-cadherin expression and inducing basement membrane formation in 3D spheroid cultures of engineered cells, which required β1-integrin-mediated cell-matrix adhesion for successful budding. Thus, stratified epithelial budding, the key first step of branching morphogenesis, is driven by an overall combination of strong cell-matrix adhesion and weak cell-cell adhesion by peripheral epithelial cells.
Topics: Animals; Basement Membrane; Cell Adhesion; Cell Division; Cell Movement; Cell Tracking; Cell-Matrix Junctions; Embryo, Mammalian; Epithelial Cells; Epithelium; Gene Expression Regulation, Developmental; HEK293 Cells; Humans; Integrins; Mice; Models, Biological; Morphogenesis; Salivary Glands; Transcriptome
PubMed: 34133940
DOI: 10.1016/j.cell.2021.05.015 -
Drugs in R&D Mar 2017Medication-induced salivary gland dysfunction (MISGD), xerostomia (sensation of oral dryness), and subjective sialorrhea cause significant morbidity and impair quality... (Review)
Review
A Guide to Medications Inducing Salivary Gland Dysfunction, Xerostomia, and Subjective Sialorrhea: A Systematic Review Sponsored by the World Workshop on Oral Medicine VI.
BACKGROUND
Medication-induced salivary gland dysfunction (MISGD), xerostomia (sensation of oral dryness), and subjective sialorrhea cause significant morbidity and impair quality of life. However, no evidence-based lists of the medications that cause these disorders exist.
OBJECTIVE
Our objective was to compile a list of medications affecting salivary gland function and inducing xerostomia or subjective sialorrhea.
DATA SOURCES
Electronic databases were searched for relevant articles published until June 2013. Of 3867 screened records, 269 had an acceptable degree of relevance, quality of methodology, and strength of evidence. We found 56 chemical substances with a higher level of evidence and 50 with a moderate level of evidence of causing the above-mentioned disorders. At the first level of the Anatomical Therapeutic Chemical (ATC) classification system, 9 of 14 anatomical groups were represented, mainly the alimentary, cardiovascular, genitourinary, nervous, and respiratory systems. Management strategies include substitution or discontinuation of medications whenever possible, oral or systemic therapy with sialogogues, administration of saliva substitutes, and use of electro-stimulating devices.
LIMITATIONS
While xerostomia was a commonly reported outcome, objectively measured salivary flow rate was rarely reported. Moreover, xerostomia was mostly assessed as an adverse effect rather than the primary outcome of medication use. This study may not include some medications that could cause xerostomia when administered in conjunction with others or for which xerostomia as an adverse reaction has not been reported in the literature or was not detected in our search.
CONCLUSIONS
We compiled a comprehensive list of medications with documented effects on salivary gland function or symptoms that may assist practitioners in assessing patients who complain of dry mouth while taking medications. The list may also prove useful in helping practitioners anticipate adverse effects and consider alternative medications.
Topics: Drug-Related Side Effects and Adverse Reactions; Humans; Oral Medicine; Salivary Glands; Sialorrhea; Xerostomia
PubMed: 27853957
DOI: 10.1007/s40268-016-0153-9 -
Radiotherapy and Oncology : Journal of... Jan 2021The presence of previously unnoticed bilateral macroscopic salivary gland locations in the human nasopharynx was suspected after visualization by positron emission...
INTRODUCTION
The presence of previously unnoticed bilateral macroscopic salivary gland locations in the human nasopharynx was suspected after visualization by positron emission tomography/computed tomography with prostate-specific membrane antigen ligands (PSMA PET/CT). We aimed to elucidate the characteristics of this unknown entity and its potential clinical implications for radiotherapy.
MATERIALS AND METHODS
The presence and configuration of the PSMA-positive area was evaluated in a retrospective cohort of consecutively scanned patients with prostate or urethral gland cancer (n = 100). Morphological and histological characteristics were assessed in a human cadaver study (n = 2). The effect of radiotherapy (RT) on salivation and swallowing was retrospectively investigated using prospectively collected clinical data from a cohort of head-neck cancer patients (n = 723). With multivariable logistic regression analysis, the association between radiotherapy (RT) dose and xerostomia or dysphagia was evaluated.
RESULTS
All 100 patients demonstrated a demarcated bilateral PSMA-positive area (average length 4 cm). Histology and 3D reconstruction confirmed the presence of PSMA-expressing, predominantly mucous glands with multiple draining ducts, predominantly near the torus tubarius. In the head-neck cancer patients, the mean RT dose to the gland area was significantly associated with physician-rated post-treatment xerostomia and dysphagia ≥ grade 2 at 12 months (0.019/gy, 95%CI 0.005-0.033, p = .007; 0.016/gy, 95%CI 0.001-0.031, p = .036). Follow-up at 24 months had similar results.
CONCLUSION
The human body contains a pair of previously overlooked and clinically relevant macroscopic salivary gland locations, for which we propose the name tubarial glands. Sparing these glands in patients receiving RT may provide an opportunity to improve their quality of life.
Topics: Head and Neck Neoplasms; Humans; Male; Parotid Gland; Positron Emission Tomography Computed Tomography; Quality of Life; Radiotherapy, Conformal; Retrospective Studies; Salivary Glands; Xerostomia
PubMed: 32976871
DOI: 10.1016/j.radonc.2020.09.034