Salivary Gland Ducts Research Articles

The Stem Cell Marker CD133 (Prominin-1) Is Expressed in Various Human Glandular Epithelia

Human prominin-1 (CD133) is expressed by various stem and progenitor cells originating from diverse sources. In addition to stem cells, its mouse ortholog is expressed in a broad range of adult epithelial cells, where it is selectively concentrated in their apical domain. The lack of detection of prominin-1 in adult human epithelia might be explained, at least in part, by the specificity of the widely used AC133 antibody, which recognizes an epitope that seems dependent on glycosylation. Here we decided to re-examine its expression in adult human tissues, particularly in glandular epithelia, using a novel monoclonal antibody (80B258) generated against the human prominin-1 polypeptide. In examined tissues, we observed 80B258 immunoreactivity at the apical or apicolateral membranes of polarized cells. For instance, we found expression in secretory serous and mucous cells as well as intercalated ducts of the large salivary and lacrimal glands. In sweat glands including the gland of Moll, 80B258 immunoreactivity was found in the secretory (eccrine and apocrine glands) and duct (eccrine glands) portion. In the liver, 80B258 immunoreactivity was identified in the canals of Hering, bile ductules, and small interlobular bile ducts. In the uterus, we detected 80B258 immunoreactivity in endometrial and cervical glands. Together these data show that the overall expression of human prominin-1 is beyond the rare primitive cells, and it seems to be a general marker of apical or apicolateral membrane of glandular epithelia. This manuscript contains online supplemental material at http://www.jhc.org. Please visit this article online to view these materials.

Optimal timing of MR sialography by use of a simple method of stimulating the salivary gland: a preliminary report

The present study was performed for determining the optimal timing of MR sialography by use of the Japanese pickled plum (umeboshi) for promoting secretion by the salivary glands. MR sialography was performed in four healthy male volunteers. The four volunteers were examined before and 10 min after stimulation with umeboshi. On the next examination, three volunteers were examined before and after umeboshi stimulation every 1 min up to 5 min to allow assessment of the temporal changes in duct visualization. Dilatation of the salivary gland ducts and improvement of the visualization of the ducts were obtained after stimulation with umeboshi. The difference in the dilatation of the parotid duct was statistically significant. In the temporal study, the salivary gland ducts were shown to be dilated at 2 min after stimulation. As a result, 2 min after stimulation is the optimal timing for MR sialography by use of umeboshi as a stimulator of salivary secretion.

Nephrology in Brief

The bone morphogenic protein (BMP) antagonist gremlin was highly expressed in the cellular and fibrocellular crescents of 30 renal biopsies of patients with pauciimmune glomerulonephritis—as well as in renal tubular and infiltrating interstitial cells. It correlated with tubulointerstitial fibrosis and co-localized with transforming growth factor beta (TGF-β), suggesting that it may be important in mediating some of its pathological effects (Nephrol Dial Transpl 22: 1882). Soluble F11 receptor (F11R) is elevated in dialysis patients and may be yet another marker of increased cardiovascular risk. It is a cell adhesion molecule expressed on the membrane surface of platelets and related to the murine protein present in the tight junctions of the vascular endothelium. In activated platelets F11R becomes phosphorylated and causes cell adhesion and aggregation—the initial step of thrombus formation in the pathogenesis of atherosclerotic plaques (J Invest Med 55:115). In order to study the mechanism of renal injury from light chains, cell cultures of human proximal cells were incubated with light chains derived from the urine of patients with multiple myeloma. This resulted in the cells producing hydrogen peroxide and monocyte chemo-attractant protein-1, both inherently nephrotoxic (J Am Soc Nephrol 18:1239). The use of estimated glomerular filtration rate (GFR) derived from the serum creatinine concentration is fraught with pitfalls. It tends to undererestimate renal function in persons with no known kidney disease and overestimate it in emaciated patients with low muscle mass and reduced creatinine production. Also problematic is its use in acute renal failure, where the change in serum creatinine is more important (BMJ 334:1198, Nephrol Dial Transplant 22:2391). Subjects in the Framingham study who had both microalbuminuria and reduced eGFR had worse cardiovascular outcomes than those with only one of these abnormalities (Arch Int Med 167:1386 2007). A study of type II diabetics with nephropathy found that simvastatin, unlike cholestyramine, appears to stabilize GFR, possibly by increasing messenger RNA expression of slit diaphragm associated proteins and reducing the albumin excretion rate (Kidney Int 70:177–186). The administration of iodine containing contrast media to a hemodialysis patient resulted in so-called iodine gout, an acute and dramatic swelling of the thyroid and salivary glands. This rare idiosyncratic complication may be related to toxic accumulation of iodide in the salivary gland ducts. The patient improved dramatically within 48 h of high-dose prednisolone therapy (Nephrol Dial Transpl 22: 1250)

Dynamic magnetic resonance sialography for patients with xerostomia

The aim was to evaluate the utility of dynamic magnetic resonance (MR) sialographic images as a diagnostic tool for patients with xerostomia as chief complaint. Various parameters of dynamic MR sialographic images from 40 healthy volunteers were compared with those from 28 patients having dry mouth as chief complaint. Dynamic MR sialographic images were acquired using a 1.5-T full-body MR system and 2-dimensional fast asymmetric spin-echo (2D-FASE) sequences. Acquisition of the optimal section using 2D-FASE sequencing with single-section acquisition of thick sections was repeated every 30 s before and after a few drops of 5% citric acid was placed on the tongue. Student t test was used to examine differences between the healthy volunteer and patient groups regarding the maximum area of salivary gland ducts before and after citric acid stimulation. The maximum area of the detectable ducts in the patient group was significantly smaller (P < 0.001), whereas the change in detectable duct area was significantly lower (P < 0.001). This study suggests that dynamic MR sialographic images and data can be useful in the diagnosis of patients with dry mouth as chief complaint.

Kyste parotidien rétentionnel révélateur d’un carcinome mucoépidermoïde

Objectives To describe a case of mucoepidermoid carcinoma of the parotid gland that caused obstruction of a salivary gland duct and manifested as a parotid retention cyst. Patient and methods A 21-year-old woman presented with a 5-cm cystic swelling in her left parotid region. Ultrasound examination and a computerized tomography scan showed a clearly outlined parotid cyst. Through a conventional parotidectomy incision, the cyst was excised with parotid gland tissue around the lesion. The patient had an uncomplicated recovery. Results Histopathological examination of the resected parotidectomy material showed a parotid retention cyst and a mucoepidermoid carcinoma measuring 5 mm in diameter. Conclusion Among acquired cysts of the parotid gland, retention cysts are the most frequent. They may be the presenting symptom in patients with occult cancer of the parotid. In this case report, a mucoepidermoid carcinoma played a significant role in the obstruction of a salivary gland duct and caused a parotid retention cyst. Thus, a wide excision of the parotid retention cyst is necessary, as is a careful review of the histology searching for malignant lesion.

Rescue of Salivary Gland Function after Stem Cell Transplantation in Irradiated Glands

Head and neck cancer is the fifth most common malignancy and accounts for 3% of all new cancer cases each year. Despite relatively high survival rates, the quality of life of these patients is severely compromised because of radiation-induced impairment of salivary gland function and consequential xerostomia (dry mouth syndrome). In this study, a clinically applicable method for the restoration of radiation-impaired salivary gland function using salivary gland stem cell transplantation was developed. Salivary gland cells were isolated from murine submandibular glands and cultured in vitro as salispheres, which contained cells expressing the stem cell markers Sca-1, c-Kit and Musashi-1. In vitro, the cells differentiated into salivary gland duct cells and mucin and amylase producing acinar cells. Stem cell enrichment was performed by flow cytrometric selection using c-Kit as a marker. In vitro, the cells differentiated into amylase producing acinar cells. In vivo, intra-glandular transplantation of a small number of c-Kit+ cells resulted in long-term restoration of salivary gland morphology and function. Moreover, donor-derived stem cells could be isolated from primary recipients, cultured as secondary spheres and after re-transplantation ameliorate radiation damage. Our approach is the first proof for the potential use of stem cell transplantation to functionally rescue salivary gland deficiency.

MR sialography: the effect of a sialogogue and ductal occlusion in volunteers

MR sialography using heavily T(2) weighted projection techniques relies upon saliva for image contrast, and the visualization of normal ducts is often limited. Methods used to increase the volume of intraductal saliva during imaging in order to improve duct visualization have not been previously evaluated. The effect of a sialogogue and passive ductal occlusion on the ability to visualize the main and intraglandular salivary gland ducts during MR sialography was investigated. Three-dimensional (3D) T(2) weighted MR sialograms were obtained from 12 healthy volunteers with and without the combined use of a sialogogue and passive ductal occlusion pad adjacent to the parotid duct orifice on one side. Two radiologists (in consensus) subjectively evaluated ductal visualization and image artefacts on the resulting blinded maximum intensity projections. The results demonstrate that main duct visualization was significantly improved (p<0.00001) by this technique, with no significant change seen in image artefacts. Although an improvement in intraglandular duct visualization was noted, this was not statistically significant (p = 0.05). Thus, the use of a sialogogue and passive ductal occlusion improves visualization of the main parotid duct in volunteers undergoing MR sialography. Further optimization and evaluation of this approach should lead to improvements in the MR sialography examination of patients.

Ascl3 expression marks a progenitor population of both acinar and ductal cells in mouse salivary glands

Ascl3, also know as Sgn1, is a member of the mammalian achaete scute ( Mash) gene family of transcription factors, which have been implicated in cell fate specification and differentiation. In the mouse salivary gland, expression of Ascl3 is restricted to a subset of duct cells. Salivary gland function depends on the secretory acinar cells, which are responsible for saliva formation, and duct cells, which modify the saliva and conduct it to the oral cavity. The salivary gland ducts are also the putative site of progenitor cells in the adult gland. Using a Cre recombinase-mediated reporter system, we followed the fate of Ascl3-expressing cells after the introduction of an EGFP–Cre expression cassette into the Ascl3 locus by homologous recombination. Lineage tracing shows that these cells are progenitors of both acinar and ductal cell types in all three major salivary glands. In the differentiated progeny, expression of Ascl3 is down-regulated. These data directly demonstrate a progenitor–progeny relationship between duct cells and the acinar cell compartment, and identify a population of multipotent progenitor cells, marked by expression of Ascl3, which is capable of generating both gland cell types. We conclude that Ascl3-expressing cells contribute to the maintenance of the adult salivary glands.

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.

Protein expression and distribution of murine calcium‐activated chloride channels 1 and 2 (mCLCA1/2) in epithelia of the gastrointestinal (GI) tract and kidney (Ki)

Calcium‐activated chloride channels (CLCA) have been implicated as anion channels, channel regulators and cystic fibrosis phenotype modulators, but their function remains unclear. We generated a polyclonal antibody (pAb 849) against a peptide that is common to mCLCA1/2, has ~70% aa identity with mCLCA3/4, but none with mCLCA5/6. pAb 849 detected mCLCA1 expressed in HEK293 by immunoblotting (IB) and immunoprecipitation, where 125 and 90 kDa bands suggest posttranslational modification. Flag‐tagging of mCLCA1 yielded only a 130 kDa band. pAb 849 cross‐reacted with mCLCA3 in IB with bands at 120, 100 and 75 kDa. Using immunohistochemistry and comparison with mCLCA3 (pAb p3a), mCLCA1/2 specific labelling was found in pancreas acini (apical (AP), zymogen granules (ZG)), but not in ducts. pAb 849 IB of ZG membranes yielded a 130 kDa band. Specific signals were also seen in small ducts of seromucous salivary glands (AP, intracellular (IC)) but not in excretory ducts or acini. Stomach parietal (AP, IC) and jejunal crypt cells (AP) were specifically labelled. Signals in stomach mucous and jejunal goblet cells may be due to mCLCA3 cross‐reactivity. Only AP areas of Ki distal tubules were stained. mCLCA1/2 positive tissues do not express mCLCA4, therefore the data indicate mCLCA1/2 expression in AP membranes of GI and Ki and ZG membranes, but a function as secretory proteins cannot be excluded.Funding: German CFF F04/04

Obestatin is present in saliva: alterations in obestatin and ghrelin levels of saliva and serum in ischemic heart disease

Ghrelin and obestatin are a single gene products and are a multiple functional peptides that regulates energy homeostasis, and food intake. In the present work, we studied the secretion of ghrelin and its co-secreted peptide obestatin in 44 patients with ischemic heart disease with that of 27 healthy matched controls. Here we first conducted using an immunohistochemistry assay to screen whether human salivary glands have any obestatin immunoreactivity. Then, serum and saliva obestatin and acylated ghrelin levels were determined by using Radioimmunoassay. Our immunohistochemical analysis demonstrated that obestatin was localized in the striated and excretory duct of human salivary gland. We also report for the first time that obestatin, like ghrelin, is present in human salivary gland and saliva. No evidence of the role of obestatin or ghrelin saliva levels in the context of ischemic heart disease was found. Salivary ghrelin and obestatin levels are correlated in controls with the blood levels. Determination of salivary values could represent a non-invasive alternative to serum ones that can be useful in clinical practice.

Histopathological variation of primary mucosa-associated lymphoid tissue lymphoma of the oral cavity

Primary mucosa-associated lymphoid tissue (MALT) type lymphoma arising in the oral cavity is rare. We examined histopathologic, immunohistological and genotypic findings of seven cases of intraoral MALT lymphoma using formalin-fixed paraffin-embedded tissues. Histologically, two variants have been delineated. (i) In four cases of minor salivary gland type, the lymphoid follicles were surrounded by centrocyte-like (CCL) cells with occasional follicular colonization. The CCL cells invaded the residual salivary gland duct resulting in a lymphoepithelial lesion. CCL cells frequently showed plasmacytic differentiation. (ii) In three cases of follicular growth type, the lesion was characterized by follicular growth pattern resulting from prominent follicular colonization. CCL cells showed minimal plasma cell differentiation. There was no residual epithelial component detected even by cytokeratin immunostaining. There were no Epstein-Barr virus-encoded small RNA-positive cells detected by in situ hybridization. API2-MALT1 fusion transcript does not appear to be associated with either histological variant of primary intraoral MALT lymphoma.

Obstructive pathologies of salivary glands—a clinical challenge

The ducts of salivary glands primarily serve to transport and subsequently evacuate the saliva secreted by the salivary glands. The salivary gland duct is considered to be a complex anatomical entity. It transports serous, mucous or mixed type of saliva through its tortuous course. Parotid gland's Stenson's duct, submandibular gland's Wharton's duct, sublingual gland's ducts of Bartholin's and revenus. Out of these the Wharton's duct has the highest incidence of obstruction due to anatomical factors like a tortuous course, flow of mixed type of saliva against gravity for a short distance of 3–3.5 cm. Also the parotid duct is commonly severed in ablative surgeries of the head and neck malignancies. The aetiology, diagnosis and surgical management of these pathologies has always been a controversial and challenging situation. The present paper will discuss these issues and concentrate on the surgical management of ductal pathologies in varied clinical presentations.

Adaptive redistribution of NBCe1-A and NBCe1-B in rat kidney proximal tubule and striated ducts of salivary glands during acid-base disturbances

The cellular distribution of the NH2-terminal electrogenic Na+-HCO3(-) cotransporter (NBCe1) variants NBCe1-A and NBCe1-B has been investigated in rat kidney and submandibular gland (SMG) under physiological conditions and after systemic acid-base perturbations. Moreover, the in vivo data were complemented in vitro by using an immortalized cell line derived from the S1 segment of the proximal tubule (PT) of normotensive Wistar-Kyoto rats (WKPT-0293 Cl.2). NBCe1-A was basolaterally localized in PT cells, whereas NBCe1-B exhibited intracellular and basolateral distribution. SMG showed transcript and protein expression for NBCe1-A and NBCe1-B. NBCe1-B was basolaterally localized in duct cells; NBCe1-A was found intracellularly in salivary striated ducts and apically in main duct cells. Acute metabolic acidosis significantly increased cells that showed basolateral NBCe1-A in the PT, indicating increased HCO3(-) reabsorption, and significantly decreased cells that exhibited basolateral NBCe1-B in the salivary ducts, suggesting decreased HCO3(-) secretion. Chronic acidosis had no effect on NBCe1 distribution in PT but significantly increased the percentage of cells with basolateral NBCe1-A in salivary striated duct cells, suggesting increased HCO3(-) reabsorption. In contrast, chronic alkalosis caused adaptive redistribution of NBCe1-A and NBCe1-B in renal PT, favoring decreased HCO3(-) reabsorption. In vitro, WKPT-0293 Cl.2 cells expressed key acid-base transporters. Extracellular alkalosis downregulated NBCe1-A protein. WKPT-0293 Cl.2 cells are therefore a useful model to study renal acid-base regulation in vitro. The results propose redistribution of the transporters as a potential posttranslational regulation modus during acid-base disturbances. Moreover, the data demonstrate that renal PT and salivary duct epithelia respond to acid-base disturbances by an opposite redistribution pattern for NBCe1-A and NBCe1-B, reflecting specialized functions as the HCO3(-)-reabsorbing and HCO3(-)-secreting epithelium, respectively.

Gene Expression of Secretory Carbonic Anhydrase Isozymes in Striated Ducts of Canine Salivary Glands Using Laser Microdissection System

To clarify whether striated duct cells in canine salivary glands synthesize secretory carbonic anhydrase (CA-VI), as is the case with serous acinar cells, the present study utilized laser microdissection to harvest striated duct cells from canine parotid and submandibular glands, and total RNA extracted from these cells was then amplified by reverse transcription-polymerase chain reaction to assess CA-VI gene expression. The results confirmed the local expression of CA-VI mRNA in striated duct cells. This clarified that, in canine salivary glands, CA-VI is synthesized in not only serous acinar cells, but also striated duct cells.

Intraductal Papilloma of the Buccal Mucosa Salivary Gland

Salivary gland papillomas are rare tumours arising from the ductal epithelium. Intraductal papillomas, the most rare of all ductal papillomas, have been reported to occur almost exclusively in the excretory ducts of the minor salivary glands. An intraductal papilloma of the left buccal mucosa in a 51-year-old man is reported. Histology of resected tumour revealed that the duct had dilated to form a thickwalled cyst that contained the papillary tumour with intracystic endoluminal proliferation. No signs of recurrence were evident 8 months after surgery.

Systemic extrapancreatic lesions associated with autoimmune pancreatitis

Autoimmune pancreatitis (AIP) is frequently associated with sclerosing cholangitis (SC). SC with AIP has a cholangiographic appearance that is often confused with primary sclerosing cholangitis (PSC) but only the former responds well to corticosteroid therapy. Detailed study of cholangiographic findings allows discrimination of SC with AIP from PSC. Band-like strictures, a beaded or pruned-tree appearance, and diverticulum-like outpouching were significantly more frequently observed in cases of PSC. In contrast, segmental strictures, dilation after confluent stricture, and strictures of the lower common bile duct were significantly more common in SC with AIP. The other systemic extrapancreatic lesions associated with AIP found in the literature were Sjögren's syndrome, ulcerative colitis, retroperitoneal fibrosis, sialadenitis, thyroiditis, and idiopathic thrombocytopenic purpura. In a comparison of the clinical course and laboratory data of our cases, gamma-globulin, IgG, and IgG4 levels were significantly higher in patients with AIP with systemic extrapancreatic lesions than those without them. In our immunohistochemical study, marked infiltration of IgG4+ plasma cells was frequently observed in the pancreas, liver, bile duct, and salivary glands of the AIP patients examined. In contrast, the degree of infiltration of IgG4+ plasma cells around the bile duct in the portal areas and the extrahepatic bile duct with PSC was significantly lower than with AIP. These results also suggest that AIP is a disease state clearly different from PSC. In addition, the normal epithelia of the pancreatic ducts, bile ducts, gallbladder, and salivary gland ducts reacting with the patients' sera was detectable by the anti-IgG4 antibody. Therefore, AIP may also affect extrapancreatic organs, and the sera of AIP patients may contain an IgG4 autoantibody to various organs.

Sialoendoscopy and Sialography: Strategies for Assessment and Treatment of Salivary Gland Obstructions

Obstruction of salivary glands is a rather common problem in which patients usually suffer from swelling and tenderness of the involved salivary gland and altered salivary flow from the duct orifice. Surgical procedures have been carried out in the past to treat such problems; however, they were indicated only for obstructions in the anterior portion of the salivary gland duct (anterior to the first molar in the Wharton’s duct and anterior to the Masseter muscle in the Stensen’s duct).

MR-Sialographie: Prospektive Evaluation ultraschneller Sequenzen mit paralleler Bildgebung und oraler Stimulation bei Patienten

To evaluate an ultra-fast sequence for MR sialography requiring no post-processing and to compare the acquisition technique regarding the effect of oral stimulation with a parallel acquisition technique in patients with salivary gland diseases. 128 patients with salivary gland disease were prospectively examined using a 1.5-T superconducting system with a 30 mT/m maximum gradient capability and a maximum slew rate of 125 mT/m/sec. A single-shot turbo-spin-echo sequence (ss-TSE) with an acquisition time of 2.8 sec was used in transverse and oblique sagittal orientation. All images were obtained with and without a parallel imaging technique. The evaluation of the ductal system of the parotid and submandibular gland was performed using a visual scale of 1-5 for each side. The images were assessed by two independent experienced radiologists. An ANOVA with post-hoc comparisons and an overall two tailed significance level of p = 0.05 was used for the statistical evaluation. An intraclass correlation was computed to evaluate interobserver variability and a correlation of > 0.8 was determined, thereby indicating a high correlation. Depending on the diagnosed diseases and the absence of abruption of the ducts, all parts of excretory ducts were able to be visualized in all patients using the developed technique with an overall rating for all ducts of 2.70 (SD +/- 0.89). A high correlation was achieved between the two observers with an intraclass correlation of 0.73. Oral application of a sialogogum improved the visibility of excretory ducts significantly (p < 0.001). In contrast, the use of a parallel imaging technique led to a significant decrease in image quality (p = 0,011). The applied ss-TSE for MR sialography allows fast and sufficient visualization of the excretory ducts of the main salivary glands in patients, and no elaborate post-processing is required. Use of an oral sialogogum is suggested to improve the results of MR sialography.

Mucocele: Two Case Reports

ABSTRACT The Mucocele or Mucus retention phenomenon is a salivary gland lesion of traumatic origin, formed when the main duct of a minor salivary gland is torn with subsequent extravasation of the mucus into the fibrous connective tissue so that a cyst like cavity is produced. The wall of this cavity is formed by compressed bundles of collagen fibrils and it is filled with mucin. Mucoceles are known to occur most commonly on the lower lip, followed by the floor of mouth and buccal mucosa being the next most frequent sites. This paper reviews the Mucocele and presents two case reports.