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REVIEW |
Department of Biomedicine, Section for Physiology, Faculty of Medicine, University of Bergen, Jonas Lies vei 91, N-5009, Bergen, Norway
* corresponding author, sivakami.rethnam{at}biomed.uib.no
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ABSTRACT |
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 TOP ABSTRACT (I) INTRODUCTION(II) CLASSIC TRANSMITTERS AND...(III) SYMPATHETIC INNERVATION(IV) SYMPATHETIC NERVOUS SYSTEM...(V) SYMPATHETIC NERVOUS SYSTEM...(VI) CONCLUSIONSREFERENCES |
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production. The SNS stimulates reparative dentin production, since reparative dentin formation was reduced after sympathectomy. Sprouting of sympathetic nerve fibers occurs in chronically inflamed dental pulp, and neural imbalance caused by unilateral sympathectomy recruits immunoglobulin-producing cells to the dental pulp. In conclusion, this article presents evidence in support of interactions between the sympathetic nervous system and dental inflammation.
KEY WORDS: immune system • dental pulp • neuropeptide Y
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(I) INTRODUCTION |
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TOPABSTRACT(I) INTRODUCTION(II) CLASSIC TRANSMITTERS AND...(III) SYMPATHETIC INNERVATION(IV) SYMPATHETIC NERVOUS SYSTEM...(V) SYMPATHETIC NERVOUS SYSTEM...(VI) CONCLUSIONSREFERENCES |
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The brain and the immune system have recently been termed the two ’super systems’ (Tada, 1997). Today, the neural and immune systems are no longer considered to be two separate entities. Studies from the last two to three decades have provided strong evidence that the central nervous system not only receives messages from the immune system, but also modulates immune function (Elenkov et al., 2000). The sympathetic nervous system (SNS), being part of the autonomic nervous system, has been shown to be an integrative interface between the two super systems (Madden et al., 1995; Tada, 1997; Straub et al., 1998; Downing and Miyan, 2000; Elenkov et al., 2000; Bedoui et al., 2003).
The current dental literature contains little information about the modulation of the SNS on inflammation. This topic, however, is being extensively studied in related fields. The present review is an attempt to provide a summary of the current concepts, ideas, and results on how the SNS and the immune system influence each other, with special emphasis on dental inflammation.
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(II) CLASSIC TRANSMITTERS AND CO-TRANSMITTERS |
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TOPABSTRACT(I) INTRODUCTION(II) CLASSIC TRANSMITTERS AND...(III) SYMPATHETIC INNERVATION(IV) SYMPATHETIC NERVOUS SYSTEM...(V) SYMPATHETIC NERVOUS SYSTEM...(VI) CONCLUSIONSREFERENCES |
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There are also other mediators in the sympathetic nerve terminals that share the vasoconstrictor role with NA. The novel neuropeptide, neuropeptide Y (NPY), is a 36-amino-acid peptide that acts as a neurotransmitter and neuromodulator in the CNS and peripheral nervous system (Tatemoto, 1982; Elenkov et al., 2000). NPY is found in sympathetic nerves in the peripheral nervous system under normal conditions (Lundberg et al., 1982; Dumont et al., 1992). Ultrastructural analysis of sympathetic nerve terminals has demonstrated that NA and NPY are stored in small and large vesicles; the small contain only NA or NPY, while the large vesicles contain both NA and NPY (Ekblad et al., 1984) (Fig. 1
). Release of both types of vesicles depends on the frequency by which the SNS is activated (Lundberg et al., 1989). NPY is also expressed in low levels in sensory neurons, but is increased after experimental manipulation like axotomy (Wakisaka et al., 1991; Fristad et al., 1996; Bongenhielm et al., 1999).
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-1 AR subtypes (1A/D, 1B, 1C), 3 -2 ARs (2A, 2B, 2C), and 3 beta; AR subtypes. NPY binds to at least 6 different NPY receptors, designated as Y1–6. Like NA, NPY is also a vasoconstrictor. It is, moreover, a potent angiogenic factor, with activity comparable with that of the basic fibroblast growth factor and vascular endothelial growth factors—two established angiogenic factors (Zukowska-Grojec et al., 1998). |
(III) SYMPATHETIC INNERVATION |
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TOPABSTRACT(I) INTRODUCTION(II) CLASSIC TRANSMITTERS AND...(III) SYMPATHETIC INNERVATION(IV) SYMPATHETIC NERVOUS SYSTEM...(V) SYMPATHETIC NERVOUS SYSTEM...(VI) CONCLUSIONSREFERENCES |
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Stimulation of sympathetic nerves and injection of NA or synthetic NPY cause a fall in pulpal blood flow (Tönder and Naess, 1978; Edwall et al., 1985; Kim, 1985). This shows that sympathetic nerves have a vasoconstrictor function in the dental pulp.
(b) Sympathectomy on Dental Tissue
To understand the physiological significance of sympathetic nerves, investigators have studied animals after surgical or chemical sympathectomy. Sympathectomy achieved by surgical removal of SCG (SCGx) results in degeneration in 5–12% of unmyelinated axons in the apical portion in cat canine teeth (Noga and Holland, 1983), while another study reported no decrease in unmyelinated axons in rat molar teeth (Fried et al., 1988). Chemical sympathectomy known to destroy adrenergic nerve fibers can be achieved by injecting guanethidine or 6 hydroxydopamine (6-OHDA). In the tooth and related structures, 6-OHDA has been shown to remove all TH-IR nerve fibers (Norevall and Forsgren, 1999). Surgical or chemical sympathectomy also eliminated all or almost all NPY-IR fibers, which indicates that these fibers are sympathetic in origin in the dental pulp (Uddman et al., 1984; Haug et al., 2001; Bletsa et al., 2004). Removing sympathetic nerves by SCGx increased the expression of sensory neuropeptides, such as substance P (SP) and calcitonin gene-related peptide (CGRP), in trigeminal ganglion neurons (Schon et al., 1985; Haug et al., 2001). There was also an increase in the number and thickness of SP-IR nerve fibers in orthodontically compressed PDL on the SCGx side (Haug et al., 2003). However, neither SP nor CGRP-IR nerve fibers were increased in the dental pulp after sympathectomy (Oswald and Byers, 1993; Haug et al., 2001; Haug, 2003).
Regional sympathectomy achieved by SCGx has been claimed to have more advantages than a general chemical sympathectomy by 6-OHDA injection, because toxic effects of 6-OHDA may make it difficult for results to be attributed to the exclusive local effects of the autonomic nerves (Kostrzewa and Jacobowitz, 1974).
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(IV) SYMPATHETIC NERVOUS SYSTEM AND INFLAMMATION |
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TOPABSTRACT(I) INTRODUCTION(II) CLASSIC TRANSMITTERS AND...(III) SYMPATHETIC INNERVATION(IV) SYMPATHETIC NERVOUS SYSTEM...(V) SYMPATHETIC NERVOUS SYSTEM...(VI) CONCLUSIONSREFERENCES |
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Immune response is a complex process, and numerous studies have demonstrated that the SNS influences various stages of immune reaction, sometimes with apparently contradictory findings. Sympathetic nerves and neurotransmitters generally exert inhibitory effects on immune mechanisms and inflammation (Besedovsky et al., 1979; del Rey et al., 1981; Kruszewska et al., 1995; De Luigi et al., 1998; Nagatomi et al., 2000). Depending on the experimental conditions or organs affected, NA may have an aggravating (pro-inflammatory) or impeding (anti-inflammatory) effect on a disease, depending on factors such as the presence of specific receptors on immune cells, the type and nature of the infecting agent, and the age of the subject (Tiegs et al., 1999; Elenkov et al., 2000; Sagiyama et al., 2004).
The anti-inflammatory effect of the SNS occurs in both normal and diseased models. In vivo studies involving chemical sympathectomy have been shown to enhance the severity of experimental allergic encephalomyelitis (Chelmicka-Schorr et al., 1988) and adjuvant-induced rheumatoid arthritis (Felten et al., 1992; Lorton et al., 1996), and to induce liver injury (Tiegs et al., 1999). Furthermore, stimulation of ß2 ARs abrogated liver disease (Tiegs et al., 1999). Taken together, these studies indicate that the SNS has an anti-inflammatory effect. However, there have been contradictory reports where sympathectomy has been shown to attenuate the severity of joint inflammation (Levine et al., 1985) and reduce capillary permeability, plasma protein extravasation, and exudation during inflammation (Helme and Andrews, 1985; Khalil and Helme, 1989).
In the dental pulp, sympathectomy had no apparent effect on the degree of inflammation induced by mustard oil (Komorowski et al., 1996), whereas we found less abscess formation 4 days after deep cavity preparation in SCGx teeth when compared with the side contralateral to the sympathectomized (non-SCGx) teeth (Haug et al., 2001). However, we could not detect any differences in the extent or severity of inflammation after pulp exposure injury in rat molars after a waiting period of more than 20 days (Haug and Heyeraas, 2003). This suggests that the effects of sympathecomy may depend on the time since exposure, and also that any differences may be at a cellular or molecular level. A recent study reported a bimodal effect of the SNS, depending on the timing of immune system activation. The SNS has been found to have both enhancing and depressing effects on experimental arthritis, depending on when the sympathectomy was done and the duration of the observation period (Harle et al., 2005).
(a) Cellular Events
The profound influence of the SNS on the immune system is further substantiated by the immediate mobilization of blood leukocytes following activation of the SNS. This phenomenon is often referred to as ’adrenergic leukocytosis’ (Benschop et al., 1996). Moreover, bilateral SCGx is found to be associated with down-regulation of neutrophil and macrophage functions (Mathison et al., 1994). Neutrophils from SCGx rats display reduced phagocytic and chemotactic responses (Ramaswamy et al., 1990; Carter et al., 1992; Mathison et al., 1994). Studies on knock-out mice that cannot produce catecholamines, due to lack of the enzyme DBH, showed a reduced neutrophil recruitment (Alaniz et al., 1999). We previously found that, after sympathectomy, granulocyte recruitment in rat molars was impaired during experimental orthodontic tooth movement (Haug et al., 2003) (Figs. 2A–2D), while electrical stimulation of sympathetic nerves caused recruitment of these cells in the dental pulp (Csillag et al., 2004) (Fig. 1
). It therefore appears that an intact sympathetic innervation is important for the recruitment and migration of granulocytes during inflammatory processes in oral tissues.
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B-lymphocytes and plasma cells are not normally present in the normal dental pulp (Pulver et al., 1977; Jontell et al., 1987; Mangkornkarn et al., 1991; Okiji et al., 1992; Fristad et al., 1995). However, antigen-presenting cells from the pulp have been shown to enter local lymph nodes and activate B-lymphocytes to differentiate into plasma cells during pulpal inflammation (Jontell et al., 1998). Chemically sympathectomized mice have been found to increase serum antibodies, such as IgM, IgG, IgG1, and IgG2A (Kruszewska et al., 1995). Furthermore, plasma cells in the lamina propria of the intestines increase after sympathectomy (Gonzalez-Ariki and Husband, 2000). We recently reported the recruitment of immunoglobulin-producing cells in the normal uninflamed dental pulp bilaterally after unilateral sympathectomy (Haug and Heyeraas, 2005). These cells presented with a characteristic localization and aggregated on the floor of the pulp chamber above the furcation region and the inner portion of the root pulp (Fig. 1). They were never observed within the odontoblast layer and in the continuously growing incisors. When present, more than 100 cells might be found in one central section of the dental pulp. A variant of plasma cells, known as Mott cells, was also found in the dental pulp after unilateral SCGx, in addition to plasma cells and B-lymphocytes. Mott cells are usually absent in normal tissue, but appear in large numbers in pathological states such as autoimmune diseases (Jiang et al., 1997). Sympathectomy thus appears to cause the dental pulp to be in a state of altered immune regulation. The appearance of Mott cells in the dental pulp indicates a possible dysregulation of the immune system after sympathectomy (Haug and Heyeraas, 2005).
(b) Th1 and Th2 Responses
The physiological functions of cytokines are derived from two phenotypically distinct subsets of T memory cells, namely, T-helper type 1 (Th1) and T-helper type 2 (Th2) cells. Th1 cells characteristically produce interleukin-1 (IL-1), IL-2, tumor necrosis factor alpha (TNF-), and interferon-gamma (IFN-
), among other cytokines. Th2 cells, in contrast, secrete cytokines such as IL-4, IL-5, IL-10, and IL-13 and are associated with suppression of some diseases. These cytokines stimulate B-cells into producing antibodies. NA, both in vivo and in vitro, has been shown to inhibit the production of pro-inflammatory cytokines such as TNF-, while stimulating the production of anti-inflammatory cytokines such as IL-10 (van der Poll et al., 1996; Hasko et al., 1998). The SNS can alter the Th1/Th2 balance, shifting it from a pro-inflammatory (Th1 response) to an anti-inflammatory response (Th2 response) (Woiciechowsky et al., 1998; Elenkov and Chrousos, 1999).
Cytokines involved in dental inflammation and periapical lesion formation are thought to be modulated predominantly by Th1 cells (Kawashima and Stashenko, 1999). We recently reported that periapical lesions in SCGx rats contained significantly more IL-1 cytokines (Bletsa et al., 2004) (Fig. 1) when compared with similar lesions on the contralateral non-SCGx side. IL-1 targets bone resorption, and the role of sympathectomy on bone remodeling will be discussed later. In the normal dental pulp, SCGx caused a reduction in TNF-. However, the significance of this finding and how it might affect the pulp in its fight against an immunological threat are unknown (Bletsa et al., 2004).
(c) Sprouting of NPY-IR Fibers after Pulp Exposure
Immunoregulation by the SNS is mediated not only by catecholamines but also by its co-transmitter, NPY. NPY has been shown to modulate differentiation of T-helper cells, stimulate release of inflammatory mediators from monocytes, and activate natural killer cells (Bedoui et al., 2003, 2004; Groneberg et al., 2004). In a recent study, sprouting of NPY-IR nerve fibers was observed in the inflamed dental pulp and apical PDL 20 days after pulp exposure (Haug and Heyeraas, 2003). Sprouting of NPY-IR fibers occurred in teeth adjacent to reparative dentin after small pulp exposures. NPY-IR fibers were not observed in SCGx teeth with similar pulp injury, which indicates that these NPY-IR fibers were sympathetic in origin (Haug and Heyeraas, 2003) (Figs. 1, 3A, 3B). Studies on extracted teeth with advanced caries lesions have shown an increase in NPY-IR fibers in the pulp horn (Rodd and Boissonade, 2002).
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The significance of the NPY-IR fiber sprouting is still not clearly understood. It is known that NPY has an effect on regulation of blood flow and immunomodulation. Since NPY is also a vascular growth factor (Zukowska-Grojec et al., 1998), it may play an important role in revascularization during repair and healing processes in the inflamed dental pulp. NPY might also cause pain sensations associated with pulp inflammation, since there is experimental evidence that NPY in the presence of nerve damage contributes to hyperalgesia (Tracey et al., 1995). One may therefore speculate that sympathetic nerves take part in the throbbing pain commonly encountered during pulpitis, or in the percussion sensitivity of the inflamed periodontium, based on the location of these nerves and the state of inflammation in the dental pulp (Haug and Heyeraas, 2003).
(d) Wound Healing and Reparative Dentin
Inflammation is an important step for wound healing to occur. Sympathectomy has been shown to impair healing of skin incisions (Kim et al., 1998), whereas local stimulation of sympathetic terminals has been reported to accelerate wound healing (Kim and Pomeranz, 1999).
Reparative dentin formation is a form of wound healing in the dental pulp. In an experimental study, we found less reparative dentin formation in inflamed SCGx teeth compared with the non-SCGx teeth (Haug and Heyeraas, 2003). However, an earlier study, involving unilateral sympathectomy and cavity preparation, did not reveal any differences in reparative dentin formation (Avery et al., 1974). This discrepancy might be due to differences in observation time after sympathectomy and the degree/state of inflammation.
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(V) SYMPATHETIC NERVOUS SYSTEM AND BONE REMODELING |
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TOPABSTRACT(I) INTRODUCTION(II) CLASSIC TRANSMITTERS AND...(III) SYMPATHETIC INNERVATION(IV) SYMPATHETIC NERVOUS SYSTEM...(V) SYMPATHETIC NERVOUS SYSTEM...(VI) CONCLUSIONSREFERENCES |
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Studies examining the effects of surgical and chemical sympathetic denervation on bone remodeling have mainly showed that the SNS has an inhibitory effect on osteoclasts (Hill et al., 1991; Sherman and Chole, 1999) (Table). Osteoclasts mediating bone resorption have been shown to increase after sympathectomy (Sandhu et al., 1987; Ladizesky et al., 2000). Sympathectomy has also been shown to cause osteopathic destruction of arthritic joints following exacerbated inflammation (Lorton et al., 1996).
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In a recent study, where a pulp exposure model was used to create periapical lesions, we found that inflammatory periapical lesions were larger following SCGx. In addition, an increased number of osteoclasts was found to be lining these periapical lesions (Haug and Heyeraas, 2003) (Figs. 1, 3C, 3D). In an experimental orthodontic tooth movement model, we showed that root resorption was increased after SCGx (Haug et al., 2003) (Fig. 1). Removing the sympathetic nerves, therefore, increases not only bone resorption but also resorption of other hard tissues, such as dentin (Haug et al., 2003).
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(VI) CONCLUSIONS |
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TOPABSTRACT(I) INTRODUCTION(II) CLASSIC TRANSMITTERS AND...(III) SYMPATHETIC INNERVATION(IV) SYMPATHETIC NERVOUS SYSTEM...(V) SYMPATHETIC NERVOUS SYSTEM...(VI) CONCLUSIONSREFERENCES |
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). In the dental pulp, sprouting of sympathetic nerve fibers occurs during chronic inflammation. Experimental evidence indicates that sympathetic nerves are important for the recruitment of inflammatory cells, such as CD 43+ granulocytes, into the dental pulp. Neural imbalance caused by unilateral SCGx results in the recruitment of immunoglobulin-producing cells to the uninflamed dental pulp. In the PDL, sympathetic nerves are important for the recruitment of CD 43+ granulocytes, as demonstrated by experimental tooth movement. In dentin, sympathetic nerves appear to have an inhibitory effect on resorption and a stimulatory effect on reparative dentin formation. In experimentally induced periapical lesions, sympathetic nerves have an inhibitory effect on the size of the lesion, the number of osteoclasts lining the lesion, and the amount of IL-1 within the lesion. In conclusion, this article has reviewed and presented evidence supporting the existence of interactions between the sympathetic nervous system and the immune system in dental tissues.
Received July 2, 2005; Accepted March 20, 2006
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TOPABSTRACT(I) INTRODUCTION(II) CLASSIC TRANSMITTERS AND...(III) SYMPATHETIC INNERVATION(IV) SYMPATHETIC NERVOUS SYSTEM...(V) SYMPATHETIC NERVOUS SYSTEM...(VI) CONCLUSIONSREFERENCES |
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