P-glycoprotein expression in human major and minor salivary glands

Sodium pump and carbonic anhydrase activity have been described in the salivary glands. However, it remains to be elucidated whether these energy sources are used for secretion, excretion or both. In addition, the differences in the function of excretion and the role of the excretory duct cells are currently unknown in salivary glands. Expression of P-glycoprotein (P-gp), which is an ATPase-binding efflux pump, was tested in normal major and minor salivary glands from humans. P-gp was distributed on the basolateral membrane of serous acinar cells in the major salivary glands and the minor salivary glands. In particular, it was found to be present on the basolateral membrane and cytoplasm of acinar demilunar cells in the anterior lingual gland. Intense expression was identified in the basolateral membrane of the striated duct cells of the major salivary glands. P-gp was distinctly positive in the basolateral and/or luminal membranes of the initial part and in the luminal membrane of the terminal part of the excretory duct cells of the major salivary glands, whereas it was positive in the luminal membranes of both the initial part and the terminal part of the excretory duct cells of the minor salivary glands. These disparate distributions between the major and the minor salivary glands suggest different physiological excretions in the striated duct. P-gp may be physiologically involved in an important part of the transporter system, not only in the acinar serous cells and the striated duct cells, but also in the excretory duct cells in the salivary glands.     

Regulation of hemodynamics in major salivary glands by parasympathetic vasodilation

Background

Since salivary fluid is created from blood plasma, hemodynamics in the salivary glands play an important role in the production of saliva. Trigeminal sensory input induces both salivary secretion and reflex parasympathetic vasodilation in salivary glands. This glandular vasodilation is thought to be important for the regulation of glandular hemodynamics due to the rapidity with which blood flow is increased. This review article summarizes recent research on the involvement of parasympathetic vasodilation in regulating hemodynamics in the salivary gland.

Changes of salivary functions in experimental periodontitis model rats

ObjectiveThis study was designed to investigate the mechanism of salivary dysfunction in an experimental periodontitis rat model and to examine the improvements in salivary secretion following treatment of the experimental periodontitis.MethodsIn the experimental periodontitis rat model, which included a unilateral ligature for 4 weeks around the second upper molar, several salivary functions were investigated. Changes in the salivary function were evaluated 4 weeks after removal of the ligature in some rats.ResultsThe periodontitis model showed significant reductions in the weight of the bilateral major salivary glands and pilocarpine-induced salivary secretion. The model also showed an increase in the number of apoptotic cells in bilateral salivary glands. According to Ca²⁺ imaging and Western blotting, there were no differences in the muscarine-induced intracellular Ca²⁺ mobilization in acinar cells or in the M3 receptor and AQP5 expression levels in the salivary glands between the sham and the periodontitis model. Following removal of the ligature, differences in the weights of salivary glands and pilocarpine-induced salivary secretion between the sham and the periodontitis model animals were not found.ConclusionThese results suggest that experimental periodontitis leads to hyposalivation and that relief from it improves salivary function. It is likely that lower levels of salivary secretion are caused by the decrease of functional acinar cells in salivary glands in the experimental periodontitis model, and the bilateral gland effects in the unilateral periodontitis model are caused by systemic rather than by local effects.     

Non-neoplastic salivary gland diseases

A wide range of non neoplastic disorders can affect the salivary glands, although the more common are: mumps, acute suppurative sialadenitis, Sj?gren's syndrome and drug-induced xerostomia. Salivary dysfunction is not a normal consequence of old age, and can be due to systemic diseases, medications or head and neck radiotherapy. Diagnosis of salivary disorders begins with a careful medical history, followed by a cautious examination. While complaints of xerostomia may be indicative of a salivary gland disorder, salivary diseases can present without symptoms. Therefore, routine examination of salivary function must be part of any head, neck, and oral examination. Health-care professionals can play a vital role in identifying patients at risk for developing salivary dysfunction, and should provide appropriate preventive and interventive techniques that will help to preserving a person's health, function, and quality of life. The present work provides an overview of most of the non neoplastic disorders of the salivary glands, in which the general presentation, pathology, and treatments are discussed.     

Minor salivary gland secretion in children and adults

The minor salivary glands are of great importance in the physiology and pathology of the oral cavity. So far, studies of the minor glands have concentrated on adults. In the present study, minor salivary gland secretion was studied in the buccal and labial mucosa of 3-year-old children, adolescents and young adults. In addition, the number of glands per surface area was assessed in the labial mucosa. A total of 90 individuals were included, 30 in each age-group. Saliva was collected on filter paper discs and the salivary secretion rate was measured using a Periotron 8000. The number of secreting labial glands was assessed on PAS-stained filter paper discs under a microscope. Salivary secretion in the buccal mucosa was found to be age-related, with a statistically significant lower rate of secretion (P=0.003) in the 3-year-olds (mean 7.7 microl x cm(-2) x min(-1)) compared with the young adults (11.9 microl x cm(-2) x min(-1)). No significant differences between the sexes were noted. For the labial glands, no age- or sex-related differences were found. In all age-groups, salivary secretion was significantly higher in the buccal than in the labial mucosal area. A statistically significant difference in number of secreting glands was found between all age-groups, with a decreasing number of glands per surface unit with age. The number of glands was significantly lower in males compared with females in the group of adults. The lower rate of buccal salivary secretion in the young children may imply that the oral mucosa is more vulnerable to external injury and that caries protection on the buccal molar surfaces is lower. Previous studies indicate that adults with a reduced rate of minor salivary gland secretion are more susceptible to caries.     

Salivary gland progenitor cell biology provides a rationale for therapeutic salivary gland regeneration

Oral Diseases (2011) 17 , 445–449 An irreversible loss of salivary gland function often occurs in humans after removal of salivary tumors, after therapeutic radiation of head and neck tumors, as a result of Sjögren’s syndrome and in genetic syndromes affecting gland development. The permanent loss of gland function impairs the oral health of these patients and broadly affects their quality of life. The regeneration of functional salivary gland tissue is thus an important therapeutic goal for the field of regenerative medicine and will likely involve stem/progenitor cell biology and/or tissue engineering approaches. Recent reports demonstrate how both innervation of the salivary gland epithelium and certain growth factors influence progenitor cell growth during mouse salivary gland development. These advances in our understanding suggest that developmental mechanisms of mouse salivary gland development may provide a paradigm for postnatal regeneration of both mice and human salivary glands. Herein, we will discuss the developmental mechanisms that influence progenitor cell biology and the implications for salivary gland regeneration.     

Expression of podoplanin in the mouse salivary glands

OBJECTIVE: Podoplanin is one of the most highly expressed lymphatic-specific genes. Here, we report the distribution of cells expressing podoplanin in mouse salivary glands. DESIGN: We immunohistochemically investigated the distribution of cells expressing podoplanin in mouse major salivary glands by laser-scanning microscopy. The expression of endothelial cell marker PECAM-1 was tested to discriminate lymphatic endothelium from salivary gland cells, and myoepithelial cells were identified by an antibody for P-cadherin. RESULTS: The podoplanin expression was rarely found in acini of the parotid gland but clearly found at the basal portion of acini in the submandibular and sublingual glands. The number of portion reacted with anti-podoplanin is greater in the sublingual gland than in the submandibular gland. The expression was also found at the basal portion of ducts in all major salivary glands. The P-cadherin expression was rarely found in acini of the parotid gland but found in acini of the sublingual gland and on ducts in parotid and sublingual glands, corresponding to the area of podoplanin expression. CONCLUSIONS: It was suggested that the acinar and myoepithelial cells in the salivary glands have the ability to express podoplanin, and that the expression may be concerned with the mucous saliva excretion.     

Morphological features of the minor salivary glands

The minor salivary, glands are important components of the oral cavity, present in most parts of the mouth, and their secretions directly bathe the tissues. Individual glands are usually in the submucosa or between muscle fibres, and consist of groups of secretory endpieces made up of mucous acinar cells and serous or seromucous demilune cells. The ductal systems comprise intercalated ducts, intralobular ducts usually lacking basal striations, and excretory ducts opening directly through the mucosa. Minor glands secrete highly glycosylated mucins, containing blood group determinants, and probably active in tissue lubrication and bacterial aggregation. They also secrete several antimicrobial proteins and immunoglobulins, and the lingual serous (van Ebner's) glands secrete digestive enzymes and proteins with possible taste perception functions. Minor gland morphology and function can conveniently be studied in the rat. There are substantial differences between major and minor salivary glands, as well as among the minor glands, in the nature and composition of their mucous and serous secretory products. The role of minor salivary glands in the function and defence of the oral cavity may be better understood as a result of new physiological and molecular methods applicable to samples of limited size and availability.     

Immunohistochemistry and ultrastructure of myoepithelium and modified myoepithelium of the ducts of human major salivary glands: histogenetic implications for salivary gland tumors

The organization of salivary gland ducts, especially the presence or absence of myoepithelial cells, is central to histogenetic approaches to the classification of salivary gland tumors. Striated and excretory ducts are reported to be devoid of myoepithelial cells but do contain basal cells. To investigate the nature of such basal cells, tissue sections of normal human salivary glands were examined by means of immunohistochemical, ultrastructural, and fluorescent microscopic techniques. With the use of a mouse monoclonal anticytokeratin antibody (3 12C8-1) that, in salivary glands, is specific for myoepithelial cells, these cells associated with acini and intercalated ducts were strongly stained, as were the basal cells of striated and excretory ducts in each case. Ultrastructurally, some basal cells of both striated and excretory ducts had narrow, elongated cellular processes or the main portion of the cell containing parallel arrays of microfilaments with linear densities and micropinocytotic vesicles, whereas in other basal cells tonofilament bundles predominated. A similar range of cytoplasmic features existed in myoepithelial cells associated with acinar and intercalated duct cells. In addition, some duct basal cells have a complement of actin filaments similar to classic myoepithelium of acini and intercalated ducts. Striated and excretory ducts of human salivary glands, therefore, contain fully differentiated and modified myoepithelial cells, both of which express a specific cytokeratin polypeptide that is absent from duct luminal and acinar cells. Differentiation patterns in the intralobular and interlobular ducts suggest that these regions of salivary gland parenchyma cannot be excluded as histogenetic sites for the induction of salivary gland tumors in which neoplastic myoepithelial cells have been shown to have a major role.     

端粒长度变化在涎腺肿瘤发生中的作用

目的 观察端粒长度变化在涎腺肿瘤形成及发展中的作用。方法 采用Ｓｏｕｔｈｅｒｎ杂交技术对１１例正常涎腺组织,１５例良性涎腺肿瘤,１８例恶性涎腺肿瘤的端粒长度进行测量。结果 良性及恶性涎腺肿瘤的平均ＴＲＦ（ｔｅｒｎｉｎａｌ ｒｅｓｔｒｉｃｔｉｏｎ ｆｒａｇｍｅｎｔ）明显比正常涎腺的平均ＴＲＦ短,且有显著性差异。良性与恶性涎腺肿瘤的平均ＴＲＦ相比,无显著性差异。结论 端粒的异常状态参与涎腺肿瘤的发生。     

Sex-related differences in gene expression in salivary glands of BALB/c mice

Sex-related differences exist in the structure and function of the major glands in a variety of species. Moreover, many of these variations appear to be unique to each tissue. We hypothesized that this sexual dimorphism is due, at least in part, to gland-specific differences in gene expression between males and females. Glands were collected from male and female BALB/c mice (n = 5/sex/experiment), and total RNA was isolated. Samples were analyzed for differentially expressed mRNAs with CodeLink microarrays, and data were evaluated by GeneSifter. Our results demonstrate that significant (P < 0.05) sex-related differences exist in the expression of numerous genes in the major salivary glands, and many of these differences were tissue-specific. These findings support our hypothesis that sex-related differences in the salivary glands are due, at least in part, to tissue-specific variations in gene expression.     

Immunohistochemical detection of salivary agglutinin/gp-340 in human parotid, submandibular, and labial salivary glands

Salivary agglutinin is a Streptococcus mutans binding protein and a member of the scavenger receptor cysteine-rich superfamily. It is identical to lung gp-340 and brain DMBT1, which possibly play a role in innate immunity and tumor suppression, respectively. The goal of this study was to localize salivary agglutinin in human salivary glands. Two monoclonal antibodies, directed against gp-340, were characterized. mAb 213-1 reacted with sialic acid epitopes and cross-reacted with MUC7. The reaction with mAb 213-6 disappeared after reduction, suggesting that a protein epitope was recognized. In the parotid gland, immunohistochemical labeling with mAb 213-6 was found in the duct cells. In the submandibular gland and labial gland, both serous acini and demilune cells were labeled. In the labial gland, labeling was found at the luminal side of the duct cells. Salivary agglutinin was distinctly localized in salivary glands, but in distinct glandular secretions, no differences in electrophoretic behavior were observed.     

唾液腺紧密连接蛋白Claudin的研究进展

紧密连接(tight junction, TJ)是参与旁细胞分泌途径中蛋白质相互作用的复杂动态系统,具有屏障功能和栅栏功能。Claudin家族构成紧密连接链的主干,在唾液腺放射性损伤、炎症性疾病、舍格伦综合征和糖尿病等病理状况下会出现表达模式的异常改变,导致紧密连接结构和功能异常,间接表现为唾液腺功能障碍。此外,唾液腺肿瘤中Claudin蛋白的表达差异也可作为判断肿瘤类型及预后的指标。本文重点综述了唾液腺常见Claudin蛋白的研究进展,包括结构、功能、相关疾病的表达模式及其应用,为Claudin蛋白相关疾病的临床研究和基础研究提供新思路。     

The molecular basis of salivary gland involvement in graft--vs.--host disease

During the past two decades, the involvement of salivary glands in graft vs. host disease (GVHD) had been intensively researched and published. GVHD occurs in 40-70% of patients treated with bone marrow and peripheral blood stem cell transplantation (PBSCT), and improved survival rates have led to a continuously increasing number of GVHD patients suffering from induced salivary insult. Limited studies suggest that a large percentage of GVHD patients is affected and that the induced salivary dysfunction occurs rapidly following the transplantation. It affects both major and minor salivary glands and reflects the severity of the disease. Moreover, profound sialochemical alterations may be diagnostic of GVHD. An additional reason for this vast research is that GVHD, as an autoimmune-like disease, seemed to be an appropriate model for studying a much more prevalent and well-known and well-studied autoimmune disease involving salivary glands: Sj?gren's syndrome. The purpose of the current review-which is, to the best of our knowledge, the first of its kind-is to describe the GVHD-related sialometric and sialochemical data published in the past two decades for both major and minor salivary glands and to discuss the pathogenesis and molecular basis of the disease.     

Murine autoimmune exocrinopathy: the minor salivary gland network shows a dichotomous pattern of histopathologic involvement

The minor salivary gland network of the MRL/1 mouse was investigated in a kinetic study and compared with the major submandibular gland. We report that minor salivary glands adopt two mutually exclusive patterns of inflammatory lesions depending on the gland. The first pattern is characteristic of human Sjogren's syndrome. It developed during the second month, affected 89% of the animals over 20 weeks old, and consisted of an accumulation of mononuclear cells around the duct system. Only the anterior buccal gland (ABG) showed this pattern, which is shared by the major salivary glands. The ratio of CD44+ to CD8+ cells was the same in lesions and in healthy tissue. No neutrophils were found in these lesions. The second pattern affected all the minor salivary glands except the ABG. These lesions were never observed before the age of 20 weeks and affected 38% of MRL/1 mice between the ages of 10–32 weeks. In this pattern, neutrophils were frequently found, but mainly gathered at the periphery of the gland lobules. That a systemic immunoregulatory defect may be expressed as two different patterns of histopathology in the minor salivary glands suggest that the network behaves as a dichotomous entity depending on particular microenvironmental influences.     

Cell surface markers CD44 and CD166 localized specific populations of salivary acinar cells

Oral Diseases (2012) 18 , 162–168 Objective: Experimental approaches tested to date for functional restoration of salivary glands (SGs) are tissue engineering, gene transfer, and cell therapy. To further develop these therapies, identifying specific cell surface markers for the isolation of salivary acinar cells is needed. To test a panel of cell surface markers [used in the isolation of mesenchymal stem cells, (MSCs)] for the localization of salivary acinar cells. Materials: Human submandibular and parotid glands were immunostained with a panel of MSC markers and co‐localized with salivary acinar cell differentiation markers [α‐amylase, Na‐K‐2Cl cotransporter‐1, aquaporin‐5 (AQP5)]. Additional cell markers were also used, such as α‐smooth muscle actin (to identify myoepithelial cells), cytokeratin‐5 (basal ductal cells), and c‐Kit (progenitor cells). Results: CD44 identified serous acini, while CD166 identified mucous acini. Cytokeratin‐5 identified basal duct cells and 50% of myoepithelial cells. None of the remaining cell surface markers (Stro‐1, CD90, CD106, CD105, CD146, CD19, CD45, and c‐Kit) were expressed in any human salivary cell. Conclusions: CD44 and CD166 localized human salivary serous and mucous acinar cells, respectively. These two cell surface markers will be useful in the isolation of specific populations of salivary acinar cells.     

A review of the proliferative capacity of major salivary glands and the relationship to current concepts of neoplasia in salivary glands

The classification of salivary gland tumors relies heavily on histogenetic postulates. One of these, the semipluripotential reserve cell theory, suggests that certain reserve cells in specific segments of the duct system of major and minor salivary glands are critical to the development of neoplasms in these glands. However, direct evidence in support of this hypothesis is unavailable. This survey of proliferative capacity in normal salivary gland is based on a review of data in the literature, our observations of DNA synthetic and mitotic activity in developing rat and human salivary gland, and autoradiographic studies of induced cell proliferation in rat salivary gland. Autoradiography of neonatal rat salivary gland after tritiated thymidine administration, and electron microscopy of these tissues, reveals that as well as duct basal cells, luminal cells at all levels of the duct system and even acinar cells are capable of DNA synthesis and mitosis. Indeed, in such studies, more luminal than basal cells are seen in mitosis. In adult rat salivary gland induced to undergo hyperplasia, more acinar cells than intercalated duct cells are in the S phase of the cell cycle. However, cycling cells were observed even in striated ducts and, importantly, both basal and luminal cells of major interlobular excretory ducts are also labeled. Similar findings are present in fetal and adult human salivary glands. From such observations, it is evident that dividing cells are not limited to basal cells of excretory ducts and luminal cells of intercalated ducts, so that there is no support for the semipluripotential bicellular reserve cell hypothesis. However, there is considerable evidence for a multicellular theory of tumor histogenesis; that is, any of the multiplicity of cell types in normal salivary gland have the potential to give use to any of the various types of tumor occurring in this organ.     

Effect on peroxidase activity and specific binding of the hormone 17 beta-oestradiol and rat salivary glands

The effect was studied on immature and adult female rats. Oestradiol, given either once (10 micrograms) or three times (3 X 10 micrograms) subcutaneously significantly retarded the total weight gain of immature rats whereas, at the same time, the weight of the uteri increased several fold. The weights of neither salivary nor lacrimal glands were dependent on oestradiol. The activity of the peroxidase enzyme, a marker of oestrogen-responsive tissues, increased significantly in the rat uteri but had no effect on lacrimal peroxidase. The levels of rat salivary peroxidase increased during oestradiol administration with considerable differences between various glands. The increase in peroxidase activities could not be explained by changes in the total protein content but seemed to be specific for this enzyme. Experiments using [3H]-oestradiol indicated specific binding to uterus, parotid and submandibular glands. It is concluded that rat salivary glands are oestrogen-responsive.     

Ultrastructural localization of salivary mucins MUC5B and MUC7 in human labial glands

Piras M, Hand AR, Tore G, Ledda GP, Piludu M. Ultrastructural localization of salivary mucins MUC5B and MUC7 in human labial glands. Eur J Oral Sci 2010; 118: 14–18. © 2010 The Authors. Journal compilation © 2010 Eur J Oral Sci
As a result of their presence throughout the mouth in the submucosa or between muscle fibers, minor salivary glands secrete directly and continuously into the oral cavity, providing mucosal surfaces with highly glycosylated proteins that are active in bacterial aggregation and in oral tissue lubrication. In this study, we investigated the ultrastructural localization of the MUC5B and MUC7 mucins in human labial glands by means of a postembedding immunogold technique. Thin sections of normal human labial glands, obtained during surgery, were incubated with polyclonal antibodies to human salivary mucins MUC5B and MUC7, and then with gold-labeled secondary antibodies. Specific MUC5B reactivity was found in the secretory granules of mucous cells of all glands examined, and was associated with the luminal membrane of duct cells. MUC7 labeling was observed in the granules of both mucous and seromucous secretory cells of the glandular parenchyma. Quantitative analyses demonstrated that seromucous granules have higher immunogold labeling densities for MUC7 than mucous granules. Our immunohistochemical data extend the results of previous light microscopic studies of MUC5B and MUC7 localizations, pointing out the significant contribution of human labial glands in the secretion process of these two mucins.