The influence of chronic apical periodontitis on oral and general health

In healthy condition, the periodontal space between the root surface and the alveolar bone is relatively poor in cells. In case of root canal infection however, large number of immune-inflammatory cells infiltrate the periapical region of the affected teeth. A major issue is if and to what extent microbial and host cells contribute to lesion formation and whether the local inflammation may impair general health. The question is important as it may fundamentally influence the therapeutic strategy in patients with apical periodontitis. The aim of this paper is to review the results of recent experimental and clinical observations that investigate the importance of cellular interactions in exerting protective and destructive effects in periapical inflammatory lesions. The majority of studies indicate that the lesion would not develop in the absence of permanent release of bacteria and their by-products from the infected root canal. On the other hand, the formation of the classical granulation tissue is dependent on the presence and proper function of host cells and regulatory molecules. The dynamic encounter of root canal microbiota and the local immune system prevents overwhelming bacterial infiltration of the periradicular space but it is also connected with degenerative changes, most importantly bone resorption, resulting ultimately in tooth loss. However, by the use of proper endodontic methods, the lesion can be successfully treated in the majority of cases. Remineralization of the lost hard tissue will occur or the lesion will transform into an inert periapical scar.     

Molecular mediators of pulp inflammation and regeneration

Dental tissue infection results in immune and inflammatory responses mediated by molecular and cellular events that, if unchecked, result in tissue breakdown. The tooth, like other tissues and organs within the body, will attempt to repair and regenerate its own hard and soft tissues given the appropriate conditions and environment. However, unchecked infection and inflammation will have a significant impact on the natural regenerative responses of the dental tissues. Thus far, there have been limited studies addressing the inter‐relationship between these two processes, which are clearly linked by molecular and cellular events. Indeed, locally derived growth factors, cytokines, and chemokines, which are all sequestrated within the dental tissue extracellular matrix and are also expressed by pulpal cells, immune cells, and/or necrotic host tissue, will have considerable impact on the cellular events within the tissue. In addition to the molecular signaling, there will be important cellular interactions that will occur as stem cells, resident or recruited to the pulp, have known immuno‐modulatory activity with significant implications for regenerative events. In this review, we aim to explore how the pulpal tissue responds to the invading bacteria and the signaling mechanisms that are now being described and are important in regulating both the immune/inflammatory and regenerative responses.     

Differential expression and distribution of syndecan-1 and -2 in periodontal wound healing of the rat

Cell-surface proteoglycans participate in several biological functions including interactions with adhesion molecules, growth factors and a variety of other effector molecules. Accordingly, these molecules play a central role in various aspects of cell-cell and cell-matrix interactions. To investigate the expression and distribution of the cell surface proteoglycans, syndecan-1 and -2, during periodontal wound healing, immunohistochemical analyses were carried out using monoclonal antibodies against syndecan-1, or -2 core proteins. Both syndecan-1 and -2 were expressed and distributed differentially at various stages of early inflammatory cell infiltration, granulation tissue formation, and tissue remodeling in periodontal wound healing. Expression of syndecan-1 was noted in inflammatory cells within and around the fibrin clots during the earliest stages of inflammatory cells infiltration. During granulation tissue formation it was noted in fibroblast-like cells and newly formed blood vessels. Syndecan-1 was not seen in newly formed bone or cementum matrix at any of the time periods studied. Syndecan-1 expression was generally less during the late stages of wound healing but was markedly expressed in cells that were close to the repairing junctional epithelium. In contrast, syndecan-2 expression and distribution was not evident at the early stages of inflammatory cell infiltration. During the formation of granulation tissue and subsequent tissue remodeling, syndecan-2 was expressed extracellularly in the newly formed fibrils which were oriented toward the root surface. Syndecan-2 was found to be significantly expressed on cells that were close to the root surface and within the matrix of repaired cementum covering root dentin as well as at the alveolar bone edge. These findings indicate that syndecan-1 and -2 may have distinctive functions during wound healing of the periodontium. The appearance of syndecan-1 may involve both cell-cell and cell-matrix interactions, while syndecan-2 showed a predilection to associate with cell-matrix interactions during hard tissue formation.     

Human T‐cell responses to oral streptococci in human PBMC‐NOD/SCID mice

We investigated cellular and humoral immune responses to oral biofilm bacteria, including Streptococcus mutans, Streptococcus anginosus, Streptococcus sobrinus, and Streptococcus sanguinis, in NOD/SCID mice immunized with human peripheral blood mononuclear cells (hu‐PBMC‐NOD/SCID mice) to explore the pathogenicity of each of those organisms in dental and oral inflammatory diseases. hu‐PBMC‐NOD/SCID mice were immunized by intraperitoneal injections with the whole cells of the streptococci once a week for 3 weeks. FACS analyses were used to determine the percentages of various hu‐T cell types, as well as intracellular cytokine production of interleukin‐4 and interferon‐γ. Serum IgG and IgM antibody levels in response to the streptococci were also determined by enzyme‐linked immunosorbent assay. S. anginosus induced a significant amount of the proinflammatory cytokine interferon‐γ in CD4⁺ and CD8⁺ T cells in comparison with the other streptococci. However, there was no significant differences between the streptococci in interleukin‐4 production by CD4⁺ and CD8⁺ T cells after inoculation. Further, S. mutans significantly induced human anti‐S. mutans IgG, IgG₁, IgG₂, and IgM antibodies in comparison with the other organisms. In conclusion, S. anginosus up‐regulated Th1 and Tc1 cells, and S. mutans led to increasing levels of their antibodies, which was associated with the induction of Th2 cells. These results may contribute to a better understanding of human lymphocyte interactions to biofilm bacteria, along with their impact on dental and mucosal inflammatory diseases, as well as endocarditis.     

Dentin-induced in vivo inflammatory response and in vitro activation of murine macrophages

The activation of inflammatory cells and consequent release of mediators play an important role in the resorption of mineralized tissues. In the present study, we examined the ability of dentin extracts to induce inflammatory cell recruitment and activation. We showed here that dentin extracts triggered an intense cell migration and progressive cell maturation, in a time- and dose-dependent manner. Expression of interleukin-1 beta (IL-1 beta), tumor necrosis factor-alpha (TNF-alpha), nitric oxide (NO), and hydrogen peroxide (H(2)O(2)) was also up-regulated by dentin extracts. These results show that inflammatory events can be elicited in response to dentin, which may suggest a possible involvement of dentin molecules in the inflammatory events, coupled with their release at the root resorption sites.     

Management of trauma‐induced inflammatory root resorption using mineral trioxide aggregate obturation: two‐year follow up

Abstract – Inflammatory root resorption is a serious complication of dental trauma, which leads to progressive loss of the root structure. This report describes the treatment a previously traumatized young maxillary lateral incisor, severely affected by inflammatory root resorption. An 11‐year‐old boy presented with pain and mobility in his maxillary incisors which experienced fall trauma 2 years earlier. Radiographic examination revealed incomplete root development of the right central incisor, associated with advanced inflammatory root resorption and a periapical lesion. Following removal of a prior long‐term calcium hydroxide dressing, the root canal was submitted to a 2‐week irrigation regimen involving 1.25% sodium hypochlorite and 2% chlorhexidine gluconate. Thereafter, the entire root was filled with mineral trioxide aggregate. The radiographic follow up at 6 months showed arrest of root resorption and initiation of periapical healing in the absence of clinical symptoms and mobility. This was followed by advanced osseous regeneration and re‐establishment of the periodontal space at 12 and 24 months. From the present case, it can be concluded that mineral trioxide aggregate obturation can be a viable option that can improve the healing outcomes in cases of severe inflammatory root resorption in young permanent teeth.     

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??Periodontal disease is considered to be one of the independent risk factors of cardiovascular diseases. Mounting evidences have demonstrated that periodontal pathogens may transfer from oral environment into blood circulation and then colonize on vascular cells??where numerous inflammatory cytokines and chemokines will be released and conduct the interactions between vascular endothelial cell and monocyte. Consequently??inflammatory injuries and vessel damages will form??resulting in atherosclerosis??the common characteristic and progression of cardiovascular diseases. This article will review the present research on periodontal pathogens-induced atherosclerosis.     

T‐ and B‐cell subsets in periodontitis

A large amount of information is available, in the medical literature, on the molecular and immunological mechanisms in which T‐ and B‐cells are involved in the pathogenesis of inflammatory diseases. This review attempts to describe the most important features of the T‐cell subsets and their cytokine networks in periodontitis, including the interaction of pathogens with different cell subsets and their gene‐expression profiles. Additionally, the known interactions of T‐ and B‐cell subsets in periodontitis are described. The purpose of this article was to provide an overview of the cell interactions and cytokine networks specifically involved in the pathogenesis of periodontitis, and models and paradigms from recent research in this area are presented. However, the review of the literature also revealed that relatively little is known about the genetic or structural factors that confer cross‐reactivity of natural and/or autoreactive antibodies in the immunopathogenesis of periodontitis. Pathogens, in turn, are continuously evolving and creating mechanisms to evade immunological reactions controlled and modulated by T‐ and B‐cells.     

Application of specialized pro‐resolving mediators in periodontitis and peri‐implantitis: a review

Scaling and root planning is a key element in the mechanical therapy used for the eradication of biofilm, which is the major etiological factor for periodontitis and peri‐implantitis. However, periodontitis is also a host mediated disease, therefore, removal of the biofilm without adjunctive therapy may not achieve the desired clinical outcome due to persistent activation of the innate and adaptive immune cells. Most recently, even the resident cells of the periodontium, including periodontal ligament fibroblasts, have been shown to produce several inflammatory factors in response to bacterial challenge. With increased understanding of the pathophysiology of periodontitis, more research is focusing on opposing excessive inflammation with specialized pro‐resolving mediators (SPMs). This review article covers the major limitations of current standards of care for periodontitis and peri‐implantitis, and it highlights recent advances and prospects of SPMs in the context of tissue reconstruction and regeneration. Here, we focus primarily on the role of SPMs in restoring tissue homeostasis after periodontal infection.     

Radiation‐induced oral mucositis and periodontitis – proposal for an inter‐relationship

Virtually all patients who receive head and neck radiotherapy develop some degree of oral mucositis. Severe oral mucositis may necessitate an interruption of the course of radiotherapy and thus can serve as a dose‐limiting factor. Periodontitis is a host‐driven inflammatory response to a pathogenic bacterial biofilm in the subgingival environment, resulting in the progressive destruction of the tissues that support the teeth, specifically the gingiva, periodontal ligament and alveolar bone. This disease affects more than 50% of the population. Considering that radiation‐induced oral mucositis and periodontitis are both linked with continuing presence of systemic inflammation, they may be associated through a primed inflammatory response as proposed by the ‘two‐hit’ model. Alternatively, both conditions may be correlated as they represent a dysregulation of the inflammatory response. To date, no studies have looked into the association between these conditions. This review considers the current evidence that provides a rationale for proposing a link between periodontitis and oral mucositis.     

How does the periapical inflammatory process compromise general health?

Several lines of evidence support the causative role of oral inflammatory lesions and certain systemic diseases, such as atherosclerosis and cardiovascular diseases, adverse pregnancy outcome and lung diseases. Properly executed epidemiologic studies identified increased odds ratios. Local or metastatic spread of oral microorganisms, local production of microbial or host‐derived soluble regulatory molecules, that may initiate or sustain inflammatory events in remote tissues and organs and the presence of (a) common – extrinsic‐ or intrinsic‐pathological mechanism(s) may result in or contribute to both local and systemic inflammation. A number of cross‐sectional studies addressing a possible association between oral health and systemic diseases have also investigated the presence or the absence of periapical lesions. However, these studies cannot either confirm or refute a role of the periapical inflammatory lesion in the observed associations, since other variables of oral health might have exerted an inestimable influence on general health of the assessed population. The literature, dealing with patients with root canal infections and apical periodontitis as sole oral inflammatory lesions is extremely sparse. Our group has demonstrated that young adults with apical periodontitis exhibit certain biochemical changes, such as elevated levels of C‐reactive protein and an increased whole blood chemiluminescence, which have been shown to elevate the risk for cardiovascular diseases. Future research will be required to determine whether and to what extent may endodontic diseases affect general health.     

Role of the epithelial cell rests of Malassez in the development,maintenance and regeneration of periodontal ligament tissues

Periodontitis is a highly prevalent inflammatory disease that results in damage to the tooth‐supporting tissues, potentially leading to tooth loss. Periodontal tissue regeneration is a complex process that involves the collaboration of two hard tissues (cementum and alveolar bone) and two soft tissues (gingiva and periodontal ligament). To date, no periodontal‐regenerative procedures provide predictable clinical outcomes. To understand the rational basis of regenerative procedures, a better understanding of the events associated with the formation of periodontal components will help to establish reliable strategies for clinical practice. An important aspect of this is the role of the Hertwig's epithelial root sheath in periodontal development and that of its descendants, the epithelial cell rests of Malassez, in the maintenance of the periodontium. An important structure during tooth root development, the Hertwig's epithelial root sheath is not only a barrier between the dental follicle and dental papilla cells but is also involved in determining the shape, size and number of roots and in the development of dentin and cementum, and may act as a source of mesenchymal progenitor cells for cementoblasts. In adulthood, the epithelial cell rests of Malassez are the only odontogenic epithelial population in the periodontal ligament. Although there is no general agreement on the functions of the epithelial cell rests of Malassez, accumulating evidence suggests that the putative roles of the epithelial cell rests of Malassez in adult periodontal ligament include maintaining periodontal ligament homeostasis to prevent ankylosis and maintain periodontal ligament space, to prevent root resorption, to serve as a target during periodontal ligament innervation and to contribute to cementum repair. Recently, ovine epithelial cell rests of Malassez cells have been shown to harbor clonogenic epithelial stem‐cell populations that demonstrate similar properties to mesenchymal stromal/stem cells, both functionally and phenotypically. Therefore, the epithelial cell rests of Malassez, rather than being ‘cell rests’, as indicated by their name, are an important source of stem cells that might play a pivotal role in periodontal regeneration.     

Root resorption — etiology, terminology and clinical manifestations

Abstract This paper is an attempt to summarize our knowledge on root resorption from the point of view of clinical relevance and to present a revised terminological system that corresponds to our present understanding of the resorptive processes in teeth. It appears practical to keep the terms inflammatory resorption and replacement resorption. Inflammatory resorption occurs when the predentin or precementum becomes mineralized or, in case of the precementum, is mechanically damaged or scraped off. It is seen on the wall of the root canal (internal resorption) and on the external surface of the root (external resorption or cervical resorption) and it may be transient or progressive. Inflammatory resorption becomes progressive when, in addition to a denuded area of an internal or external root surface, there is additional long–lasting stimulation of the resorbing cells, like sharp edges, increased pressure in the tissue, infection, or certain systemic diseases. Replacement resorption is seen in ankyloscd teeth that have become incorporated in bone. It is not a result of a disease process, but occurs as a “mistake” because the cells involved in the remodeling of bone are not able to distinguish between the dental tissues and bone. Whereas progressive inflammatory resorption today can be treated with a high rate of success, replacement resorption still remains beyond our clincial competence.     

Extracellular matrices and polypeptide growth factors as mediators of functions of cells of the periodontium. A review

This is a review of the interactions between cells and their extracellular matrices and polypeptide growth factors. The review not only attempts to provide a basic understanding of the functions of extracellular matrices and polypeptide growth factors but, in addition, suggests the role these biological molecules may play in periodontal regeneration. It is conceivable that future periodontal therapy will include the treatment of a scaled root with biological response modifiers to predictably attain a true new connective tissue attachment.     

Reprint of: Relationship Between Surface and Inflammatory Resorption and Changes in the Pulp After Replantation of Permanent Incisors in Monkeys

The etiology of surface and inflammatory root resorption after the replantation of incisors was examined in green vervet monkeys. The teeth were examined histologically and histobacteriologically for pulpal healing and root resorption 2 and 8 weeks after replantation. In contrast to surface resorption, inflammatory resorption was related to infected necrotic tissue or an infected leukocyte zone in the root canal. The following theory for surface and inflammatory resorption is presented. Damaged periodontal ligament areas and damaged parts of the root surface are attacked by a resorption process whereby resorption of cementum and dentin may occur. Inflammatory resorption or surface resorption will then occur depending on the pulpal status and the depth of the resorption cavity. If the resorption cavity penetrates the intermediate layer of cementum and contacts dentinal tubules that are in communication with infected necrotic pulp tissue or an infected leukocyte zone, then inflammatory resorption will take place as a result of the diffusion of toxic elements from the pulp canal to the resorption cavity. However, if the resorption cavity is shallow and does not penetrate the intermediate layer of cementum, a tooth that displays similar pulpal changes will elicit only surface resorption because the intermediate layer of cementum will tend to arrest the diffusion of toxic elements. Finally, if the pulp contains vital, inflamed, or noninflamed tissue or if root canal treatment has been performed, surface resorption will occur regardless of the depth of the cavity.     

Orthodontics. Part 11: orthodontic tooth movement

Orthodontic tooth movement is dependent on efficient remodelling of bone. The cell-cell interactions are now more fully understood and the links between osteoblasts and osteoclasts appear to be governed by the production and responses of osteoprotegerin ligand. The theories of orthodontic tooth movement remain speculative but the histological documentation is unequivocal. A periodontal ligament placed under pressure will result in bone resorption whereas a periodontal ligament under tension results in bone formation. This phenomenon may be applicable to the generation of new bone in relation to limb lengthening and cranial-suture distraction. It must be remembered that orthodontic tooth movement will result in root resorption at the microscopic level in every case. Usually this repairs but some root characteristics apparent on radiographs before treatment begins may be indicative of likely root resorption. Some orthodontic procedures (such as fixed appliances) are also known to cause root resorption.     

Adhesion of viridans group streptococci to sialic acid‐, galactose‐ and N‐acetylgalactosamine‐containing receptors

The binding of 10 viridans group streptococci to sialic acid‐, galactose (Gal)‐ and N‐acetylgalactosamine (GalNAc)‐containing receptors was defined by analysis of the interactions between these bacteria and structurally defined glycoconjugates, host cells and other streptococci. All interactions with sialic acid‐containing receptors were Ca²⁺‐independent as they were not affected by ethyleneglycoltetraacetic acid (EGTA), whereas all interactions with Gal‐ and GalNAc‐containing receptors were Ca²⁺‐dependent. Recognition of sialic acid‐, Gal‐ and GalNAc‐containing receptors varied widely among the strains examined, in a manner consistent with the association of each of the three lectin‐like activities with a different bacterial cell surface component.     

Tooth avulsion and replantation — A review

Abstract The major causes of post-replantation tooth loss are inflammatory root resorption and root resorption associated with ankylosis. Recent studies have concentrated on delineating the cellular interactions in the pulp and periodontium in order to more fully understand the various factors affecting the prognoses of such teeth. The aim of this report is to discuss the nature of the pathology responsible for tooth loss following avulsion and to review recent replantation and attachment studies.     

Periodontal disease: modulation of the inflammatory cascade by dietary n‐3 polyunsaturated fatty acids

Periodontal disease, including gingivitis and periodontitis, is caused by the interaction between pathogenic bacteria and the host immune system. The ensuing oxidative stress and inflammatory cascade result in the destruction of gingival tissue, alveolar bone and periodontal ligament. This article reviews the underlying mechanisms and host–bacteria interactions responsible for periodontal disease and evidence that nutritional supplementation with fish oil may provide a protective effect. Historical investigations of diet and disease have highlighted an inverse relationship between ingestion of fish oil, which is high in n‐3 polyunsaturated fatty acids, and the incidence of typical inflammatory diseases such as arthritis and coronary heart disease. Ingestion of n‐3 polyunsaturated fatty acids, such as docosahexaenoic acid and eicosapentaenoic acid, results in their incorporation into membrane phospholipids, which can alter eicosanoid production after stimulation during the immune response. These eicosanoids promote a reduction in chronic inflammation, which has led to the proposal that fish oil is a possible modulator of inflammation and may reduce the severity of periodontal diseases. Tentative animal and human studies have provided an indication of this effect. Further human investigation is needed to establish the protective effects of fish oil in relation to periodontal disease.     

Interleukin‐17/T‐helper 17 cells in an atopic dermatitis mouse model aggravate orthodontic root resorption in dental pulp

Interleukin (IL)‐17 is an important mediator of orthodontically induced inflammatory root resorption (OIIRR). However, its role in the dental pulp (DP) has not been studied. The aim of this study was to investigate, using an atopic dermatitis (AD) model, how IL‐17 contributes to OIIRR in DP. Atopic dermatitis is the most common IL‐17‐associated allergic disease. Atopic dermatitis model mice (AD group) and wild‐type mice (control group) were subjected to an excessive orthodontic force. The localization of T‐helper (Th)17 cells, IL‐17, IL‐6, and keratinocyte chemoattractant (KC; an IL‐8‐related protein in rodents) were determined in DP. In addition, CD4⁺ T cells, including IL‐17 production cells, were obtained from patients with AD and from healthy donors, and the effects of IL‐17 on the production of IL‐6 and IL‐8 were investigated using a co‐culture of CD4⁺ T cells with human dental pulp (hDP) cells stimulated with substance P (SP). Immunoreactivity for Th17 cells, IL‐17, IL‐6, and KC was increased in DP tissue subjected to orthodontic force in the AD group compared with DP tissue subjected to orthodontic force in the control group. The cells obtained from the AD patients displayed increased IL‐6 and IL‐8 production. These results suggest that IL‐17 may aggravate OIIRR in DP.