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The Authors report their experience in the surgical treatment of submandibular sialolithiasis, particularly as far as simple sialolithotomy of Wharton's duct and submandibular gland resection are concerned. Care must be taken to minimize the risk of nerve damage (marginal mandibular branch of the facial nerve; lingual nerve; hypoglossal nerve).
OBJECTIVE: To investigate the role of transforming growth factor beta3 (TGF-beta3) on the amylase secretion of rat submandibular gland cells (RSGCs). METHODS: The RSGCs were cultured and identified. The expressions of CK 8.13, S-100 and Vimentin in the RSGCs were examined by immunohistochemical staining. The experimental group was divided into 5 groups according to different concentrations of TGF-beta3 (0.5, 1.0, 5.0, 10.0 and 25.0 ng/ml) and no TGF-beta3 culture was used as control group. The effects of TGF-beta3 on the cell proliferation and amylase secretion were examined at the 24th, the 48th, the 72nd and the 96th hour. MTT colorimetric method was used to estimate vital force of culture cells. Amylase protein was assayed by auto-biochemistry equipment and Western blotting. RESULTS: The RSGCs were stained positively for CK 8.13 and S-100, but negatively for Vimentin. There were no significant differences in absorbency between the experimental groups and the control group (P>0.05). Compared with the control group, TGF-beta3 at concentrations of 0. 5-10. 0 ng/ml significantly stimulated the amylase secretion of RSGCs after 72 and 96 hours (P<0.01). But high concentration of TGF-beta3 (25.0 ng/ml) showed no stimulation. Western blotting demonstrated that the cultured RSGCs and submandibular gland had the same band of amylase electrophoresis. CONCLUSION: TGF-beta3 can stimulate RSGCs to differentiate and to secrete amylase, but TGF-beta3 has no effect on proliferation of RSGCs.
Mammalian salivary glands are known to produce a number of biologically active peptides. The aim of this study was to extend our previous results showing the presence of a biologically active insulin-like immunoreactive peptide in rat salivary glands. In rodents, where two nonallelic and functional insulin genes are expressed, the co-expression of both genes seems to be limited to beta-cells of pancreatic islets or to embryologic developmental processes. We have investigated the expression of insulin genes in rat submandibular glands and in a murine immortalized submandibular cell line, SCA-9. For this purpose, total RNAs were isolated and submitted to reverse transcription. The cDNAs obtained were amplified by a nested polymerase chain reaction using rat preproinsulin I and II primers. Our data show that both preproinsulin I and II mRNAs are expressed in adult rat submandibular glands as well as in the SCA-9 cell line. The identification of salivary gland rat preproinsulin I and II was confirmed by direct sequencing. These results provide, for the first time, evidence for the expression of both preproinsulin I and II mRNA in an extra-pancreatic tissue from adult rodents.
Two cases of chronic sialadenitis of the submandibular gland (so-called Küttner tumor) are reported. Clinically, they are asymptomatic except for firm swellings which are similar to neoplasms. Light microscopic observations revealed that the lesion is characterized by various degrees of atrophy and/or destruction of acini, infiltration of inflammatory cells, periductal fibrosis and lymph follicle formation. With the electron microscope, a marked increase of collagen fibers are observed throughout the gland parenchyma, and the secretory granules of acinal cells in the remaining acini remarkably decreased in number. We suggest that an autoimmune mechanism may play a role in case 1 and that an ascending infection through the duct system may be a main factor in case 2.
The effects of different doses of p-tyramine injected i.v. and i.p. on salivary flow rates and proteins secreted by the submandibular glands of rats were studied with and without various types of autonomic blockers and two enzyme inhibitors. The salivary flow rates and the amounts of protein secreted progressively increased with increasing doses injected both i.v. and i.p., whereas they were dramatically reduced with all autonomic blockers except the lowest doses of beta-blockers, atropine, and yohimbine. Salivation in response to p-tyramine injected i.v. and i.p. was completely abolished by simultaneous injections of both prazosin and propranolol. The concentration of protein was not dose-dependent and was not reduced by yohimbine and phenoxybenzamine at almost all doses used. However, prazosin significantly increased the protein concentration. Protease activities were dose-dependent but were significantly reduced with alpha-blockers other than yohimbine, and with most beta-blockers. The proteins secreted in response to p-tyramine at all doses injected i.v. and i.p. were of the alpha-type except with the lowest dose injected i.p. However, the alpha-type was completely replaced by the beta-type in the presence of all alpha-blockers except yohimbine, but not with beta-blockers, atropine, or two enzyme inhibitors. Pargyline, a monoamine-oxidase inhibitor, but not disulfiram, a dopamine-beta-hydroxylase inhibitor, affected all parameters except the type of protein. Thus, p-tyramine may activate both the alpha 1- and beta 1-adrenoceptors in the submandibular glands of rats directly or indirectly.
Previously, administration of VIP has been shown to elicit no flow of saliva from the submandibular gland of the dog. However, in the present study we found VIP to cause release of protein in vitro from canine submandibular gland tissue. Furthermore, VIP-containing nerve fibres were demonstrated in large numbers in association with acini. Thus, VIP may be involved in the nervous regulation of salivary protein secretion in the dog.
Expression of SMR2, a member of the gene family encoding salivary glutamine/glutamic acid-rich proteins, is regulated by androgens in rat submandibular gland acinar cells. To further characterize SMR2 regulation, we analyzed SMR2 expression during submandibular gland postnatal development and rat puberty at both a global and a single-cell level. Using in situ detection of mature and primary SMR2 transcripts, we show that SMR2 expression is heterogeneous among acinar cells. However, only one cell population with various amounts of mRNAs can be defined. The number of high-expressing cells increases in males during puberty and in females up to 6 weeks of age, suggesting that some factor in addition to acinar differentiation might be important for SMR2 expression in female rats. Involvement of the beta-adrenergic system in regulating SMR2 expression was tested in rats exposed daily to isoproterenol for 4 days. Under these conditions we found an increase in SMR2 expression in female rats, associated with an increase in SMR2 mRNA levels in most acinar cells. This suggests that a signaling cascade, elicited by beta-adrenergic stimuli, might act in concert with androgens to regulate SMR2 expression.
We studied the involvement of the apoptotic mechanism(s) in cell differentiation in the developing male rat submandibular gland using the TUNEL (terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick-labeling) assay in combination with light and electron microscopy. Whereas the proacinar cells were completely transformed into acinar cells within 2 weeks after birth, starting on postnatal Day 21, the terminal tubule cells formed vacuoles that disappeared by postnatal Day 35. During this period, positive TUNEL reactivity was seen in the terminal tubule cells, and electron microscopic analysis showed that certain morphological features of apoptosis, including fragmentation of nuclei and the presence of apoptotic bodies in the cytoplasm, were present in and restricted to the terminal tubule cells. These results indicate that, in addition to an autophagocytosis-mediated mechanism, apoptosis may also be involved in reducing the number of terminal tubule cells during postnatal development in the submandibular gland.
p-Nitrophenyl phosphatase (p-NPPase) activity of (Na+-K+)-activated adenosine triphosphatase ((Na+-K+)-ATPase) on the acinar cells of dog submandibular gland was demonstrated by using light microscopy. The reaction products of p-NPPase of fresh frozen sections were seen to be localized on the basal parts of acini, and disappeared when the sections were incubated in medium containing 10(-3) Mouabain or in a K-free medium. Under the electron microscope, the reaction products of ATPase were found to be localized on the basolateral plasma membrane of both serous and mucous cells. On the microvilli of the luminal plasma membrane of the acinar cell, a small quantity of the reaction products was also present. This localization of ATPase reaction products on the serous and mucous cells seemed to coincide well with that of p-NPPase activity observed on the acini under light microscopy. Possible explanations are given regarding distribution of the above mentioned enzymes in relation to the cation transport of the plasma membrane. Structural and functional asymmetrical properties of acinar cells of the dog submandibular gland are also discussed.
We report a case of a 57-year-old man who developed a fibrosclerosing lesion in the submandibular gland and idiopathic retroperitoneal fibrosis (IRF) involving the unilateral periureteral region within a year. Both lesions were resected surgically because of the suspicion of neoplasm. Pathologic examination revealed similar histologic and immunohistochemical features for both lesions, namely, fibrosclerosis with prominent hyalinizing collagen bundles and proliferation of myofibroblastic cells, and a non-neoplastic reactive nature. There was infiltration by lymphocytes with prominent lymph follicles, plasma cells and macrophages. The histologic and immunohistochemical findings suggest that the two lesions were of a similar pathogenesis, which was possibly mediated by macrophages. We think that the present case may be an unusual form of multifocal fibrosclerosis. Although sialolithiasis is thought to be a major pathogenic factor for chronic sclerosing sialadenitis of the submandibular gland, the present case suggests that certain cases might have an etiology similar to IRF.
The effects of altered thyroid function on the sensitivity of isoproterenol induced secretion of saliva and in the characteristics of adrenergic receptors from the rat submandibular gland were examined. Hyperthyroidism produced an increased sensitivity to beta-adrenergic stimulation of the gland, and this phenomenon was associated with an increase in the number of beta and alpha 1-adrenoceptors. On the other hand, surgical thyroidectomy produced a decrease sensitivity to isoproterenol stimulation of the submandibular gland and a diminished density of beta-adrenoceptors. In this case, no changes in alpha-adrenoceptors were observed. These results are discussed emphasizing the correlation between the functional control of saliva secretion and the adrenergic receptors in different thyroid states.
The effects of the undecapeptide, substance P(SP), on the secretion of mucin and proteolytic enzymes from dispersed cells of the rat submandibular gland were studied. The peptide, at a concentration of 1 X 10(-7) M, stimulated the release of 31.9 +/- 3.0% (mean +/- SEM) of intracellular mucin over 40 min, compared with 12.5 +/- 1.5% in untreated controls (p less than 0.01). This effect was duplicated by the homologous peptides, physalaemin, and eledoisin-related peptide. Substance P action was not affected by pre-incubation of cells with phentolamine or propranolol and was therefore independent of adrenergic stimulation. Furthermore, SP did not enhance the intracellular concentrations of cyclic AMP or cyclic GMP, confirming that cyclic nucleotides were not involved in its stimulus-secretion coupling mechanism. The isoproterenol-stimulated secretion of mucin from dispersed cells was reduced to 75.7% of the normal response (p less than 0.01) after a brief exposure to SP. This inhibitory effect was probably mediated by intracellular events rather than by direct effects on cell surface receptors. However, mucin release after treatment with SP followed by norepinephrine (NE) was 161% of that caused by NE alone (p less than 0.01) and may reflect an additive response to the independent stimulation of SP and NE receptors. Substance P and related peptides had no effect on arginine esterase secretion in the experimental model, although a response was elicited by alpha- and beta-adrenergic agonists. It is, therefore, proposed that serous cells of the granular convoluted tubule in the rat submandibular gland lack substance P receptors.
Ouabain (10(-3) M) caused a 95.8% reduction in the volume of saliva secreted during a 60-min period by the isolated, perfused submandibular gland of the rat exposed to acetylcholine (10(-6) M) and modified salivary cation (Na and K) concentrations but not salivary Cl concentrations. Furosemide (10(-3) M) caused a 74.9% reduction in saliva volume and significantly reduced salivary Cl concentrations but did not modify salivary Na or K. Ethacrynic acid (10(-4) M) resulted in a 58.6% reduction in saliva volume, increased salivary Na and Cl concentrations, and reduced salivary K+ concentrations at low rates of flow. The results suggest that an ouabain-sensitive Na+-K+-ATPase and a furosemide-sensitive NaCl cotransport system contribute to acetylcholine-induced fluid secretion in the rat submandibular gland. The Na+-K+-ATPase probably provides the energy or driving force for the NaCl cotransport system by maintaining a Na+ gradient in the salivary cells. The lesser effect of ethacrynic acid on saliva volumes may result from a quantitatively smaller action on the same NaCl cotransport affected by furosemide. An ouabain-sensitive pump present in salivary ducts regulates transductal transport of Na and K.
We examined long-term effects of neonatal hyperthyroidism in female mice by measuring the epidermal growth factor levels in the submandibular gland, urine, and serum at the age of 31 days. Hyperthyroxinemia was induced by thyroxine injections (0.4 microgram/g/day) on days 0-6. Littermate controls received the alkaline saline vehicle. The treatment accelerated incisor eruption and eyelid opening. It also retarded growth. The elevation of plasma thyroxine concentration which normally occurs during wk 2 to reach a peak around day 15 was abolished. Submandibular gland epidermal growth factor levels on day 31 were markedly subnormal, indicating maturational delay. In contrast, epidermal growth factor levels were unaffected in urine and supranormal in serum. These differences in response suggest that the regulatory mechanisms governing epidermal growth factor levels in tissues and fluids may acquire thyroid hormone dependence at different stages.
Three types of cells - terminal tubule cells, proacinar cells and acinar cells - have been observed during the development of acini in the rat submandibular gland. The terminal tubules are lined by terminal tubule cells which show PAS-positive, dark granules. From the terminal tubules pouches develop which are lined by similar cells to those lining the terminal tubules. These pouches give rise to the next generation of terminal tubules. The last generation of terminal tubules, whose cells lose their dark, PAS-positive granules, develop into secondary tubules lined by proacinar cells. At 14 days of age large coarse granules appear in the cytoplasm of the proacinar cells lining the secondary tubules as well as in the cells of intercalated ducts. These granules are discharged into the lumen of the tubule and the proacinar cells become foamy-looking acinar cells, while the secondary tubule becomes an acinus. Thus the terminal tubule cells give rise to proacinar cells which become acinar cells and cells to the intercalated duct cells. The development of acini in the rat submandibular gland thus takes place in three stages: (1) development of terminal tubules by continuing pouch formation up to 12 days of age, (2) conversion of terminal tubules into secondary tubules tined by proacinar cells from 6 to 12 days of age, and (3) development of large coarse granules in proacinar cells and their excretion into the lumen of tubules, resulting in the transformation of proacinar cells into acinar cells between 14 and 21 days.
Case report of a 42 year old female, who received 14th-20th year of life six radioiodine therapies with altogether 19.2 GBq131I because of a papillary thyroid carcinoma. 17 years after the last therapy, she developed a histologically proven chronic radiogenic sialadenitis of the left submandibular gland. Further four years later, the right submandibular gland has been extirpated because of a mucoepidermoid carcinoma with infiltration of a regionary lymphatic node. Review of the previous published secondary-malignancies of the salivary glands after high-dose radioiodine therapies.
The existence of ryanodine-sensitive Ca2+ stores and their role in the Ca2+ entry mechanism were examined in the rat submandibular gland acinar cells, using the microfluorimetry of intracellular Ca2+ concentration ([Ca2+]i). In the presence of thapsigargin, a Ca(2+)-ATPase inhibitor of inositol (1, 4, 5) triphosphate (InsP3)-sensitive Ca2+ stores, caffeine caused an increase in [Ca2+]i, which was inhibited by treatment with ryanodine (a ligand to the Ca(2+)-induced Ca2+ release channels). In the cells treated with ryanodine, 1 mM Ca2+ addition to a Ca(2+)-free solution caused a marked increase in [Ca2+]i, which was eliminated by application of Ni2+ or SK & F 96365, suggesting a Ca2+ entry triggered by ryanodine. The maximal change in the net increase in [Ca2+]i caused by the ryanodine-coupled Ca2+ entry, was 104.0 +/- 16.0 nM, which intense was caused by 10 microM ryanodine. Emptying the InsP3-sensitive stores by treatment with thapsigargin also caused Ca2+ entry, which maximally changed [Ca2+]i by 349.6 +/- 15.1 nM. Ten mumol/liter ryanodine was confirmed to cause a release of 45Ca2+ from the parotidic microsomal fraction enriched in endopalsmic reticulum. We propose that ryanodine-sensitive Ca2+ stores are present in rat submandibular gland acinar cells. We further propose that release of Ca2+ from the ryanodine-sensitive stores, which means eventually depletion of the ryanodine-sensitive Ca2+ stores, can activate the Ca2+ entry. The ability for Ca2+ entry coupled with the ryanodine-sensitive Ca2+ stores seems to be about 30% of the ability for Ca2+ entry coupled with the thapsigargin-sensitive Ca2+ stores.
The actions of dobutamine (DOB) and terbutaline (TER) on the secretion of marker glycoprotein (GP) from the secretory cells of the glands and secretion of fluid from rat submandibular gland (SMG) were investigated in combination with two antagonists, metoprolol (MET) and ICI-118551 (ICI). The ED50 value of fluid secretion was 8.7 mg/kg for DOB and 5.9 mg/kg for TER. MET, administered prior to either agonists at a dose of 40 mg/kg, inhibited the fluid secretion. However, the blocking effects of ICI were considerably lower than those of MET. The electrophoretic profiles of GP in DOB-evoked saliva were similar to those in TER-evoked saliva, and included two characteristic main bands of GP I (130 KDa) and GP IV (21.5 KDa) from the acinar cells and a minor band of GP III (31 KDa) which originated in the cells of the granular tubules. When MET was administered at a dose of 5 mg/kg prior to DOB, the intensity of band I decreased, whereas that of band III did not change. These results showed that the SMG of rats contains both beta 1- and beta 2-adrenoceptors and that beta-receptors which mediate the secretion of GP from the acinus and fluid from the gland are mainly of the beta 1-subtype.