Review

Authors: Alejandro M Chibly, Marit H Aure, Vaishali N Patel...

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

Review

Authors: Frans G M Kroese, Erlin A Haacke, Michele Bombardieri...

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

Review

Authors: Cristina Porcheri, Thimios A 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. 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

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.

Authors: Andy Wolff, Revan Kumar Joshi, Jörgen Ekström...

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

Review

Authors: Gwenny M Verstappen, Sarah Pringle, Hendrika Bootsma...

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

Authors: Shaohe Wang, Kazue Matsumoto, Samantha R Lish...

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

Authors: Guiquan Zhu, Chunjie Li

More than 30 years of rapid development of endoscopic surgery has led to the mainstreaming of this procedure in many surgical departments in China. Since the first report on endoscopy, it has been used in salivary gland resection for more than 20 years. The overall development of endoscopic surgery indicates that its use in oral and maxillofacial surgery is still in the early exploration stage; it has not yet been maturely developed or applied. Owing to the advancement of other disciplines and corresponding widening experiences in those fields, the development of endoscopic technology in oral and maxillofacial surgery will likely achieve a leapfrogging. Learning from the general development pattern of endoscopy, this research explores the application history, current situation, and future direction of the application of endoscopy in salivary gland surgery.

Topics: Endoscopy; Endoscopes; Salivary Glands; China

PubMed: 37474469
DOI: 10.7518/hxkq.2023.2023116

Review

Authors: Alen Zabotti, Ivan Giovannini, Simone Longhino...

Primary Sjögren's syndrome (pSS) is a chronic, systemic, inflammatory autoimmune disease characterised by lymphocyte proliferation and progressive damage to exocrine glands. Salivary gland histopathology based on salivary gland biopsy is relevant for the diagnosis of pSS and therefore broadly applied in clinical practice. Tissue can be obtained from labial salivary glands (LSG) biopsy or from major salivary glands (MSG) biopsy, namely the parotid; in this latter scenario, the procedure can be either an open surgical biopsy or a US guided core needle biopsy.In this review we will: i) present the histopathological findings that may be encountered by pathologists on biopsies from pSS patients; ii) discuss the advantages and disadvantages of the surgical and/or imaging guided procedures to obtain tissues from LSG or MSG; iii) describe the histopathological features of lymphoma of MSG in pSS patients.

Topics: Humans; Sjogren's Syndrome; Salivary Glands; Parotid Gland; Salivary Glands, Minor; Lymphoma; Biopsy

PubMed: 38079343
DOI: 10.55563/clinexprheumatol/fcjoqx

Review

Authors: Aaron Mattingly, Jennifer K Finley, Sarah M Knox...

Mammalian salivary glands synthesize and secrete saliva via a vast interconnected network of epithelial tubes attached to secretory end units. The extensive morphogenesis required to establish this organ is dependent on interactions between multiple cell types (epithelial, mesenchymal, endothelial, and neuronal) and the engagement of a wide range of signaling pathways. Here we describe critical regulators of salivary gland development and discuss how mutations in these impact human organogenesis. In particular, we explore the genetic contribution of growth factor pathways, nerve-derived factors and extracellular matrix molecules to salivary gland formation in mice and humans.

Topics: Animals; Extracellular Matrix; Humans; Morphogenesis; Organogenesis; Salivary Glands; Signal Transduction

PubMed: 25970268
DOI: 10.1002/wdev.194

Review

Authors: Lindsay R Piraino, Danielle S W Benoit, Lisa A DeLouise...

Salivary gland regeneration is important for developing treatments for radiation-induced xerostomia, Sjögren's syndrome, and other conditions that cause dry mouth. Culture conditions adopted from tissue engineering strategies have been used to recapitulate gland structure and function to study and regenerate the salivary glands. The purpose of this review is to highlight current trends in the field, with an emphasis on soluble factors that have been shown to improve secretory function in vitro. A PubMed search was conducted to identify articles published in the last 10 years and articles were evaluated to identify the most promising approaches and areas for further research. Results showed increasing use of extracellular matrix mimetics, such as Matrigel, collagen, and a variety of functionalized polymers. Soluble factors that provide supportive cues, including fibroblast growth factors (FGFs) and neurotrophic factors, as well as chemical inhibitors of Rho-associated kinase (ROCK), epidermal growth factor receptor (EGFR), and transforming growth factor β receptor (TGFβR) have shown increases in important markers including aquaporin 5 (Aqp5); muscle, intestine, and stomach expression 1 (Mist1); and keratin (K5). However, recapitulation of tissue function at in vivo levels is still elusive. A focus on identification of soluble factors, cells, and/or matrix cues tested in combination may further increase the maintenance of salivary gland secretory function in vitro. These approaches may also be amenable for translation in vivo to support successful regeneration of dysfunctional glands.

Topics: Animals; Cell Culture Techniques; Humans; Salivary Glands; Tissue Engineering

PubMed: 34359893
DOI: 10.3390/cells10071723