Heterogeneous radiotherapy dose-outcomes response in parotid glands

Neuropeptide Y in salivary glands of the rat: origin, release and secretory effects

The objective of this study is to investigate the functions of parotid and pancreatic glands in response to intoxication with parathion-methyl (PM) and the effects of treatment in rats. Seventy-five male Wistar rats were divided equally into five groups: Group I, control; group II, received atropine and pralidoxime (2-PAM) for 24 h, but no PM; group III, oral PM but no atropine and 2-PAM; group IV, PM and atropine for 24 h and 2-PAM; group V, PM and atropine for 96 h and 2-PAM. After the administration of the chemicals, blood samples were drawn to test for amylase, lipase, acetylcholinesterase (AChE), and butyrylcholinesterase (BChE), while pancreatic and parotid glands of each rat were removed for light microscopic examination. Amylase levels were found significantly elevated in groups II, III, IV, and V, whereas lipase levels were supranormal in groups III, IV, and V. The blood levels of AChE were decreased in groups III and IV and BChE were decreased in II, III, IV, and V. No evidence of pancreatitis and parotitis was identified in the histopathologic evaluation in any group in 96 h; however, hyperchromasia, irregularity in nuclei, and binuclear cells were observed in all parotid glands in group V. Parotitis and pancreatitis were not evident; however, hyperamylasemia and hyperlipasemia were found, whereas various histologic changes in parotid glands were documented in the groups that were administered organophosphate and treatment.

Effect of isoproterenol analogs on the polypeptide composition of mouse parotid glands: relationship to enhanced growth

The effects of clonidine and three 2-imidazoline derivatives on the secretion of protein and some electrolytes by rat submandibular and parotid glands

Radiation therapy for head and neck cancer frequently leads to salivary gland damage and subsequent xerostomia. The radiation response of the parotid glands of rats, mice, and patients critically depends on dose to parotid gland stem cells, mainly located in the gland's main ducts (stem cell rich [SCR] region). Therefore, this double-blind randomized controlled trial aimed to test the hypothesis that parotid gland stem cell sparing radiation therapy preserves parotid gland function better than currently used whole parotid gland sparing radiation therapy. Patients with head and neck cancer (n=102) treated with definitive radiation therapy were randomized between standard parotid-sparing and stem cell sparing (SCS) techniques. The primary endpoint was >75% reduction in parotid gland saliva production compared with pretreatment production (FLOW12M). Secondary endpoints were several aspects of xerostomia 12 months after treatment. Fifty-four patients were assigned to the standard arm and 48 to the SCS arm. Only dose to the SCR regions (contralateral 16 and 11 Gy [P=.004] and ipsilateral 26 and 16 Gy [P=.001] in the standard and SCS arm, respectively) and pretreatment patient-rated daytime xerostomia (35% and 13% [P=.01] in the standard and SCS arm, respectively) differed significantly between the arms. In the SCS arm, 1 patient (2.8%) experienced FLOW12M compared with 2 (4.9%) in the standard arm (P=1.00). However, a trend toward better relative parotid gland salivary function in favor of SCS radiation therapy was shown. Moreover, multivariable analysis showed that mean contralateral SCR region dose was the strongest dosimetric predictor for moderate-to-severe patient-rated daytime xerostomia and grade ≥2 physician-rated xerostomia, the latter including reported alteration in diet. No significantly better parotid function was observed in SCS radiation therapy. However, additional multivariable analysis showed that dose to the SCR region was more predictive of the development of parotid gland function-related xerostomia endpoints than dose to the entire parotid gland.

Electrical stimulation of the sympathetic innervation evoked secretion of submandibular and parotid saliva. By changing the mode of stimulation from a continuous to an intermittent one the fluid response increased and glandular blood flow improved. The volumes from the submandibular glands were larger than those from the parotid glands and further, the protein concentration of submandibular saliva was higher than that of parotid saliva. Adrenaline, isoprenaline and phenylephrine evoked larger fluid responses from submandibular than from parotid glands. However, the fluid response was small compared to the parasympathetic one. Substance P-evoked saliva was used as carrier for protein released by sympathetic nerve stimulation or administration of adrenaline and isoprenaline. In vitro tissues of submandibular and parotid glands responded to adrenaline with a dose-dependent release of protein. Taken together, the analytical pharmacology performed in vivo and in vitro, and including the antagonists phentolamine, dihydroergotamine, propranolol and metoprolol, showed that in submandibular glands, alpha(alpha 1)adrenoceptors were predominantly involved in fluid secretion and beta(beta 1)-adrenoceptors predominantly involved in protein secretion. In parotid glands, fluid secretion seemed solely to depend on alpha(alpha 1)-adrenoceptors, while beta(beta 1)-adrenoceptors seemed almost solely involved in protein secretion.

Nitric oxide has been implicated in mechanisms mediating nerve-evoked vasodilatory and secretory responses in salivary glands. In the present study, the occurrence and distribution of nitric oxide synthase (NOS)-immunoreactive nerves in ferret and rat salivary glands were investigated using immunocytochemistry with rabbit and sheep NOS antisera, and using NADPH-diaphorase enzyme histochemistry. In the parotid, submandibular and sublingual glands of the rat and the ferret, NOS-immunoreactive varicose terminals encircled acini and arteries of various sizes. In the ferret, collecting ducts were also supplied with NOS-immunoreactive fibres. In the rat, only the granular ducts of the submandibular gland were supplied with such fibres. The NOS-immunoreactive innervation of acinar cells was more abundant in the rat than in the ferret, whereas the opposite was true for the innervation of blood vessels. No NOS immunoreactivity was observed in the vascular endothelium. In both species, NOS-positive ganglionic cell bodies were found in the hilar regions of the submandibular and sublingual glands, whereas none could be detected in the parotid glands. NADPH-diaphorase reactivity had the same neuronal distribution as NOS immunoreactivity and, in addition, NADPH-diaphorase reactivity was expressed in ductal epithelium. Neither sympathetic denervation (by removal of the superior cervical ganglion) nor treatment with the sensory neurotoxin capsaicin reduced the NOS-immunoreactive innervation of the parotid gland. However, parasympathetic denervation (by cutting the auriculo-temporal nerve) caused an almost total disappearance of the NOS-immunoreactive innervation. The present findings provide a morphological background to the suggested role of nitric oxide in parasympathetic secretory and vascular responses of salivary glands.

1. Secretory responses of ferret parotid and submandibular glands were investigated in the presence of muscarinic, alpha- and beta-adrenoceptor blocking agents. 2. In pentobarbitone-anaesthetized animals I.V. doses of vasoactive intestinal peptide (VIP) failed to elicit overt secretion of saliva from either gland. 3. However, an occult secretion of protein occurred in response to VIP from both types of gland. This was revealed by means of a subsequent I.V. wash-out injection of substance P, which is a potent secretagogue in ferrets. This effect of VIP was much more marked in the submandibular than in the parotid gland. 4. Electrical stimulation of the chorda-lingual nerve gave rise to protein secretion in the submandibular gland at subthreshold frequencies for overt non-cholinergic, non-adrenergic secretion of saliva, as revealed by subsequent wash-out I.V. injection of substance P. 5. Protein secretion in response to VIP was also demonstrated in vitro by perifusing small pieces of the two glands. The sensitivity of submandibular tissue to VIP greatly exceeded that of the parotid tissue. 6. It is concluded that VIP, or a structurally related peptide, may be involved in the non-cholinergic, non-adrenergic secretory response of ferret salivary glands evoked by parasympathetic nerve stimulation.

11C-methionine PET, a novel method for measuring regional salivary gland function after radiotherapy of head and neck cancer

Response of rat salivary glands to mastication of pelleted vitamin A-deficient diet

Secretion of proteins by rat parotid glands in response to parasympathetic nerve stimulation was studied in vivo during pentobarbitone anaesthesia. Parasympathetic stimulation (3-10 Hz) via the auriculotemporal nerve resulted in a copious flow of saliva low in protein. In contrast, sympathetic stimulation (5 Hz) via the cervical sympathetic trunk evoked saliva low in volume but high in protein. Nevertheless, the specific concentrations of amylase and peroxidase (mg/mg protein) and the ratio of amylase to peroxidase remained constant. Sodium dodecyl sulphate (SDS) polyacrylamide gel electrophoresis revealed a single, rapidly migrating protein band of unknown identity in proportionately greater amounts in parasympathetic saliva than in sympathetic saliva. Bilateral adrenalectomy led to reduced amylase and peroxidase secretion in response to parasympathetic stimulation both on a mg/ml and a mg/mg protein basis. SDS gel electrophoresis also demonstrated the decrease in specific amylase concentration following adrenalectomy. The ratio of amylase to peroxidase, however, was not significantly affected. Administration of 6-hydroxydopamine 17-72 h prior to adrenalectomy caused no further reduction in the secretion of amylase and peroxidase. Chronic sympathectomy of 2.5-4 months duration resulted in an increased protein secretion (mg/ml) by the parotid gland in response to parasympathetic stimulation. This increase was only slightly reduced by bilateral adrenalectomy. However, as observed in non-sympathectomized rats, adrenalectomy caused a significant reduction in the specific concentrations of both amylase and peroxidase, but did not affect the amylase to peroxidase ratios. We conclude that parasympathetic nerve stimulation of rat parotid glands after overnight starvation causes secretion of proteins in proportions similar to, but in significantly lower concentrations than those found in sympathetic saliva. Circulating catecholamines, however, influence the amount of amylase and peroxidase secreted by the rat parotid gland in response to parasympathetic nerve stimulation and account for most of the increased secretion of these enzymes following chronic sympathectomy.

FDG-PET Assessment of the Effect of Head and Neck Radiotherapy on Parotid Gland Glucose Metabolism

The response of the major salivary glands, the parotid glands, to radiation dose is patient-specific. This study was designed to investigate whether parotid gland changes seen in weekly CT during treatment, quantified by delta-radiomics features (Δfeatures), could improve the prediction of moderate-to-severe xerostomia at 12 months after radiotherapy (Xer12m). Parotid gland Δfeatures were extracted from in total 68 planning and 340 weekly CTs, representing geometric, intensity and texture characteristics. Bootstrapped forward variable selection was performed to identify the best predictors of Xer12m. The predictive contribution of the resulting Δfeatures to a pre-treatment reference model, based on contralateral parotid gland mean dose and baseline xerostomia scores (Xerbaseline) only, was evaluated. Xer12m was reported by 26 (38%) of the 68 patients included. The most predictive Δfeature was the contralateral parotid gland surface change, which was significantly associated with Xer12m for all weeks (p < 0.04), but performed best for week 3 (ΔPG-surfacew3; p < 0.001). Moreover, ∆PG-surfacew3 showed a significant predictive contribution in addition to the pre-treatment reference model (likelihood-ratio test; p = 0.003), resulting in a significantly better model performance (AUCtrain = 0.92; AUCtest = 0.93) compared to that of the pre-treatment model (AUCtrain = 0.82; AUCtest = 0.82). These results suggest that mid-treatment parotid gland changes substantially improve the prediction of late radiation-induced xerostomia.

Calium, prostaglandins and the phosphatidylinositol effect in exocrine gland cells

Responses of salivary glands to intake of soft diet