vasoactive-intestinal-peptide and Sjogren-s-Syndrome

The neuroendocrine and immune systems are coordinated to maintain the homeostasis of the organism, generating bidirectional communication through shared mediators and receptors. Vasoactive intestinal peptide (VIP) is the paradigm of an endogenous neuropeptide produced by neurons and endocrine and immune cells, involved in the control of both innate and adaptive immune responses. Exogenous administration of VIP exerts therapeutic effects in models of autoimmune/inflammatory diseases mediated by G-protein-coupled receptors (VPAC1 and VPAC2). Currently, there are no curative therapies for inflammatory and autoimmune diseases, and patients present complex diagnostic, therapeutic, and prognostic problems in daily clinical practice due to their heterogeneous nature. This review focuses on the biology of VIP and VIP receptor signaling, as well as its protective effects as an immunomodulatory factor. Recent progress in improving the stability, selectivity, and effectiveness of VIP/receptors analogues and new routes of administration are highlighted, as well as important advances in their use as biomarkers, contributing to their potential application in precision medicine. On the 50th anniversary of VIP's discovery, this review presents a spectrum of potential clinical benefits applied to inflammatory and autoimmune diseases.

Topics: Animals; Autoimmune Diseases; Diabetes Mellitus, Type 1; Humans; Inflammation; Inflammatory Bowel Diseases; Receptors, Vasoactive Intestinal Peptide, Type II; Receptors, Vasoactive Intestinal Polypeptide, Type I; Rheumatic Diseases; Sjogren's Syndrome; Vasoactive Intestinal Peptide

Sjogren's syndrome (SS) is a chronic inflammatory disease characterized by salivary and lacrimal gland dysfunction although extraglandular manifestations are also found. Suitable study models and in vitro cell culture designs are used to approach SS pathogenic mechanisms. Cellular and molecular pathways involved in gland homeostasis loss and the autoimmune response are focused in the search of novel drug targets and biomarkers. Vasoactive intestinal peptide (VIP) has trophic, pro-secretory and immunomodulatory effects in several chronic and autoimmune disease models. Here we review evidence pointing to its role as an endogenous modulator of gland homeostasis at early stages of the disease. Particularly, mechanisms involving VIP/VPAC system in the course of salivary function impairment in the non obese diabetic (NOD) mouse model of Sjögren's syndrome are described.

Topics: Animals; Disease Models, Animal; Epithelial Cells; Humans; Immune System; Mice; Salivary Glands; Sjogren's Syndrome; Vasoactive Intestinal Peptide

Sjögren's disease (SjD) is a chronic autoimmune disease characterized by the loss of the secretory function of the exocrine glands. At present, drugs that can both correct the immune imbalance and improve exocrine gland function are needed. Meanwhile, vasoactive intestinal peptide (VIP) has been reported as a candidate with anti-inflammatory and immunoregulatory properties for treating autoimmune diseases.. Nonobese diabetic (NOD) mice and the primary splenic lymphocyte cells (SPLCs) were used to construct the SS model. The therapeutic effects of VIP for SjD by evaluating water consumption, histopathology, T cell subsets, and related cytokines. RT-qPCR and Western blot analysis were used to identify the expression of the PTEN/PI3K/AKT pathway.. We found that VIP therapy in NOD mice could increase the expression of PTEN and VIP/VPAC1 receptor, as well as decrease the PI3K/AKT pathway. In vitro, the results showed that the PTEN knockdown decreased the Treg/Th17 ratio and enhanced the phosphorylated PI3K/AKT pathway, which were reversed with VIP treatment.. VIP exerts potential therapeutic action in SjD by upregulating PTEN through the PI3K/AKT pathway and Treg/Th17 cell balance.

Topics: Animals; Autoimmune Diseases; Mice; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Sjogren's Syndrome; Vasoactive Intestinal Peptide

To investigate the protective effect of Zengye Decoction (, ZYD) on the submandibular glands (SMGs) in nonobese diabetic (NOD) mice.. Twenty-seven female NOD mice were randomly equally divided into 3 groups: the model group, the hydroxychloroquine (HCQ) group, and the ZYD group. Nine C57/B6 mice served as the normal group. After 1-week acclimation, the HCQ and ZYD groups were intragastrically administered with HCQ and ZYD, respectively, and the normal and model groups were administered with normal saline. Changes in the salivary flow rate were observed. Mice from all 4 groups were sacrificed at the age of 20 weeks. The serum and SMGs were collected. Serum cytokines gamma-interferon (IFN-γ), interleukin-10 (IL-10) were detected by enzyme-linked immunosorbent assay. Histological changes in the submandibular glands were examined by hematoxylin and eosin staining. The mRNA expression of IFN-γ, IL-10 and vasoactive intestinal peptide (VIP) in the submandibular glands were measured by real-time polymerase chain reaction.. Compared with the model group, the salivary flow of the ZYD group significantly increased (P<0.05), the extent of the histological changes was ameliorated (P<0.05), and the Th1/Th2 cytokine imbalance was remedied (P<0.05). In the ZYD-treated mice, the VIP mRNA was up-regulated (P<0.05).. ZYD is beneficial in protecting structure and function of SMGs in NOD mice. The mechanism may be associated with the correction of the Th1/Th2 cytokine imbalance, and with the prevention of a progressive decline of the VIP level.

Topics: Animals; Cytokines; Drugs, Chinese Herbal; Female; Mice; Mice, Inbred C57BL; Mice, Inbred NOD; Salivation; Sjogren's Syndrome; Submandibular Gland; Th1 Cells; Th2 Cells; Vasoactive Intestinal Peptide

Sjögren syndrome (SS) is an autoimmune disease involving exocrine glands. Currently, drugs that can improve both abnormal immunity and exocrine gland function are needed. The study aimed to investigate the effect and mechanism of vasoactive intestinal peptide (VIP) on the immune response and exocrine gland function in SS.. We investigated the effects of VIP on the immune response and secretory function of submandibular glands using NOD mice, and analyzed the expression of IL-17A and AQP5 (aquaporin 5). The submandibular gland cells from healthy 8-day-old Sprague-Dawley rats were used to observe the influence of VIP on AQP5 expression.. Our study shows that treatment with VIP in an SS mouse model could not only reduce the immune injury to exocrine glands but also improve the secretory function of these glands. Furthermore, VIP was shown to improve the abnormal immune status by downregulating IL-17A expression in the exocrine glands. It also enhanced the secretory function of exocrine glands by upregulating AQP5 expression.. Using a model of SS, we found that VIP could not only modulate the immune response but also affect exocrine gland function, and that these therapeutic effects were associated with IL-17A and AQP5 regulation.

Topics: Animals; Aquaporin 5; Disease Models, Animal; Female; Interleukin-17; Mice; Mice, Inbred BALB C; Mice, Inbred NOD; Rats; Rats, Sprague-Dawley; Salivary Glands; Sjogren's Syndrome; Vasoactive Intestinal Peptide

Sjögren's syndrome (SS) is a chronic autoimmune disease characterized by salivary and lacrimal gland dysfunction. Clinical observations and results from animal models of SS support the role of aberrant epithelial cell apoptosis and immune homeostasis loss in the glands as triggering factors for the autoimmune response. Vasoactive intestinal peptide (VIP) promotes potent anti-inflammatory effects in several inflammatory and autoimmune disease models, including the non-obese diabetic (NOD) mouse model of SS. With the knowledge that VIP modulates monocyte function through vasoactive intestinal peptide receptors (VPAC) and that immune homeostasis maintenance depends strongly upon a rapid and immunosuppressant apoptotic cell clearance by monocytes/macrophages, in this study we explored VPAC expression on monocytes from primary SS (pSS) patients and the ability of VIP to modulate apoptotic cell phagocytic function and cytokine profile. Monocytes isolated from individual pSS patients showed an increased expression of VPAC2 subtype of VIP receptors, absent in monocytes from control subjects, with no changes in VPAC1 expression. VPAC2 receptor expression could be induced further with lipopolysaccharide (LPS) in pSS monocytes and VIP inhibited the effect. Moreover, monocytes from pSS patients showed an impaired phagocytosis of apoptotic epithelial cells, as evidenced by reduced engulfment ability and the failure to promote an immunosuppressant cytokine profile. However, VIP neither modulated monocyte/macrophage phagocytic function nor did it reverse their inflammatory profile. We conclude that monocytes from pSS patients express high levels of VPAC2 and display a deficient clearance of apoptotic cells that is not modulated by VIP.

Topics: Adult; Aged; Apoptosis; Case-Control Studies; Cytophagocytosis; Gene Expression Regulation; Humans; Lipopolysaccharides; Middle Aged; Monocytes; Receptors, Vasoactive Intestinal Peptide; Receptors, Vasoactive Intestinal Peptide, Type II; Sjogren's Syndrome; Vasoactive Intestinal Peptide; Young Adult

Sjögren's syndrome (SS) is a chronic autoimmune disease characterized by a progressive oral and ocular dryness that correlates poorly with the autoimmune damage of the glands. It has been proposed that a loss of homeostatic equilibrium in the glands is partly responsible for salivary dysfunction with acinar cells involved actively in the pathogenesis of SS. The non-obese diabetic (NOD) mouse model of Sjögren's syndrome develops secretory dysfunction and early loss of glandular homeostatic mechanisms, with mild infiltration of the glands. Based on the vasodilator, prosecretory and trophic effects of the vasoactive intestinal peptide (VIP) on acini as well as its anti-inflammatory properties we hypothesized that the local expression of VIP/vasoactive intestinal peptide receptor (VPAC) system in salivary glands could have a role in acinar cell apoptosis and macrophage function thus influencing gland homeostasis. Here we show a progressive decline of VIP expression in submandibular glands of NOD mice with no changes in VPAC receptor expression compared with normal mice. The deep loss of endogenous VIP was associated with a loss of acinar cells through apoptotic mechanisms that could be induced further by tumour necrosis factor (TNF)-α and reversed by VIP through a cyclic adenosine-5'-monophosphate (cAMP)/protein kinase A (PKA)-mediated pathway. The clearance of apoptotic acinar cells by macrophages was impaired for NOD macrophages but a shift from inflammatory to regulatory phenotype was induced in macrophages during phagocytosis of apoptotic acinar cells. These results support that the decline in endogenous VIP/VPAC local levels might influence the survival/apoptosis intracellular set point in NOD acinar cells and their clearance, thus contributing to gland homeostasis loss.

Topics: Acinar Cells; Animals; Apoptosis; Autoimmune Diseases; Cell Survival; Cells, Cultured; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Disease Models, Animal; Macrophages; Mice; Mice, Inbred BALB C; Mice, Inbred NOD; NF-kappa B; Phagocytosis; Receptors, Vasoactive Intestinal Peptide; Sjogren's Syndrome; Submandibular Gland; Tumor Necrosis Factor-alpha; Vasoactive Intestinal Peptide

The role of apoptotic secretory epithelium as a pro-inflammatory triggering factor of exocrine dysfunction is currently explored in Sjogren's syndrome patients and in the nonobese diabetic (NOD) mouse model. Vasoactive intestinal peptide (VIP) has anti-inflammatory effects in various models of chronic inflammation. Our goal was to analyse the effect of TNF-alpha on apoptotic mediators in isolated acinar cells from NOD submandibular gland and their modulation by VIP.. Acinar cells were isolated from submandibular glands of 16-week-old NOD females with salivary flow decline. Age-matched BALB/c females or eight-week-old NOD females were used as controls. Apoptotic mediators and TNF-alpha receptor expression were assessed by immunoblotting and RT-PCR, caspase 3 activity was assessed by optical density at 405 nm with Ac-DEVD-pNA as a substrate and chromatin condensation by Hoechst stain. They were evaluated in resting conditions and after a 3.5 or 6 hours of culture with TNF-alpha. VIP effects in acinar cells were assessed at 100 nM in TNF-alpha-treated cultures and VIP receptor functional assays by radio immunoassay (cAMP) or enzymatic detection (amylase).. NOD acinar cells at 16 weeks present an increased expression of TNF-alpha receptor1 together with increased Bax, tumour protein 53-induced nuclear protein1alpha (TP53INP1alpha), caspase 3 activity and chromatin condensation. Acini from NOD mice were more sensitive to TNF-alpha-induced increases of apoptotic mediators than control cells. VIP inhibited TNF-alpha-induced apoptotic events through functional VPAC1 receptors coupled to the protein kinase A (PKA) signalling pathway.. Our results indicate that acinar cells isolated from submandibular glands of NOD mice with salivary dysfunction are more sensitive to apoptosis induced by TNF-alpha which could be prevented by VIP through a PKA-mediated pathway.

Topics: Animals; Apoptosis; Blotting, Western; Cyclic AMP-Dependent Protein Kinases; Disease Models, Animal; Female; Mice; Mice, Inbred BALB C; Mice, Inbred NOD; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction; Sjogren's Syndrome; Submandibular Gland; Tumor Necrosis Factor-alpha; Vasoactive Intestinal Peptide

Sjogren's syndrome (SS) is a chronic autoimmune disorder of exocrine glands characterized as an autoimmune exocrinopathy and more specifically as an autoimmune epithelitis. An impaired balance of neuroimmune interactions mediated by vasoactive intestinal peptide (VIP) in the target organ at early stages of disease is explored by means of the nonobese diabetic (NOD) mouse model of SS. We have previously described a reduced salivary secretion and signaling upon VIP stimulation. The effect reflected a differential regulation of the neural isoform of nitric oxide synthase by calcium calmodulin kinase II and occurred prior to the appearance of detectable levels of cytokines in NOD glands. VIP acting on NOD macrophages treated with lipopolysaccharide promoted anti-inflammatory effects by inhibiting nitric oxide synthase induction as well as IL-12 and TNF-alpha production, while stimulating IL-10. Here we present evidence on the ability of apoptotic acinar cells from submandibular glands of NOD mice to stimulate nitric oxide in both peritoneal and glandular macrophage pools to a similar extent as lipopolysaccharide + IFN-gamma. VIP was not effective to prevent nitrite accumulation and modestly increased IL-10 levels in macrophages coincubated with acinar cells. An enhanced nitrite response of NOD glandular macrophages in basal and stimulated conditions compared to peritoneal cells is also shown.

Topics: Animals; Apoptosis; Cells, Cultured; Disease Models, Animal; Epithelial Cells; Epithelium; Female; Inflammation Mediators; Interferon-gamma; Interleukin-10; Lipopolysaccharides; Macrophages; Mice; Mice, Inbred BALB C; Mice, Inbred NOD; Neuroimmunomodulation; Nitric Oxide; Peritoneum; Sjogren's Syndrome; Submandibular Gland; Vasoactive Intestinal Peptide

Sjögren's syndrome (SS), an autoimmune exocrinopathy mainly affecting lachrymal and salivary glands, results in ocular and oral dryness (keratoconjunctivitis sicca and xerostomia). The aetiology and pathogenesis are largely unknown; currently, only palliative treatment is available.. To determine whether gene transfer of vasoactive intestinal peptide (VIP), based on its immunomodulatory properties, might be useful in the management of SS.. A recombinant serotype 2 adeno-associated virus encoding the human VIP transgene (rAAV2hVIP) was constructed and its efficacy tested in the female non-obese diabetic (NOD) mouse model for SS after retrograde instillation in submandibular glands (SMGs). 10(10) particles/gland of rAAV2hVIP or rAAV2LacZ (encoding beta-galactosidase; control vector) were administered at 8 weeks of age (before sialadenitis onset). Salivary flow rates were determined before vector delivery and at time of death (16 weeks). After death, saliva, serum, and SMGs were harvested. Salivary output, inflammatory infiltrates (focus scores), VIP protein expression, cytokine profile, and serum anti-VIP antibodies were analysed.. rAAV2hVIP significantly improved the salivary flow, increased SMG and serum expression of VIP, and reduced SMG cytokines interleukin (IL) 2, IL10, IL12 (p70), and tumour necrosis factor alpha, and serum RANTES, compared with the control vector. No difference in focus scores or apoptotic rates was found; neutralising antibodies were not detected.. Local delivery of rAAV2hVIP can have disease modifying and immunosuppressive effects in SMGs of the NOD mouse model of SS. The new strategy of employing VIP prophylactically may be useful for both understanding and managing the salivary component of SS.

Topics: Adenoviridae; Animals; Antibodies; Apoptosis; Cytokines; Epithelial Cells; Female; Gene Expression; Genetic Engineering; Genetic Therapy; Genetic Vectors; Lac Operon; Mice; Mice, Inbred NOD; Models, Animal; Sjogren's Syndrome; Submandibular Gland; Transduction, Genetic; Transgenes; Vasoactive Intestinal Peptide

A functional interaction between progesterone, Th2 cytokines and a suitable balance between nitric oxide and prostaglandins in the uterus is considered to have a major role in the success of embryo implantation and pregnancy. Non-obese diabetic (NOD) mice offer a suitable model to study the modulatory role of Th1 cytokines on uterus signalling and function, since at the prediabetic stage they develop a spontaneous Th1 autoimmune response against exocrine glands similar to Sjögren's syndrome. Vasoactive intestinal peptide (VIP) is a vasoactive neuro- and immunopeptide that promotes Th2 profiles and contributes to the smooth muscle relaxation and vasodilation. The aim of the present study was to investigate the activities of nitric oxide synthase and cyclo-oxygenase and the effect of VIP in the uterus of NOD mice with an emerging Th1 cytokine response. We present evidence of a reduced basal and VIP-stimulated activity of both enzymes in the uterus of NOD mice compared with normal BALB/c mice in proestrus. An altered functional interaction between both enzymes is also present in NOD mice at the time when increased levels of serum interleukin (IL)-12 and tumour necrosis factor-alpha but not interferon (IFN)-gamma or IL-10 were detected. We conclude that signalling alterations in uteri of NOD mice are simultaneous to the onset of a systemic Th1 cytokine response.

Topics: Animals; Cyclooxygenase Inhibitors; Diabetes Mellitus, Type 1; Dinoprostone; Enzyme Activation; Female; Immunohistochemistry; Indomethacin; Interferon-gamma; Interleukin-10; Interleukin-12; Mice; Mice, Inbred BALB C; Mice, Inbred NOD; Models, Animal; Nitric Oxide Synthase; omega-N-Methylarginine; Pregnancy; Prostaglandin-Endoperoxide Synthases; Sjogren's Syndrome; Th1 Cells; Tumor Necrosis Factor-alpha; Uterus; Vasoactive Intestinal Peptide

A predominance of sensory neuropathy was earlier described in Sjögren's syndrome (SS), which might precede the presence of sicca symptoms. The mechanism of sensory neuropathy in SS is unknown. Therefore, the aim of this study was to determine the quantitative changes of the different neuropeptide containing nerve terminals and the immunocompetent cells in labial salivary glands of primary SS.. Immunohisto- and immunocytochemical methods were used for the detection of immunoreactive (IR) elements and the data were compared with the healthy controls.. All of the investigated IR nerve fibres were found in different quantity and localisation in both of control and SS glands. The density of them was changed variously in SS. The number of the substance P (SP), neuropeptide Y (NPY) (P < 0.05), galanin (GAL) IR nerve terminals was decreased, however, the number of vasoactive intestinal polypeptide (VIP) and tyrosine beta-hydroxylase (TH) IR nerve fibres (P < 0.05) was increased compared to the control. There were no IR immunocompetent cells in the control materials, however, a large number of them showed IR for SP (46.2%) and NPY (34.4%) in the SS. The IR was demonstrated mainly in the mast cells, plasma cells and some of the lymphocytes.. These neuropeptides might have a role in the sensory neuropathy; they might activate nociceptive and sympathetic pathways. Some neuropeptides (SP, NPY) are endogenous in the immune system and produced in certain conditions, e.g. inflammation and chronic autoimmune disorders such as SS, so they might participate in the neuroimmunomodulation and contribute to the atrophy, apoptosis and necrosis.

Topics: Adult; Aged; Female; Galanin; Humans; Lymphocytes; Male; Mast Cells; Microscopy, Electron; Middle Aged; Nerve Fibers; Neuroimmunomodulation; Neuropeptide Y; Neuroprotective Agents; Peripheral Nervous System Diseases; Plasma Cells; Salivary Glands, Minor; Sjogren's Syndrome; Substance P; Tyrosine 3-Monooxygenase; Vasoactive Intestinal Peptide

A large number of nerve fibres containing different neuropeptides/transmitters are also found in the salivary glands. The number and the distribution of nerve fibres is altered in many diseases, including in Sjögren's syndrome.. Therefore in the present study the distribution and precise localisation of the nerve fibres containing the frequently observed neuropeptides were studied in the minor salivary glands.. Vasoactive intestinal polypeptide, neuropeptide Y, substance P, calcitonin gene-related peptide, somatostatin, nitric oxide synthase and tyrosine beta-hydroxylase antibodies were used as primary antisera, and then by the aid of avidin-biotin-peroxidase complex method the immunoreactive fibers in human labial glands (control and with Sjögren's syndrome) and in minor glands of the root of the rat's tongue were detected.. Large number of vasoactive intestinal polypeptide and nitric oxide synthase immunoreactive nerve fibres were seen around the acini. The neuropeptide Y and tyrosine beta-hydroxylase positive nerve fibres were mainly found around the blood vessels. Some of the IR fibers were also found around the excretory ducts. In the biopsy of patients with Sjögren's syndrome, the acini were destroyed and only few excretory ducts were seen. The number of the nerve fibres was significantly decreased and many degenerated fibres were also observed among the acini. The electron-microscopic examinations showed that the immunoreactive nerve fibres were in close association to the secretory cells, to the smooth muscle cells of blood vessels and to the immunocells. The synaptic gap between the nerve fibres and the target cells were 40-200 nm.. On the bases of the distribution of the different transmitters containing nerve fibres and their relationship to effector cells, the authors suppose that these transmitters control the function of the gland and regulate the blood flow. The close association to immunocells and decreasing the nerve fibres in Sjögren's syndrome imply that they may have also a role in the neuroimmunologic processes.

Topics: Adult; Autonomic Fibers, Postganglionic; Calcitonin Gene-Related Peptide; Female; Humans; Immunoenzyme Techniques; Immunohistochemistry; Male; Neuropeptide Y; Neurotransmitter Agents; Nitric Oxide Synthase; Salivary Glands, Minor; Sjogren's Syndrome; Substance P; Tyrosine 3-Monooxygenase; Vasoactive Intestinal Peptide

The autoimmune sialadenitis developed by non-obese diabetic (NOD) mice is considered a suitable model to study the ethiopathogenic mechanisms leading to sicca symptoms in Sjögren's syndrome (SS). Evidence supporting a neural rather than immune origin of the secretory dysfunction has been provided. As both nitric oxide and vasoactive intestinal peptide (VIP) are common messengers to nervous and immune systems mediating secretory and inflammatory responses, we examined nitric oxide synthase (NOS) activity with special focus on VIP-mediated effects in salivary glands of NOD mice. We found a decreased NOS activity and expression in major salivary glands of NOD mice with respect to control mice. In addition, there was a deficient VIP-activated signaling associated with a reduced saliva and amylase secretion in response to VIP. Our results support the hypothesis of an impaired balance of neuroimmune interactions in salivary glands as early events to take place in the progressive loss of secretory function of NOD mice.

Topics: Age Factors; Animals; Female; Male; Mice; Mice, Inbred BALB C; Mice, Inbred NOD; Neuroimmunomodulation; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type I; Parasympathetic Fibers, Postganglionic; Protein Isoforms; Receptors, Muscarinic; Saliva; Salivary Glands; Signal Transduction; Sjogren's Syndrome; Vasoactive Intestinal Peptide

Histopathological parameters of the main lachrymal gland from patients with primary Sjögren's syndrome (SS1) were investigated, and the relation between morphological and immunohistochemical changes in the innervation of lachrymal gland in patients with SS1, as well as the immunopathological differences between SS1, non-autoimmune keratoconjunctivitis sicca (KCS) and controls were analysed.. Lachrymal glands from patients with SS1, KCS and control subjects were biopsied and examined using standard transmission electron microscopic techniques and an immunohistochemical method (vasoactive intestinal polypeptide-VIP).. Moderate numbers of myelinated and non-myelinated nerve fibres were found in the connective tissue around lachrymal glands in patients with SS1. Non-myelinated nerve fibres made contact with glandular epithelium, myoepithelial cells, vascular endothelium, plasma cells and fibroblasts. Patients with non-immunological KCS had similar characteristics as SS1 in number and activity, showing a normal morphological pattern. Control subjects showed a higher number of active nerve fibres.. Main lachrymal gland from patients with SS1 were therefore definitively innervated with moderate activity and normal structures. The ultrastructural study demonstrated there were no statistical differences with respect to patients with non-autoimmune KCS. Immunohistochemical studies showed a similar VIP activity in lachrymal gland between patients with SS1 and KCS, but there was a significant decrease in the innervation activity with regard to control subjects. All this implies that the autoimmunological factor in patients with SS1 does not significantly affect the lachrymal gland innervation.

Topics: Adult; Aged; Aged, 80 and over; Female; Fluorescent Antibody Technique, Indirect; Humans; Keratoconjunctivitis Sicca; Lacrimal Apparatus; Male; Middle Aged; Nerve Fibers; Parasympathetic Nervous System; Sjogren's Syndrome; Vasoactive Intestinal Peptide

The non-obese diabetic (NOD) mouse model of autoimmune sialadenitis offers the possibility of studying the L-arginine/nitric oxide signaling pathway in salivary glands in basal and neurotransmitter-stimulated conditions and, thus, of analyzing the neural control of the secretory process in the target organ. The purpose of this study was to explore putative alterations in the activity and expression of nitric oxide synthase (NOS) in submandibular glands of NOD mice in relation to parotid glands and unrelated tissues. Here we report that NOD mice with incipient signs of secretory dysfunction presented a marked decrease in basal and vasoactive intestinal peptide (VIP)-stimulated NOS activity and a differential expression of NOS I in submandibular glands compared to control BALB/c mice. Similar alterations in NOS I were found in parotid glands but not in brain or spleen of NOD mice. No differences between NOD and controls appeared in NOS II and NOS III expression in any of the tissues studied.

Topics: Amylases; Animals; Culture Techniques; Female; Mice; Mice, Inbred BALB C; Mice, Inbred NOD; Nitric Oxide Synthase; Nitric Oxide Synthase Type I; Parotid Gland; Protein Isoforms; Saliva; Sialadenitis; Sjogren's Syndrome; Submandibular Gland; Vasoactive Intestinal Peptide

Different neuropeptide-containing nerve fibers (vasoactive intestinal polypeptide, substance P, neuropeptide Y) and nitric oxide synthase (NOS) positive nerve fibers were investigated to clarify their role in the function of human labial glands using immunohisto- and immunocytochemical techniques. The distribution pattern of all immunoreactive nerve fibers was similar both in the control and in the Sjögren's syndrome specimens. A large number of thin varicose vasoactive intestinal polypeptide and NOS positive nerve fibers were seen around or in close contact with the acini. Some of the immunoreactive nerve fibers were associated with the salivary ducts and blood vessels. Substance P and neuropeptide Y immunoreactive nerve fibers were located mainly around the blood vessels. Immunocytochemistry demonstrated that some of the positive nerve fibers were in direct contact with the acini, blood vessels and with the lymphocytes. The gap between the membranes of immunoreactive nerve terminals and the target cells was 40 to 200 nm. The number of the nerve terminals in Sjögren's syndrome specimens was decreased and some degenerated axons were also found. These results suggest that these neuropeptides and nitric oxide might act as a neurotransmitter in the regulation of secretion and blood flow in the labial glands. These fibers might also alter the neuroimmunological processes, because the investigated neuropeptides are known to be immunoregulators.

Topics: Axons; Blood Vessels; Humans; Immunohistochemistry; Lip; Lymphocytes; Nerve Degeneration; Nerve Endings; Nerve Fibers; Neuropeptide Y; Neuropeptides; Nitric Oxide; Nitric Oxide Synthase; Regional Blood Flow; Salivary Ducts; Salivary Glands, Minor; Sjogren's Syndrome; Substance P; Vasoactive Intestinal Peptide; Vasodilator Agents

To measure levels of salivary nitrite (NO2-) and to localize nitric oxide synthases (NOS) in the labial salivary glands (LSGs) of patients with Sjögren's syndrome (SS).. NO2- was measured by the Griess reaction. LSGs were analyzed using NADPH-diaphorase histochemical and immunohistochemical studies to determine the constitutive NOS (neuronal [ncNOS] and endothelial [ecNOS]) and inducible NOS (iNOS) isoforms.. The NO2- concentration (mean +/- SEM 307 +/- 51 microM versus 97 +/- 16 microM; P < 0.05) and output (166 +/- 46 nmoles/minute versus 37 +/- 7 nmoles/minute) were increased in SS patients compared with healthy control subjects. NADPH-diaphorase was found in some nerve fibers and endothelial cells, and, in SS, was found in myoepithelial, acinar, and ductal epithelial cells, but in only a few inflammatory cells. In SS, ncNOS-immunoreactive nerve fibers were sparse and ecNOS was found in a minority of the CD31-positive vascular endothelial cells and acinar cells, whereas iNOS was localized in myoepithelial, acinar, and ductal epithelial cells, often together with tumor necrosis factor alpha.. Nitrite was found in normal human saliva. NO produced by ncNOS probably acts as a nonadrenergic, noncholinergic neurotransmitter, whereas that produced by ecNOS exerts a vasodilatory effect. SS patients had increased NO2- concentrations, with most of the superfluous salivary NO being produced not by the immigrant inflammatory cells, but rather, by the resident salivary gland cells. NO may contribute to inflammatory damage and acinar cell atrophy in SS.

Topics: Adult; Aged; Endothelium, Vascular; Enzyme Induction; Female; Humans; Isoenzymes; Middle Aged; NADPH Dehydrogenase; Nitric Oxide; Nitric Oxide Synthase; Nitrites; Saliva; Salivary Glands; Sjogren's Syndrome; Vasoactive Intestinal Peptide

To assess the activity level of the autonomic nervous system in Sjögren's syndrome (SS) and to correlate this with stress.. Patients with SS (n = 12) and healthy controls (n = 10) were analysed for the content of vasoactive intestinal peptide (VIP) and neuropeptide Y (NPY) in their stimulated saliva by radioimmunoassays and for stress by the use of a modified Jenkins Activity Survey (JAS).. The data are expressed as median (interquartile range). Salivary VIP output (pg/min) and NPY output (pg/min) were high in SS compared with healthy controls (30.0 (15.6, 36.6) versus 12.3 (9.2, 24.0), p = 0.045, 4.8 (0.6, 24.1) versus 0.7 (0.0, 2.4), p = 0.038, respectively). Patients experienced only a little, but not significantly, more stress than the healthy controls (stress index -2.8 (-7.7, 6.9) versus -5.2 (-12.9, 2.7), p > 0.05). Stress in general was associated with high salivary VIP concentrations (r = 0.41, p = 0.05).. These findings show that adequately processed saliva (containing aprotinin and EDTA as neuropeptidase inhibitors) contains measurable amounts of marker peptides of the autonomic nervous system. Secondly, VIP concentration but not output may be affected by stress, which may act by decreasing watery salivary flow. In patients with SS, VIP and NPY outputs are increased. This may indicate increased leakage into saliva or efforts to compensate for the diminished salivary flow, or both.

Topics: Adult; Autonomic Nervous System; Female; Humans; Middle Aged; Neuropeptide Y; Radioimmunoassay; Saliva; Salivation; Sjogren's Syndrome; Stress, Psychological; Vasoactive Intestinal Peptide

Topics: Humans; Microscopy, Immunoelectron; Salivary Glands; Sjogren's Syndrome; Vasoactive Intestinal Peptide

The presence and spatial distribution of peptide-containing nerves in labial salivary glands from 10 Sjögren's syndrome patients were compared with those in salivary glands from 7 healthy controls.. Immunoperoxidase staining was used to demonstrate vasoactive intestinal peptide (VIP)-immunoreactive (IR) fibers, postganglionic sympathetic fibers containing the C-flanking peptide of neuropeptide Y (CPON), and sensory fibers containing calcitonin gene-related peptide (CGRP) and substance P.. Acini, intralobular ducts, small arteries, and postcapillary veins were richly innervated by VIP-IR fibers, whereas CPON-, CGRP-, and substance P-IR fibers were restricted to blood vessels. Peptide-containing nerves were found surrounding, but not in the middle of, the highly inflamed mononuclear cell areas.. This topologic distribution suggests involvement of VIP-IR fibers in vascular, motor, and secretory components of the reflex salivary secretion, whereas the distribution and the vasoactive actions of CPON, CGRP, and substance P suggest a role in the regulation of the salivary gland circulation, and thus of transcapillary flow. Excessive release may contribute to a neurogenic inflammation. Local depletion and absence of trophic neuropeptide stimuli may contribute to acinar atrophy.

Topics: C-Peptide; Calcitonin Gene-Related Peptide; Humans; Immunoenzyme Techniques; Neuropeptide Y; Neuropeptides; Peripheral Nerves; Reference Values; Salivary Glands; Sjogren's Syndrome; Substance P; Vasoactive Intestinal Peptide