An Overview of the Dental Pulp: Functions and Responses to Injury (2007 PDF)

Australian Dental Journal Supplement 2007;52:(1 Suppl):S4-S16 An overview of the dental pulp: its functions and responses to injury C Yu,* PV Abbott* Abstract should not be underestimated. The most serious...

Australian Dental Journal Supplement 2007;52:(1 Suppl):S4-S16 An overview of the dental pulp: its functions and responses to injury C Yu,* PV Abbott* Abstract should not be underestimated. The most serious consequence of pulp disease is oral sepsis, which can be The dental pulp is a unique tissue and its importance in the long-term prognosis of the tooth is often life threatening.1,2 If the infection spreads from the ignored by clinicians. It is unique in that it resides in maxillary teeth, it may cause purulent sinusitis, a rigid chamber which provides strong mechanical meningitis, brain abscess, orbital cellulitis and support and protection from the microbial rich oral cavernous sinus thrombosis, whereas infection from the environment. If this rigid shell loses its structural mandibular teeth may cause Ludwig’s angina, integrity, the pulp is under the threat of the adverse parapharyngeal abscess, mediastinitis, pericarditis, stimuli from the mouth, such as caries, cracks, fractures and open restoration margins, all of which emphysema and jugular thrombophlebitis. Moreover, provide pathways for micro-organisms and their the number of teeth that are extracted result in toxins to enter the pulp. The pulp initially responds mutilated dentitions, malnutrition and possible to irritation by becoming inflamed and, if left emotional problems. untreated, this will progress to pulp necrosis and Toothache is a common complaint in the dental infection. The inflammation will also spread to the clinic, and yet diagnosis of pulp disease is often difficult surrounding alveolar bone and cause periapical pathosis. The magnitude of pulp-related problems due to the seemingly unclear symptoms and the should not be underestimated since their most inaccessibility of the pulp for clinical tests. This is further serious consequence is oral sepsis, which can be life complicated by referred toothache originating from the threatening, and hence correct diagnosis and tissues other than the pulp. Improper diagnosis can lead management are essential. Clinicians must have a to improper treatment, causing distress to the patient thorough understanding of the physiological and and embarrassment to the practitioner. An understanding pathological features of the dental pulp as well as the biological consequences of treatment interventions. of the histophysiology of the healthy pulp and the possible underlying pathological processes in the Key words: Dental pulp, pulp disease, inflammation, diseased pulp, careful assessment of the pain history, necrosis. and appropriate clinical examination and diagnostic Abbreviations and acronyms: CGRP = calcitonin gene- tests, should aid the dental practitioner in reaching an related peptides; IL = interleukins; PBF = pulp blood flow; accurate diagnosis and a positive treatment outcome. SP = substance P; TTXr = tetrodotoxin-resistant; TTXs = tetrodotoxin-sensitive. The dental pulp and its nature The dental pulp derives from neural crest cells (the ectomesenchyme). Proliferation and condensation of INTRODUCTION these cells lead to formation of the dental papilla from The dental pulp resides in a rigid chamber comprising which the mature pulp is derived. The mature pulp dentine, enamel and cementum, which provide strong bears a strong resemblance to the embryonic connective mechanical support and protection from the microbial tissue, with a layer of highly specialized cells, the rich oral environment. However, if this rigid shell loses odontoblasts, along its periphery.3 The physical its structural integrity, the pulp is under the threat of confinement of the dental pulp, its high incidence of the adverse stimuli from the mouth. Caries, cracks, sensory nerve innervation and the rich microcirculatory fractures and open restoration margins provide components make the dental pulp a unique tissue. pathways for micro-organisms and their toxins to enter Knowledge of the normal pulp function, its components the pulp. The response of the pulp to irritation is and their interaction is necessary to provide a frame- inflammation and, if unattended, this will eventually work for understanding the changes that occur in progress to pulp necrosis. Inflammation may spread to diseased pulps. the surrounding alveolar bone and cause periapical pathosis. The magnitude of pulp-related problems Functions of the dental pulp A fundamental question that needs to be addressed is *School of Dentistry, The University of Western Australia. whether the dental pulp is necessary in a fully formed S4 Australian Dental Journal Endodontic Supplement 2007;52:1. tooth. One can argue that the tooth can continue to destroyed. The rate seems to depend inversely on the function normally after the pulp is removed and rate of carious attack; that is, more dentine is formed in replaced with a root canal filling. In such situations, the response to slowly progressing carious lesions. The circulation of the periodontal ligament and the tubules in the reparative dentine are irregular or surrounding tissues will support a pulpless or an frequently absent, which makes it less permeable to endodontically treated tooth. external stimuli. Cells forming the reparative dentine A recent study on the bacterial invasion into dentinal are thought not to be the primary odontoblasts but are tubules of human teeth with or without viable pulp has derived from the cells deeper in the pulp such as fibro- shown that teeth with pulps are much more resistant to blasts in the cell-rich zone, endothelial cells or pericytes bacterial invasion into the dentinal tubules than are of the blood vasculature which are differentiated upon teeth with root canal fillings.4 In the latter, bacteria are the stimulation by tissue growth factor-␤.10,11 The able to enter teeth and reach the root canal system in a reparative dentine, especially at the junctional zone relatively short period of time.4 Hence, the pulp plays between primary and secondary dentine, has low an important role in this defense process. In teeth with permeability and may block the ingress of irritants to pulps, the dentinal tubules are occupied by dentinal the pulp. fluid and odontoblastic processes, which may behave Pulp is equipped with the cellular components collectively as a positively charged hydrogel.5,6 The necessary for the initial recognition and the subsequent hydrogel is capable of arresting a great number of the processing of antigens hence its ability to elicit an bacteria that enter the pulp. The outward flow of the immune defense reaction.12-15 The main immune cells in dentinal fluid is important in the pulp’s defense against a normal pulp are peripheral T cells (helper/inducer and the entry of harmful substances because it affects the cytotoxic/suppressor). The major antigen presenting rate at which toxic substances from the mouth diffuse cells in the dental pulp are the dendritic cells located into the dentinal tubules.7,8 Moreover, antibodies or primarily in the odontoblastic layer.16 These cells other antimicrobial agents may be present within the uptake, process, and present foreign antigens as dentinal fluid in response to bacterial infection of the HLA-DR antigens on the cell surface to CD4+ dentine.3 The possible build-up of immune complexes T-lymphocytes. Other antigen-presenting cells are and the precipitation of high molecular weight plasma similar to macrophages and are located in the more proteins, such as fibrinogen, in the dentinal fluid may central portions of the pulp. In rat incisors, Class II reduce the functional radius of the dentinal tubules and antigen activated macrophages are four times more hence reduce the dentine permeability.9 common than the dendritic cells.14 It is noteworthy that The pulp’s specialized cells, the odontoblasts, and the normal dental pulp does not appear to have B perhaps undifferentiated mesenchymal cells (which may cells.15 differentiate into dentine-forming cells if stimulated), Pulp is also a sensory organ. Its sensitivity to thermal retain the ability to form dentine throughout life. This stimuli is well recognized.17 Regardless of the nature of enables the healthy pulp to partially compensate for the the sensory stimuli, such as thermal change, mechanical loss of enamel or dentine caused by dental caries or deformation or trauma, the pulp registers different tooth wear through the formation of a hard tissue impulses as a common sensation, i.e., pain. Such pain- barrier that isolates irritants from the remaining pulp registering ability is important as part of the defense tissue. Secondary dentine is deposited circumferentially mechanisms of the pulp. Patients with an inflamed pulp at a very slow rate throughout the life of a normal tend to seek treatment earlier while the injury is tooth. The odontoblasts secrete the dentinal matrix and confined within the tooth, as opposed to those whose retreat toward the pulp center. They become crowded teeth have been root-filled where the pain sensation will and their direction can be altered. The dentine thus not be experienced until substantial damage has produced is “wavier” and contains fewer tubules. occurred in the tissues surrounding the root. In Odontoblasts may also form sclerotic dentine, addition, the proprioceptive function of the pulp limits reactionary dentine and reparative dentine in response the load imposed on teeth by the masticatory muscles, to adverse stimuli, such as caries or operative thus further protecting the tooth from injury.18,19 procedures. In sclerotic dentine, the dentinal tubules become partially or completely filled with mineral Odontoblasts deposits consisting of hydroxyapatite and whitlockite The odontoblasts are unique cells. Whilst the cell crystals, resulting in a decrease in the permeability of body of other mineral forming cells is close to the cell the dentine. However, for sclerosis to occur, viable process and stays within the calcified matrix, the cell odontoblast processes must be present within the process of odontoblasts extends a considerable distance tubules. In reactionary dentine, the tubules are into the dentine matrix and perhaps all the way to the continuous with the primary dentine and extend down outer boundary of the dentine in some cases while the to the odontoblasts. Reparative dentine occurs at the cell body remains in the pulp at the inner boundary of pulp surface of primary or secondary dentine and it will the dentine.20 In other words, the cell process extends be localized to the site of irritation. It forms some distance from its nutritional and controlling proportionally to the amount of primary dentine centre. The odontoblastic process is extremely fine and Australian Dental Journal Endodontic Supplement 2007;52:1. S5 resides within a dentinal tubule, which is like a cell layer occurs even before the appearance of capillary tube with a diameter that is much smaller than inflammatory changes in the pulp.36 An electromicro- that of an erythrocyte. Microtubules and microfilaments scopic study on the ultrastructural changes of ischaemic are the principal components of the process, providing pulps induced experimentally by extraction has shown infrastructure for transportation from the cell body to that distinct cellular changes, such as chromatin the remote cell process. clumping, irregular nuclear membrane and swollen In addition to a role in forming dentine, odontoblasts mitochondria, appear in odontoblasts as early as one may be involved in sensory transduction.21 The hour after extraction.37 Although no explanation has presence of tight, adhering and gap junctions may been offered for the vulnerability of odontoblasts to imply that these cells communicate with each other; insults, it can be speculated that the lack of oxygen due and if one is affected, many others are also affected. to circulatory disturbance during pulp inflammation Gap junctions exist between and among odontoblasts may be the main contributing factor. and nerve fibres,22,23 and they provide a pathway of low electrical resistance between and among the odonto- Pulp microcirculation blasts and nerve fibres. The hydrodynamic effects of The resilience to noxious insults and the inherent fluid displacement within the dentinal tubules or the healing potential of the dental pulp is well recognized. odontoblasts may activate mechanoreceptors of sensory Since the pulp is relatively incompressible, the total nerve axons.24 The odontoblast itself may be capable of volume of blood within the pulp space cannot be greatly mechanotransduction by stretch-activated ion channels increased. Hence careful regulation of pulp blood flow in the cell membrane.25 Odontoblasts are also implicated is of critical importance and alterations in pulp micro- in the regulation of pulp blood flow and in the circulation may be the first to occur with the onset of development of pulp inflammation. The enzyme pulp inflammation.3,34,38 NADPH-diaphorase involved in the production of In general, the pulp microcirculation is supplied nitric oxide, a potent vasodilator, is present in the through the maxillary artery, which is a branch of the odontoblasts.26,27 Their capacity to synthesize the external carotid artery. The maxillary artery leads into inflammatory mediator PGI2 has been demonstrated the dental artery and enters the tooth via arterioles and this may excite nerves in the vicinity resulting in a feeding each individual pulp microvasculature. Pulp brief hyperalgesia.28 vessels are arranged in a hierarchical system:39-41 the Although there is abundant information on the arterioles course up centrally and give off branches to structural aspects of odontoblasts, very little is known form a capillary network at the periphery of the pulp about the dynamic aspect of these cells, especially in the and the blood drains into venules at the centre of the mature pulp. Forming and maintaining dentine involves pulp. The capillary network provides the odontoblasts active transportation of calcium ions, collagen with a rich source of nutrients. The vascularity of the precursors or components of the extracellular matrix pulp is comparable with that of the most vascular parts from the pulp proper to the long process,20 an activity of the brain and the tongue, indicating that the pulp that presumably requires energy and hence oxygen. An is a highly vascular tissue.42 One study has shown in vitro respiratory study using the direct method of that pulp vessels are immune to artherosclerosis in Warburg has demonstrated significantly higher oxygen monkeys.43 uptake in the peripheral regions of bovine molar pulps, The dental pulp has a relatively high blood flow. It is indicating that odontoblasts may have a high oxidative estimated to be 40–50ml/min/100g of pulp tissue in a metabolism.29 A study with an in vitro culture system mature tooth as determined by radioactive microsphere has demonstrated that a large amount of oxygen is techniques.44-46 This flow is relatively high, compared to essential for maintaining proper functions of odonto- that of other oral tissues and skeletal muscle.47 blasts.30 Using oxygen-sensitive micro-electrodes, it has Numerous shunt vessels have also been observed in the been shown that odontoblast cells consume a relatively dental pulp, although their function is less well high amount of oxygen in the rat incisor pulp in vivo.31 understood.39,48 These vessels can be arterio-venous The average oxygen consumption rate of the odonto- anastomoses, venous-venous anastomoses or U-turn blasts obtained from that study is 3.2mL/O2/min/100g loops. They provide a direct communication between tissue, which is comparable with that of the brain.32 arterioles and venules, hence bypassing the capillary Furthermore, a transmission electron microscope study bed. Considerable shunting occurs in the apical half of has shown that odontoblasts are the cells most sensitive the pulp.48 When the intrapulpal pressure rises during to ischaemia.33 Odontoblasts in the pulp horn of rat inflammation, these shunt vessels may open up to molars with experimentally-induced hypoxia retain reduce the intrapulpal pressure so that the normal tritiated misonidazole, a marker preferentially labeling blood flow is maintained.49 cells with hypoxia.34 The earliest signs of pulp reaction to insults (such as Special features of the pulp with respect to its dental caries) are morphological changes and an over- circulation all reduction in the number and size of odontoblast cell The dental pulp has an unusual combination of bodies.35 The disruption in the underlying odontoblast features that makes its circulation rather unique. S6 Australian Dental Journal Endodontic Supplement 2007;52:1. Firstly, the compliance of the pulp is low because it providing an exit route for metabolic waste products resides in a rigid, unyielding calcified wall. A near from the tissue. Blood is brought to the tissue through simultaneous increase in pulp tissue pressure has been pulp arterioles. Oxygen, nutrients and wastes are recorded as a result of vasodilatation.50 Because exchanged in capillaries by diffusion, and waste capillary dilation and the transudation of fluids that products are removed by pulp venules. In general, comprise the early stages of acute inflammation blood flow to any organ must be high enough to ensure increase the volume of tissue, such swelling in the sufficient oxygen and nutrient supply. On the other dental pulp is likely to cause a pressure increase that hand, an excessively high blood flow level is undesirable stimulates pulp nerves to register pain. Secondly, the as it leads to a waste of energy. Hence, it is plausible dental pulp is a firm and resilient connective tissue, that the main purpose of the relatively high blood flow composed principally of a gelatin-like material, such as in the pulp is to serve the pulp cells, perhaps the proteoglycans and other glycoproteins, reinforced odontoblasts in particular, with important nutrients in throughout by irregularly arranged and interlaced an adequately high concentration in the capillary bed. collagen fibres. The resilient ground substance limits The pulp microcirculation also acts to maintain an intrapulpal pressures to the site of irritation, and is not intraluminal pressure within the pulp vasculature in transmitted throughout the pulp space.51 Significant harmony with the pulp tissue pressure. Studies using pressure differences have been observed at sites only servo-nulling techniques have demonstrated that the 1 to 2mm apart.52 Pressure from the increased tissue dental pulp has a relatively high tissue pressure but it is fluid collapses the thin-walled veins and venules only in considerably lower than the blood pressure inside the the area of the affected pulp tissue, causing a localized vessels.54 Bulk flow of fluid occurs across the capillary vascular stasis and ischaemia, resulting in local cellular walls for distribution of the extracellular fluid. Positive death. The gelated extracellular matrix may also act as net capillary filtration pressure leads to bulk flow of a barrier against the spread of micro-organisms and fluid out of the capillary into the extraluminal tissue toxic products. However, the inflammatory process and space, which in turn is balanced by an equal lymphatic resultant intrapulpal pressure changes may progress return.55,56 Thus, the tissue fluid volume in the pulp apically by increments circumferentially from compart- remains constant. The relatively high pulp tissue ment to compartment. When the structural integrity of pressure results in an outward flow of fluid in the the pulp tissue is lost with overwhelming inflammation, dentinal tubules, which helps to dilute toxins and wash the increased tissue pressure can spread with a resultant out bacteria. compression of the blood vessels at the apex and result in total necrosis.53 Thirdly, although the dental pulp is a Control of pulp blood flow rich vascular tissue, terminal arteries supplying it fall There has been some disagreement as to whether the within the microcirculatory diameter range.3 Unlike in pulp microcirculation is capable of functional regulation. most tissues, the pulp circulation lacks a true collateral Pulp blood flow in anaesthetized animals is dependent blood supply. This restricted blood source may on alterations in systemic blood pressure.57 Stealing presumably limit the blood supply to the dental pulp, perfusion of the surrounding tissues has been implicated making it less capable of overcoming a severe irritant in the paradoxical decrease in pulp blood flow in than other better-supplied tissues. Fourthly, because the response to arterial infusion of well-known vasodilators tooth bridges between the bacteriologically sterile in other circulations.58 “Stealing” of the blood supply to environment of the jawbone and the heavily the dental pulp is thought to occur when vasodilation contaminated environment of the mouth through an of the neighbouring tissues reduces the perfusion oral epithelial membrane, diseases in the pulp will pressure to the pulp, thus producing a decrease in the invariably extend through the apical foramen into the blood flow to the pulp.58 However, the passive view of surrounding bone causing further problems. pulp microcirculation has been challenged by a body of As a consequence of these features, the degree of pulp in vivo data: topical application or close intra-arterial inflammation does not necessarily need to be severe to bolus injection of various vasoactive substances alter cause pulp death, and if left untreated, progression to pulp blood flow while systemic blood pressure is the surrounding alveolar bone is likely to occur. Hence, unaltered.38,59-62 Pulp blood flow in anaesthetized careful regulation of the pulp microcirculation seems to animals of several species is under the influence of local be critically important in order to maintain the nerve impulses unrelated to systemic haemodynamics.63 well-being of the pulp. The fact that most pulps survive Perivascular sympathetic nerve fibres liberate life-long exposure to various inimical attacks implies noradrenaline and possible neuropeptide Y causing a the presence of a well-regulated microcirculation in the reduction of pulp blood flow,64-67 whereas intradental pulp. sensory nerves liberate neuropeptides causing an increase in pulp blood flow.50,68-71 Reflex excitation of Functions of the pulp microcirculation the sympathetic nervous system causes pulp The primary function of the pulp microcirculation, in vasoconstriction and a reduction in pulp blood flow.72 common with all circulation in the body, is to supply Reflex activation of sensory axons causes pulp oxygen and nutrients to its constituent cells, as well as vasodilatation spreading beyond the site stimulated as Australian Dental Journal Endodontic Supplement 2007;52:1. S7 a result of branching of sensory axons.73 Beaded nerve of free nerve fibres that are specific receptors for pain. terminals are found in intimate association with From there, the free nerve terminals may enter the smooth muscle in the walls of arterioles and venules. odontoblastic layer, and penetrate into the predentine The peri-vascular nerve endings are adrenergic post- zone or to the inner dentine next to the odontoblastic ganglionic fibres containing noradrenaline, or cell process, but not every dentinal tubule will contain somatosensory nerve fibres containing substance P or nerve endings. Myelinated nerves do not reach their calcitonin gene-related peptides.74,75 These nerve fibres maximal development and penetration into the pulp appear to participate in the regulation of the pulp blood until the tooth is fully formed, which may explain why flow by affecting vascular smooth muscle tone, thereby young teeth are less sensitive than adult teeth. The changing vessel diameter. Pulp blood flow is hence branching of nerve axons has been observed not only considered to be predominantly under neural control.63 within the pulp but also occurs in the periapical region The possible existence of a local vascular regulation where these axons may branch to supply the pulps of in the pulp has been proposed recently.76-79 It is adjacent teeth just prior to entering the pulp.85 important in the confined and restricted circulation It has been postulated that the A-␦ and A-␤ fibres that microvascular tone is modulated locally to match produce the initial rapid sharp pain in response to the nutrient flow and tissue demands. Using an isolated external stimuli without the presence of tissue injury pulp arteriole preparation combined with in vivo because of their peripheral location, low threshold of measurement of pulp blood flow and pulp oxygen excitability and fast conduction. On the other hand, the tension, it has been demonstrated that the pulp smaller C fibres cause a slow, dull and crawling pain vasculature is capable of responding to a range of related to pulp tissue damage and the inflammatory vasoactive mediators and the pulp microcirculation process due to their much higher threshold of excitability may be controlled locally by endothelium-related and slow conduction. Almost all of the A-␦ fibres are factors, metabolic (tissue-related) factors, as well as located in the coronal portion of the pulp, with the humoral (blood-borne) factors. greatest nerve density in the pulp horns. In contrast, C- It is important to study the pulp microcirculation fibres are located in the pulp proper, extending most because of its brave but limited success in dealing with likely into the cell-rich zone.86 injury in a restricted low compliance environment. Pulp usually responds to various stimuli as one Studies of oxygen tension in the tissue and the individual sensation, i.e., pain. However, the exact mechanism properties of the pulp vessels will help to understand that transmits the stimuli through the dentine to initiate the mechanism that leads to necrosis in hypoxia and pain is largely unknown. anoxia following vessel collapse after progressive Several hypotheses about dental pain transmission spread in raised interstitial fluid pressure. Two practical have been proposed including hydrodynamic outcomes of this understanding would be the discovery mechanism, odontoblastic transduction and dentine of therapeutic agents and strategies that could help the innervation. pulp survive, and the developments of techniques for Among these hypotheses, the hydrodynamic theory measuring pulp blood flow clinically such that a true enjoys the most popularity.7 The free nerve endings at diagnosis of the presence and extent of pulp the periphery of the pulp are exquisitely sensitive to inflammation could be made. Both outcomes may sudden pressure changes and fluid movement. The enable practitioners to diagnose and treat pulp diseases dentine contains thousands of capillary-like tubules at an early stage. that are filled with water-like dentinal fluid. A stimulus such as cold or compressed air will extract tubular fluid Pulp nerves from its outer surface and cause an outward flow The dental pulp contains both sensory and autonomic whereas other stimuli, such as heat or chewing pressure nerves to fulfill its vasomotor and defensive on a loose filling, will drive the tubular fluid inward functions.75,80-84 towards the pulp. This rapid fluid movement, either inward or outward, exerts a direct mechanical Sensory nerves deformation on the low-threshold A-␦ fibres within the The sensory nerves, which are involved in pulp pain tubules or in the subjacent pulp tissue. The fluid perception and transduction, are branches of the movement may also cause a concomitant movement of maxillary and mandibular divisions of the trigeminal odontoblasts, which may in turn deform nerve fibres in nerve. The small branches enter the apical foramina contact with their process or cell body. The deformed and progress coronally and peripherally following the nerve membrane increases its permeability to Na+ ions. route of the blood vessels, and they branch extensively The rapid inward movement of the sodium depolarizes subjacent to the cell-rich zone, forming the plexus of the A-␦ fibre membrane, and an action potential (pain Raschkow. The plexus contains both large myelinated impulse) is initiated. A-␦ and A-␤ fibres (2–5µm in diameter) and the smaller The dentine innervation theory postulates that nerve unmyelinated C fibres (0.3–1.2µm). At about the level endings penetrate dentine and extend to the dentino- of the cell-rich zone, myelinated fibres lose their myelin enamel junction. Direct mechanical stimulation of these sheath. In the cell-free zone, they form a rich network nerves will initiate an action potential. Free nerves have S8 Australian Dental Journal Endodontic Supplement 2007;52:1. been demonstrated to penetrate into the dentine, but as cognitive, motivational and affective processes, also these nerves are confined to the inner one-third of modulate the gate. Ascending pain pathways, the dentine. Moreover, pain producing substances such as sensory-discriminative pathway, allows localization of bradykinin fail to induce pain when applied to dentine, pain and reticular information pathway deals with the and bathing dentine with local anesthetic solutions unpleasant, aversive and emotional aspects of pain. does not prevent pain. The transduction theory states that odontoblasts can Sympathetic nerves transduce a mechanical stimulus and transfer that A sympathetic adrenergic vascular control exists in signal to a closely opposed nerve terminal. the dental pulp.89 Mediators presently known are Odontoblasts are derived from the neural crest and noradrenaline and neuropeptide Y. The sympathetic their cellular processes extend into the dentinal tubules nerve fibres originate from the cervical sympathetic which extend to the dentino-enamel junction. ganglion, and after joining the trigeminal nerve at its Odontoblasts communicate with each other via gap ganglion, most of them follow the course of the sensory junctions, and are closely associated with nerve nerves to the teeth, or they possibly travel via the blood terminals. Nonetheless, odontoblasts are matrix- vessels. Sympathetic vasoconstriction is typically forming cells and hence they are not considered to be activated by stress stimuli and by painful stimuli directed excitable cells, and no synapses have been demonstrated at almost any part of the body. Sympathetic vaso- between odontoblasts and nerve terminals. That is, constriction may modulate the excitability of the sensory they have no means of chemical transmission. nerves. In the compromised pulp, sympathetic vaso- Dental pain is also modulated and influenced by the constriction is attenuated. Local sensory vasodilation higher centres in the body. It is a subjective experience becomes predominant, which may contribute to further and to a great extent depends on psychological progression of pulp inflammation.63 phenomena. The precise mechanism for the transmission of pain and the specific pathway to the higher centre is Neurogenic inflammation not completely understood. The gate control theory has Activation of sensory nerves in the pulp (either by been proposed but it is still speculative.87 This theory electrical stimulation of the inferior alveolar nerve or suggests that there is a gating mechanism in the directly on the tooth crown) induces a long-lasting substantia gelatinosa of the spinal cord and brainstem blood flow increase in the pulp and increased vascular on which both peripheral nerve fibres and descending permeability. Furthermore, excitation of A-␦ fibres central influences exert their effect in the pain seems to have an insignificant effect on pulp blood flow experience.88 Depending on the degree of activity in (PBF), whereas C fibre activation causes an increase in large diameter and small diameter afferent nerve fibres, PBF. Neurogenic inflammation is thought to be mediated the gating mechanism either inhibits or facilitates by neuropeptides released from sensory nerves, such as transmission of impulses: the large diameter fibres are substance P (SP) and calcitonin-gene-related-peptides activated by non-noxious stimuli and close the gate, (CGRP), and possibly the reactive oxygen species at the whereas the small diameter fibres are activated by site of inflammation.59,63,79,90,91 However, little is known noxious stimuli and open the gate. Descending control about the correlation between the symptoms and levels mechanisms from higher central nervous centres, such of neuropeptides in the pulp except that the amount of Table 1. Common causes of pulp disease Group Type Examples or reasons Microbial Coronal ingress Caries, marginal breakdown of restorations, fractures, cracks Radicular ingress Advanced periodontal disease, cracks, fractures, breakdown of root canal fillings, advanced external invasive resorption Traumatic Accidental Fractures, concussion, luxation, avulsion, traumatic occlusion Physiological Attrition, abrasion, traumatic occlusion Iatrogenic Cavity preparation Heat, deep cavity, dehydration, pulp exposure Restoration procedures Insertion, fracture, cementing, polishing Accumulative Area of dentine cut Prosthetic manipulation Fixed and removable prosthodontics Orthodontics Tooth movement Periodontics Treatment of deep pockets Radiation Radiotherapy for carcinoma General anaesthesia Trauma during intubation procedures Surgery Rhinoplasty, Caldwell-Luc, dento-alveolar surgery, oral surgery Electrical Galvanic reaction Local analgesia Reduced blood flow due to vasoconstrictors Smoking Reduced blood flow Chemical Restorative materials Material toxicity Erosion Various acids, foods Others Ageing Blood supply reduced Systemic diseases Hypophosphataemia External invasive resorption Advanced cases – pulp may be exposed, or plaque enters through the defect Australian Dental Journal Endodontic Supplement 2007;52:1. S9 Table 2. Common reactions of the dental pulp to stimuli Type of stimulus Examples Pulp reaction Outcome if not treated Short-term – Cavity preparation procedures such Acute inflammation Healing and recovery (since the stimulus is not as cutting dentine, heat produced, continuous or it is removed) drying, etc – Trauma without luxation Long-term – Dental caries Chronic inflammation a) Necrosis – Restoration breakdown b) Then infection of the pulp space – bacterial – Erosion, attrition pathway of entry created by the loss of tooth – Chemical irritation structure (i.e. loss of coronal tooth c) Once infected, the tooth will eventually become structure or its integrity) pulpless Trauma – Luxation Necrosis a) Infection of the pulp space if a pathway for – Avulsion bacterial entry is present (i.e. any injury that severs the apical b) Once infected, the tooth will eventually become blood vessels) pulpless SP increases with the progression of caries. displacement (luxation or avulsion) of the teeth will Furthermore, its expression is significantly higher in result in severing of the apical blood vessels. In teeth painful pulp with large carious lesions than in with fully developed roots, these blood vessels will asymptomatic pulps with similar size carious lesions.92 often not be able to heal and revascularize the pulp. Excitatory amino acids have been suggested to activate Therefore, in these cases, the response of the pulp to the sensory nerves to release CGRP.93 injury is immediate necrosis. Subsequently, the necrotic Neuropeptides may also have some modulatory role pulp may become infected but this requires that there in the pulp immune defense system.94 Pulp dendritic be a pathway for bacterial entry such as through a cells may interact with T lymphocytes by the generation crack or fracture. A crack or a fracture may have been of cytokines, which up regulate the expression of created during the same traumatic incident that adhesion molecules on vascular endothelial cells to displaced the tooth so infection is not unusual in these facilitate immune-cellular infiltration. They may induce cases. No matter what the cause, once a pulp has transendothelial migration of immunocompetent cells, necrosed and become infected, in all such cases the such as CD43+ cells during acute neurogenic bacteria within the root canal system will digest and inflammation.95 remove the necrotic pulp so the tooth then becomes pulpless. Diseases of the pulp The dental pulp may be exposed to a number of Bacteria irritants that are noxious to the health of the pulp and Bacterial infection is the most frequent cause of pulp jeopardize the functions of the pulp. They may be either and periapical diseases.96-101 Bacteria may enter the constant irritants or specific events that interfere with tooth via caries,102-105 dental anomalies (e.g., dens the pulp blood supply (Table 1). Irritants can be invaginatus, deep lingual and palatal grooves), exposed classified as being short-term, long-term or due to lateral canals or damaged cementum as a result of trauma. Each type of irritant or injury will have a periodontal diseases,106,107 tooth cracks or fractures,108,109 different effect on the pulp – in general, the effects will and marginal breakdown at the restoration-tooth be acute inflammation, chronic inflammation or necrosis interface.110-113 (Table 2). Short-term irritants will usually cause acute Bacterial infections of the pulp space consist of inflammation which will then be followed by resolution mixed microbial and predominantly anaerobic flora.114-117 of the inflammation and repair of the tissue since the It has been found that Streptococcus mutans by itself irritant does not persist or is no longer occurring. will not induce pulp inflammation.114,115 Although Common examples of short-term irritants are the cut- several species of bacteria have been identified, there is ting or drying of cavities during their preparation and no absolute correlation with clinical signs and traumatic injuries that have not displaced the tooth so symptoms; and it is noteworthy that the pulp may the apical blood supply has not been disrupted. In become inflamed long before the bacteria physically contrast, typical long-term irritants are dental caries, reach the pulp.103 Superficial caries in pits and fissures restorations breaking down, cracks, erosion and may cause pulp inflammation.118 Substances such as chemical substances which all lead to the loss of tooth bacterial toxins, enzymes, antigens, chemotoxins, structure. Long-term irritation will cause chronic organic acids and products of tissue destruction may inflammation of the pulp and, if left for long enough, diffuse through the dentinal tubules to cause pulp pulp necrosis which will then be followed by infection irritation.99 of the pulp space since bacteria will have a pathway by The response of pulp to bacteria depends on many which they can enter the tooth. In these situations, the factors, such as the speed of bacterial ingress and the pathway of entry for the bacteria will be where the speed of progress of caries, which can be slow, rapid or tooth structure has been lost. Trauma that causes completely inactive (caries tends to be an intermittent S10 Australian Dental Journal Endodontic Supplement 2007;52:1. process, with periods of rapid activity alternating with preparation is a common cause of pulp inflammation. periods of quiescence). Caries progresses quickly High-speed cutting is superior to low-speed even when through demineralized enamel, but will progress more air and water coolant are used but some degree of pulp slowly in demineralized but more organic dentine.119 In irritation will still occur. Heat, cutting depth (within young teeth, bacteria may cause the early death of 0.5mm of the pulp) and dehydration cause damage to odontoblasts, and those dentinal tubules devoid of the pulp. Pin insertion can crack dentine and predispose odontoblast cell processes become dead tracts. These the tooth to bacterial infection. Large restorations may tracts are highly permeable, and therefore they are a cause cracks in teeth when under load. Pressure from potential threat to the integrity of the pulp. Fortunately, condensing restorative materials may intensify pulp the healthy pulp responds by depositing a layer of responses induced by the cutting procedure. Acid reparative dentine over its pulp surface, thus walling it etching, a common procedure in adhesive dentistry, off. The pulp response is also related to the thickness removes the smear layer and this may allow bacteria to and degree of calcification of the remaining dentine, enter the dentinal tubules.123,124 Orthodontic movement, since dentine permeability can be reduced by dentinal periodontal curettage, and prosthodontic manipulation sclerosis and reparative dentine formation.104 If the may also cause pulp inflammation. distance between the caries and the pulp is 1.1mm or more, pulp inflammation may be negligible. When the Medical procedures, such as rhinoplasty, may caries reaches within 0.5mm of the pulp, there is a damage pulps adjacent to the surgical area or they may significant increase in the extent of inflammation, but interfere with the blood supply to the pulp. The the pulp becomes acutely inflamed only when the Caldwell-Luc surgical technique, which involves reparative dentine is invaded by irritants such as removal of the lining of the maxillary antrum, may also bacteria or their toxins. cause pulp inflammation, necrosis or anaesthesia. Bacterial entry via periodontal pockets is less likely to cause pulp inflammation unless the main apical Chemical foraminae are involved in the pocket which contains Most of the current restorative materials are relatively bacterial plaque.120 inert. However, it is usually bacteria penetrating the restoration margins which causes pulp inflammation, Trauma rather than the chemicals themselves.113 Trauma from accidents or bruxism may cause pulp inflammation. Crown fractures may provide a pathway Others for microbial invasion108 which can lead to pulp necrosis Pulps age! With age, nerve and blood supply to the and infection of the root canal system. Root fractures pulp tends to decrease, and the pulp becomes more affect the pulp differently since they may disrupt the fibrous and less cellular.125 As a result, the pulp may pulp vascular supply within the portion of the tooth become less equipped to mount a defensive reaction to that is coronal to the fracture line and this can lead to injuries. However, dentine permeability reduces with necrosis of the pulp in that segment of the tooth. age as a result of a progressive reduction in tubular However, the rate of survival of the pulp following root diameter and an increase in the formation of peritubular fractures is high and the pulp can initiate a callus-like dentine. This provides a more protective environment form of healing at the fracture site, especially in for the pulp. immature teeth. Impact trauma may squash the blood The dental pulp usually remains walled off by a thin vessels at the apex of tooth and cause temporary layer of dentine and predentine until late in the disease disruption of blood flow, resulting in vascular stasis process of external invasive resorption. Secondary with subsequent development of hypoxia and invasion of micro-organisms into the pulp will elicit ischaemia. However, a young tooth with a wide apical foramen may recover by re-establishing blood flow. pulp inflammation when enough dentine has been Severe impact (such as intrusion) may destroy the pulp destroyed.126 vessels at the apical foramen and lead to pulp necrosis. Some systemic diseases have dental anomalies. In However, depending on the severity of the impact, the hereditary hypophosphataemia, the size of the pulp age of the patient and the prior health status of the horns tends to increase and dentine is more susceptible pulp, revascularization may occur, especially in to bacterial ingress. Patients with sickle cell anaemia immature teeth. This usually results in calcification of tend to have more frequent toothache which may be the root canal in the longer term but occasionally due to abnormal blood flow to the pulp.127,128 internal resorption has been observed. Trauma from occlusion can play a role in the Pathogenesis initiation and progression of pulp inflammation, how- Mild and moderate injury to the odontoblast cell ever the inflammatory changes tend to be transient.121,122 processes may produce tubular sclerosis and reparative dentine, but prolonged or severe irritation can cause the Iatrogenic factors death of the odontoblasts and initiation of an Paradoxically, the very dental treatment designed to inflammatory response. The dynamics of pulp repair the tooth may do harm to the dental pulp. Cavity inflammation is not different to that of inflammation in Australian Dental Journal Endodontic Supplement 2007;52:1. S11 the periapical and other tissues. Depending on the Odontoblasts severity and duration of the irritants, the pulp response As mentioned above, the earliest sign of pulp ranges from reversible to irreversible pulpitis, then to inflammation is disruption of the odontoblastic layer. partial necrosis which leads to total necrosis. This may Even before the appearance of inflammatory changes in occur without pain.129 The dental pulp may also the pulp, there is an overall reduction in the number respond to irritation with a range of degenerative and size of odontoblast cell bodies. The nuclei of the changes including fibrosis and calcification. cells may be aspirated into the dentinal tubules due to the outward flow of tubular fluid, or the cells may be Inflammation irreversibly damaged which results in the release of The initial inflammatory cell infiltrate consists tissue injury factors affecting neigbouring odontoblasts principally of lymphocytes, plasma cells and and underlying connective tissue. Cells may undergo macrophages. A wide range of non-specific mediators vacuolization, ballooning degeneration of mitochondria, of inflammation such as histamine, bradykinin, and reduction in the number and size of the endoplasmic serotonin, interleukins (IL) and arachidonic acid reticulum. However, it is still unknown whether metabolites are released in response to bacterial odontoblasts die of apoptosis or necrosis. invasion and tissue injury.130 In addition, many neuropeptides, e.g., substance P (SP) and calcitonin Disease progression gene-related peptide (CGRP), are also involved and The two key components in pulp inflammation are may interact with the mediators produced during the microcirculation and the sensory nerve activity.137 inflammation. Injury to the pulp may activate the intradental sensory The IL-1 and IL-2 producing cells are located nerves to release neuropeptides, which in turn cause within the connective tissue stroma of pulps.131 Mast alteration of microcirculatory haemodynamics. cells, which are the main source of histamine, are found The response of sensory nerves to stimuli depends in inflamed pulp. A fourfold increase can be found in upon the severity of the pulp injury and the stages of pulp histamine levels within 30 minutes of thermal inflammation. Within the first few minutes of injury, injury, suggesting that histamine may play a role in the destruction and disruption of nerve fibres in the injured initial stages of pulp inflammation.132 Platelets dentine and pulp occurs, followed by hypersensitivity aggregated in the vessels release serotonin, which along of the surviving nerve fibres and the release of with the other inflammatory mediators induce a state of neuropeptides into the pulp. Inflammatory mediators, hyperalgesia in the pulp nociceptors. Plasma or tissue such as bradykinin and the prostaglandin E2, may also kallikreins contact kinogens leading to the production evoke the neurosecretion of CGRP.138 of bradykinin and other kinins to produce many signs These neuropeptides cause vasodilatation and and symptoms of inflammation. Phospholipase A2 increased vascular permeability, hence the neurogenic causes release of arachidonic acid from cell membranes, inflammation. The tissue becomes oedematous as a resulting in the formation of various prostaglandins, result of filtration of serum proteins and fluid from the thromboxanes, and leukotrienes. vessels. In the low-compliant environment of the pulp, the increase in both interstitial fluid volume and blood Immune defense system volume leads to an increase in the tissue pressure, In addition to non-specific inflammatory reactions, which in turn causes compression of the thin-walled immunologic responses may also initiate and perpetuate venules, resulting in a decrease in blood flow and an pulp disease. It has been reported that in patients with increase in flow resistance in the venules. The flow hereditary combined immunodeficiency, deep caries stasis causes an aggregation of red blood cells and an only produces a mild inflammation and relatively little elevation of blood viscosity. It also produces tissue destruction of the pulp despite the presence of a large hypoxia or ischaemia, which suppress cellular number of bacteria.133 In mild to moderate metabolism in the affected area of the pulp. This results inflammation, the cell-mediated immunity in tissue necrosis. An increase in carbon dioxide and a predominates.105 In severe inflammation, the appearance decrease in pH levels alter the local micro-environment, of B cells and plasma cells indicates local antibody and may lead to vasodilatation in the adjacent area and production, hence the predominance of humoral the gradual spread of inflammation. immunity.134,135 Specific IgG has been found in pulp with However, it should be remembered that pulp is deep caries.136 Bacterial substances may trigger the capable of localizing the inflammation and the tissue complement system via the antigen and antibody adjacent to the inflammatory lesion may be completely complex, which become chemotactic for poly- normal.139 If healing is favourable, the increase in tissue morphonuclear leukocytes. There is a distinct ratio pressure may open the shunt vessels and subsequently difference between T-helper and T-suppressor redirect the blood before it reaches the inflamed region lymphocytes in reversible and irreversible pulpitis. The of the pulp.140 This prevents a further increase in blood predominant T-suppressor cells are able to suppress the flow and tissue pressure. Also the increase in tissue inflammatory process and reverse the condition in the pressure may initiate increased lymph flow and pulp. absorption of fluid into capillaries in nearby non- S12 Australian Dental Journal Endodontic Supplement 2007;52:1. inflamed tissue.53,56,139 All these factors will transport done.144 Inflammatory mediators lower the sensory fluid away from the affected area and out of the tooth nerve threshold. The increased tissue pressure acts which will consequently lower the tissue pressure. directly on sensory nerve receptors. An increase in pulp Furthermore, increased tissue pressure will promote blood flow causes excitation of both A-␦ and C fibres outward flow of fluid through exposed dentine tubules via an increase in tissue pressure, whereas reduction in and thereby help to protect the pulp against the entry blood flow has an inhibitory effect on A-␦ fibres due to of harmful substances. hypoxia, but no discernible effect on C fibre activity. As Sprouting of sensory nerve terminals and up- a consequence, the gate remains open and stimuli that regulation of the neuropeptides may also occur.141,142 It were not noxious to a normal pulp (such as heat and would be expected that sensory nerves participate in cold) trigger a more painful response because of the the inflammatory process by an increased release of the small-fibre activity (unmyelinated C fibres). neuropeptides. The nerve growth factor produced by During neurogenic inflammation, sodium channel pulp fibroblasts may mediate the nerve sprouting expression shifts from tetrodotoxin-sensitive (TTXs) to reactions. tetrodotoxin-resistant (TTXr), leading to hyperalgesia Should the irritant be eliminated or become inactive, of C fibres.145 These TTXr sodium channels are tissue granulation becomes predominant as it replaces relatively resistant to local anaesthetics compared with inflammation and nerve sprouting subsides when TTXs channels. In this situation, bupivicaine may be reparative dentine covers the injury site. There is a the anaesthetic of choice because it is found to be more proliferation of small blood vessels and fibroblasts potent than lidocaine in blocking TTXr channels.146 together with the deposition of collagen fibres. CONCLUSION Alternatively, if the irritant overwhelms the pulp’s defense ability, blood flow to the area ceases and the The dental pulp is a unique tissue and its importance injured tissue undergoes necrosis. Neutrophils in the in the long-term prognosis of the tooth is often ignored area degenerate and release intracellular lysosomal by clinicians. While pursuing technical excellence in enzymes to digest the surrounding tissue, forming endodontics, it is important that clinicians also have an necrotic tissue. Pulp microcirculation may also be awareness and understanding of the physiological and adversely affected by accidental injury or any event that pathological features of the dental pulp as well as the causes long-term interruption of the blood supply to biological consequences of treatment interventions. the pulp.143 REFERENCES As time progresses, necrotic pulp tissue will become 1. Walsh LJ. 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