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Identification and Quantification of Vasoactive Intestinal Peptide in Periradicular Lesions
... Vasoactive intestinal peptide (VIP) has been associated with the development of chronic periapical lesions suggesting that it could participate in their growth and maturation (Azuero-Holguin et al. 2003). VIP is a parasympathetic neuropeptide consisting of 28 amino acids, distributed throughout the central and peripheral nervous systems (Gozes et al. 1999). ...
... This neuropeptide has a vasodilator effect and is expressed in healthy and inflamed human dental pulps (Caviedes-Bucheli et al. 2006). The presence of VIP in periapical lesions has been reported with an inversely proportional relationship between lesion size and neuropeptide concentration (Azuero-Holguin et al. 2003). However, its role in the development in chronic periapical lesions remains unclear. ...
... Vasoactive Intestinal Peptide expression in chronic periapical lesion has been established before, being inversely proportional to lesion size, using a 5 mm diameter as a cut-off point to classify lesions as smaller than and greater than 5 mm (Azuero-Holguin et al. 2003). However, to validate VIP participation in growth and maturation of periapical lesions, the appropriate receptor should be found in the tissue. ...
To use radioreceptor analysis for evaluating whether vasoactive intestinal peptide (VIP) receptors are present in chronic periapical lesions and to determine whether differences in its expression are found according to the size of the lesions.
Twelve periapical lesions were obtained from teeth diagnosed with chronic apical periodontitis and indicated for endodontic surgery; they were classified according to the size of the lesion in two groups of six samples (lesion size greater or smaller than 5 mm), and then processed and labelled with (125)I-VIP. Binding sites were identified by (125)I-VIP and standard VIP competition assays. Mann-Whitney's test was used to establish statistically significant differences in the VIP receptor expression between groups.
Vasoactive intestinal peptide receptor expression was found in all periapical lesion samples. There was a statistically significantly higher expression in periapical lesions <5 mm (P < 0.001).
Vasoactive intestinal peptide receptors were expressed in chronic periapical lesions with levels inversely proportional to lesion size.
... At the subodontoblast layer, there are very few VIP fibers (Fig 8) (58). VIP has also been found expressed in periradicular lesions (59). . Different stimuli that trigger neuropeptide release and their role in neurogenic inflammation. ...
... However, it appears that noxious stimulation of dental pulp does not influence VIP release, because its expression remained unchanged during inflammatory phenomena (22). VIP has shown potent immunomodulator properties, which might account for variable VIP release according to stage of periradicular lesions (59). ...
... The presence of VIP in periapical lesion has been reported, and its levels are inversely related to lesion size. Given the functions of this neuropeptide in other tissues, it has been hypothesized that VIP participates in regulating the growth of periapical lesions (59). Results from another study showed that VIP receptors are expressed in chronic periapical lesions, and its levels are also inversely proportional to the lesion sizes, suggesting that VIP could have an important role in regulating the inflammatory phenomenon in the development of periapical lesions via cellular receptors (66). ...
Dental pulp is a soft mesenchymal tissue densely innervated by afferent (sensory) fibers, sympathetic fibers, and parasympathetic fibers. This complexity in pulp innervation has motivated numerous investigations regarding how these 3 major neuronal systems regulate pulp physiology and pathology. Most of this research is focused on neuropeptides and their role in regulating pulpal blood flow and the development of neurogenic inflammation. These neuropeptides include substance P, calcitonin gene-related peptide, neurokinin A, neuropeptide Y, and vasoactive intestinal polypeptide among others. The purpose of this article is to review recent advances in neuropeptide research on dental pulp, including their role in pulp physiology, their release in response to common dental procedures, and their plasticity in response to extensive pulp and dentin injuries. Special attention will be given to neuropeptide interactions with pulp and immune cells via receptors, including studies regarding receptor identification, characterization, mechanisms of action, and their effects in the development of neurogenic inflammation leading to pulp necrosis. Their role in the growth and expansion of periapical lesions will also be discussed. Because centrally released neuropeptides are involved in the development of dental pain, the pain mechanisms of the pulpodentin complex and the effectiveness of present and future pharmacologic therapies for the control of dental pain will be reviewed, including receptor antagonists currently under research. Finally, potential clinical therapies will be proposed, particularly aimed to manipulate neuropeptide expression or blocking their receptors, to modulate a variety of biologic mechanisms, which preliminary results have shown optimistic results.
... Indeed, VIP can inhibit Th1 and Th17 cells while boosting Th2 and Treg activity [6][7][8][9] , reinforcing its potential regulatory action in periapical lesions. In the periapical lesion context, scarce previous studies describe the expression of VIP in chronic periapical lesions in levels inversely proportional to lesion size 10,11 . Additionally, intracanal calcium hydroxide resulted in increased VIP levels, suggesting its potential involvement in periapical healing 8 . ...
... Our results show that VIP expression was higher in the periapical granuloma lesions than the controls and was positively associated with the expression of anti-inflammatory and healing markers (ie, OPG, IL-4, IL-9, IL-10, FOXp3, and TGF-B1). Accordingly, a previous study described the expression of VIP in human periapical lesions with an inverse correlation with lesion size 10,11 . Additionally, the stratification of human samples based into tertiles based on VIP and/ or the RANKL/OPG ratio reveals that VIP presents an inverse/opposite correlation with RANKL/OPG. ...
Introduction:
The balance between the host proinflammatory immune response and the counteracting anti-inflammatory and reparative responses supposedly determine the outcome of periapical lesions. In this scenario, the vasoactive intestinal peptide (VIP) may exert a protective role because of its prominent immunoregulatory capacity. In this study, we investigated (in a cause-and-effect manner) the potential involvement of VIP in the development of human and experimental periapical lesions.
Methods:
Periapical granulomas (n = 124) and control samples (n = 48) were comparatively assessed for VIP and multiple immunologic/activity marker expression through real-time polymerase chain reaction. Experimental periapical lesions (C57Bl/6 wild-type mice) were evaluated regarding endogenous VIP expression correlation with lesion development and the effect of recombinant VIP therapy in lesion outcome. CCR4KO and IL4KO strains and anti-glucocorticoid-induced TNFR-related protein inhibition were used to test the involvement of Treg and Th2 cells in VIP-mediated effects.
Results:
VIP expression was more prevalent in periapical granulomas than in controls, presenting a positive association with immunoregulatory factors and an inverse association/correlation with proinflammatory mediators and the receptor activator of nuclear factor kappa B ligand/osteoprotegerin ratio. Endogenous VIP expression up-regulation was temporally associated with lesion immunoregulation and a decline of bone loss. VIP therapy in mice prompted the arrest of lesion development, being associated with an anti-inflammatory and proreparative response that limits the proinflammatory, Th1, Th17, and osteoclastogenic response in the periapex. The VIP protective effect was dependent of Treg migration and activity and independent of interleukin 4.
Conclusions:
Our results show that VIP overexpression in human and experimental periapical lesions is associated with lesion inactivity and that VIP therapy results in the attenuation of experimental lesion progression associated with the immunosuppressive response involving Treg cells.
... Sympathetic nerves inhibit the production of the bone-resorbing pro-inflammatory cytokine IL-1a that can increase the number of osteoclasts (Bletsa et al. 2004). Furthermore, VIP from parasympathetic fibres might also participate in the development and healing of periapical lesions (Azuero-Holguin et al. 2003). What is worth mentioning, in particular, is that both osteoblasts and osteoclasts have been shown to express VIP receptors. ...
As one of the most densely innervated tissues, the dental pulp contains abundant nerve fibres, including sensory, sympathetic and parasympathetic nerve fibres. Studies in animal models and human patients with pulpitis have revealed distinct alterations in protein expression and histological appearance in all types of dental nerve fibres. Various molecules secreted by neurons, such as classical neurotransmitters, neuropeptides and amino acids, not only contribute to the induction, sensitization and maintenance of tooth pain, but also regulate non‐neuronal cells, including fibroblasts, odontoblasts, immune cells and vascular endothelial cells. Dental nerves are particularly important for the microcirculatory and immune responses in pulpitis via their release of a variety of functional substances. Further, nerve fibres are found to be involved in dental soft and hard tissue repair. Thus, understanding how dental nerves participate in pulpitis could have important clinical ramifications for endodontic treatment. In this review, the roles of dental nerves in regulating pulpal inflammatory processes are highlighted and their implications for future research on this topic are discussed.
Bone metabolism is dependent on cells of the osteoblast and osteoclast lineage. These cells play a major role in the synthesis and degradation of osteoid and in its mineralization and demineralization. Bone cells are under the influence of various systemic and local auto/paracrine factors. One further regulatory element that can play both a sensory/ afferent and a regulatory/efferent role, consists of neuropeptide-containing nerves. In particular, the calcitonin gene-related peptide (CGRP) and vasoactive intestinal peptide (VIP) have been implicated; their distribution in bone and their molecular biology are discussed in some detail. Bone neuropeptides can function as direct bone cell regulators, with additional amplifying indirect effects mediated by vascular endothelial cells, monocyte/macrophages and mast cells and their mediators. Recent experimental and clinical work has implicated bone nerves in processes varying from normal remodelling to fracture healing and non-union. Apart from systemic endocrine influences on bone stock and osteoclast/ osteoblast coupling (activation-resorption-formation cycle) mediated by local auto/paracrine factors, bone nerves/neuropeptides may explain why various inputs/outputs are transformed in a meaningful way to altered mass and quality of bone.
Vasoactive intestinal peptide (VIP) stimulated bone resorption in mouse calvaria in organ culture. The effect was dose dependent between 0.01–1.0 fig VIP/ml (3–300 nM). Stimulation over a period of 48 h was greater when the peptide was added in four staggered doses than if the same total dose was added at time zero. VIP-stimulated bone resorption was as great as that produced by two other polypeptides, epidermal growth factor and platelet-derived growth factor, which we have previously found to act via a prostaglandin (PG)-mediated mechanism. However, unlike these polypeptides, the action of VIP on bone was not blocked by inhibitors of PG synthesis, such as indomethacin or cortisol. RIA of bone culture medium showed no increase in the concentration of PGE2 in the presence of maximum stimulatory concentrations of VIP. VIP rapidly enhanced (<1 h) the production of cAMP by calvaria 8- to 13-fold. Increases in cAMP accumulation were potentiated by the phosphodiesterase inhibitor isobutylmethylxanthine, and isobutylmethylxanthine potentiated the resorptive response to low concentrations of VIP. Homologous desensitization to VIP was observed. Calvaria preincubated with VIP for 8–48 h were refractory to a second acute challenge by VIP, but they did respond partially to PTH. VIP pretreatment did not affect the response to PGE2. Pretreatment with PTH caused complete desensitization to a second challenge with PTH and partial heterologous desensitization to VIP, without altering PGE2 responsiveness. We conclude that VIP acts to enhance bone resorption via a cAMP-dependent, PG-independent mechanism, which is probably similar to that induced by PTH.
Multiple mechanisms are involved in the pathologic changes associated with formation of acute and chronic periradicular lesions. Mechanical injury to the periradicular tissues can cause activation of several pathways of inflammation and release of nonspecific mediators. Continuous irritation of periradicular tissues can cause activation of several pathways of inflammation and release of nonspecific mediators. Continuous egress of antigens from a pathologically involved root canal can also result in one or a combination of the various types of immunologic reactions. A number of these reactions participate in the destruction of periradicular tissues. Because of complex interactions between the various components of these systems, the dominance of any one pathway or substance may be difficult to establish.
Clinical and experimental observations, together with immunohistochemical findings, suggest that neuro-osteogenic interactions may occur in the skeleton. In this study, we have examined the effect of vasoactive intestinal peptide (VIP), one of the neuropeptides present in bone, on the activity of the bone-resorbing osteoclast. Effects on bone resorption were assessed by counting the number of pits formed by rat osteoclasts incubated on devitalized slices of bovine cortical bone. Under conditions with an initially sparse density of stromal cells/osteoblasts, VIP caused a rapid cytoplasmic contraction and decreased motility of osteoclasts. This was coupled with a decrease in the number of resorption lacunae and a decrease in the total area resorbed by the osteoclasts in 48-h cultures. Time-course experiments revealed that the inhibitory effects on contraction and motility were transient and that the cells gradually regained their activity, such that, when culture time was prolonged to 120 h, a stimulatory effect by VIP on bone resorption was observed. When osteoclasts were incubated on bone slices, in the presence of an initially large number of stromal cells/osteoblasts, VIP treatment increased the number of resorption pits and total bone area resorbed in 48-h cultures. Using atomic force microscopy, we provide direct evidence that both osteoclasts and stromal cells/osteoblasts bind VIP. Also, VIP was shown to cause a rapid rise of intracellular calcium in osteoclasts and in a proportion (20%) of stromal cells/osteoblasts. Taken together, these data suggest that differentiated osteoclasts are equipped with receptors for VIP that are linked to a transient inhibition of osteoclast activity and, in addition, that stromal cells/osteoblasts have VIP receptors coupled to a delayed stimulation of osteoclastic resorption.