Related Articles

Inflammation is a complex reaction to injurious agents and includes vascular responses, migration, and activation of leukocytes. Inflammation starts with an acute reaction, which evolves into a chronic phase if allowed to persist unresolved. Acute inflammation is a rapid process characterized by fluid exudation and emigration of leukocytes, primarily neutrophils, whereas chronic inflammation extends over a longer time and is associated with lymphocyte and macrophage infiltration, blood vessel proliferation, and fibrosis. Inflammation is terminated when the invader is eliminated, and the secreted mediators are removed; however, many factors modify the course and morphologic appearance as well as the termination pattern and duration of inflammation. Chronic inflammatory illnesses such as diabetes, arthritis, and heart disease are now seen as problems that might have an impact on the periodontium. Reciprocal effects of periodontal diseases are potential factors modifying severity in the progression of systemic inflammatory diseases. Macrophages are key cells for the inflammatory processes as regulators directing inflammation to chronic pathological changes or resolution with no damage or scar tissue formation. As such, macrophages are involved in a remarkably diverse array of homeostatic processes of vital importance to the host. In addition to their critical role in immunity, macrophages are also widely recognized as ubiquitous mediators of cellular turnover and maintenance of extracellular matrix homeostasis. In this review, our objective is to identify macrophage-mediated events central to the inflammatory basis of chronic diseases, with an emphasis on how control of macrophage function can be used to prevent or treat harmful outcomes linked to uncontrolled inflammation.

It has become clear in recent years that periodontitis is an inflammatory disease initiated by oral microbial biofilm. This distinction implies that it is the host response to the biofilm that destroys the periodontium in the pathogenesis of the disease. As our understanding of pathways of inflammation has matured, a better understanding of the molecular basis of resolution of inflammation has emerged. Resolution of inflammation is an active, agonist-mediated, well-orchestrated return of tissue homeostasis. There is an important distinction between anti-inflammation and resolution; anti-inflammation is pharmacologic intervention in inflammatory pathways, whereas resolution is biologic pathways restoring homeostasis. A growing body of research suggests that chronic inflammatory periodontal disease involves a failure of resolution pathways to restore homeostasis. This article reviews the resolution of inflammation in the context of periodontal disease and the potential for the modification of resolution pathways for the prevention and treatment of periodontal diseases. Proof-of-concept studies in the 1980s demonstrated that pharmacologic anti-inflammation prevented and slowed the progression of periodontal diseases in animals and man. However, the side-effect profile of such therapies precluded the use of non-steroidal anti-inflammatory drugs or other enzyme inhibitors or receptor antagonists in periodontal therapy. The isolation and characterization of resolving agonist molecules has opened a new area of research using endogenous lipid mediators of resolution as potential therapeutic agents for the management of inflammatory periodontitis. Work in animal models of periodontitis has revealed the potential of this therapeutic approach for its prevention and treatment and forced the reconsideration of our understanding of the pathogenesis of human periodontal diseases.

The recent focus on the potential link between periodontal and cardiovascular disease (PD and CVD) is part of the larger renewed interest on the role of infection and inflammation in the etiology of atherosclerosis and its clinical manifestations. Periodontal Disease is an inflammatory process affecting the periodontium, the tissue that surrounds and supports the teeth. The process usually starts with an inflammatory process of the gum (gingivitis) but it may progress with an extensive involvement of the gum, as well as the periodontal ligament and the bone surrounding the teeth resulting in substantial bone loss. Periodontal disease is a common oral pathological condition in the adult age and represents the leading cause of tooth loss. PD prevalence increases with age and there are estimates that up to 49,000,000 Americans may suffer from some form of gum disease. The gingival plaque associated with PD is colonized by a number of gram-positive and gram-negative bacteria that have been shown to affect the initiation and development of PD and have been associated with the potential etiological role of PD in CVD and other chronic conditions. A potential etiological link between PD and CVD may have important public health implications as both the exposure (PD) and the outcomes (CVD) are highly prevalent in industrialized societies. In situations in which both the exposure and the outcome are highly prevalent even modest associations, like those observed in the studies reporting on the link between PD and CVD outcomes, may have relevance. There are not definite data on the effect of periodontal treatment on CVD clinical outcomes (either in primary or secondary prevention) however it should be pointed out that the limited (both in terms of numbers and study design) experimental evidence in humans suggests a possible beneficial effect of periodontal treatment of indices of functional and structural vascular health.

Chronic, plaque-associated inflammation of the gingiva and the periodontium are among the most common oral diseases. Periodontitis (PD) is characterized by the inflammatory destruction of the periodontal attachment and alveolar bone, and its clinical appearance can be influenced by congenital as well as acquired factors. The existence of a rheumatic or other inflammatory systemic disease may promote PD in both its emergence and progress. However, there is evidence that PD maintains systemic diseases. Nevertheless, many mechanisms in the pathogenesis have not yet been examined sufficiently, so that a final explanatory model is still under discussion, and we hereby present arguments in favor of this. In this review, we also discuss in detail the fact that oral bacterial infections and inflammation seem to be linked directly to the etiopathogenesis of rheumatoid arthritis (RA). There are findings that support the hypothesis that oral infections play a role in RA pathogenesis. Of special importance are the impact of periodontal pathogens, such as Porphyromonas gingivalis on citrullination, and the association of PD in RA patients with seropositivity toward rheumatoid factor and the anti-cyclic citrullinated peptide antibody.

It is now well accepted that besides the cholesterol associated mechanisms of atherogenesis, inflammation plays a crucial role in all stages of the development of the atherosclerotic lesion. This “inflammation hypothesis” raises the possibility that, through systemic elevations of pro-inflammatory cytokines, periodontal diseases might also contribute to systemic inflammation and, therefore, to atherogenesis. In fact, there is evidence that periodontal diseases are associated with higher systemic levels of high-sensitivity C-reactive protein and a low grade systemic inflammation. This phenomenon has been explained based on mechanisms associated with either the infectious or the inflammatory nature of periodontal diseases. The purposes of this article are to review (1) the evidence suggesting a role for oral bacterial species, particularly periodontal pathogens, in atherogenesis; (2) the potential mechanisms explaining an etiological role for oral bacteria in atherosclerosis; (3) the evidence suggesting that periodontal infections are accompanied by a heightened state of systemic inflammation; (4) the potential sources of systemic inflammatory biomarkers associated with periodontal diseases; and (5) the effects of periodontal therapy on systemic inflammatory biomarkers and cardiovascular risk.

Periodontal disease is characterized by both inflammation and bone loss. Advances in research in both these areas have led to a new appreciation of not only each field but also the intimate relationship between inflammation and bone loss. This relationship has resulted in a new field of science called osteoimmunology and provides a context for better understanding the pathogenesis of periodontal disease. In this review, we discuss several aspects of the immuno-inflammatory host response that ultimately results in loss of alveolar bone. A proposal is made that periodontal inflammation not only stimulates osteoclastogenesis but also interferes with the uncoupling of bone formation and bone resorption, consistent with a pathologic process. Furthermore, arguments based on experimental animal models suggest a critical role of the spatial and temporal aspects of inflammation in the periodontium. A review of these findings leads to a new paradigm to help explain more fully the impact of inflammation on alveolar bone in periodontal disease so that it includes the effects of inflammation on uncoupling of bone formation from resorption.

Periodontitis is a common chronic inflammatory disease characterised by destruction of the supporting structures of the teeth (the periodontal ligament and alveolar bone). It is highly prevalent (severe periodontitis affects 10–15% of adults) and has multiple negative impacts on quality of life. Epidemiological data confirm that diabetes is a major risk factor for periodontitis; susceptibility to periodontitis is increased by approximately threefold in people with diabetes. There is a clear relationship between degree of hyperglycaemia and severity of periodontitis. The mechanisms that underpin the links between these two conditions are not completely understood, but involve aspects of immune functioning, neutrophil activity, and cytokine biology. There is emerging evidence to support the existence of a two-way relationship between diabetes and periodontitis, with diabetes increasing the risk for periodontitis, and periodontal inflammation negatively affecting glycaemic control. Incidences of macroalbuminuria and end-stage renal disease are increased twofold and threefold, respectively, in diabetic individuals who also have severe periodontitis compared to diabetic individuals without severe periodontitis. Furthermore, the risk of cardiorenal mortality (ischaemic heart disease and diabetic nephropathy combined) is three times higher in diabetic people with severe periodontitis than in diabetic people without severe periodontitis. Treatment of periodontitis is associated with HbA1c reductions of approximately 0.4%. Oral and periodontal health should be promoted as integral components of diabetes management.

Obesity is a multifaceted subject. It has increased at an alarming rate in recent years. Being overweight increases the likelihood of a patient having associated health and social problems which may affect dental services and dental management. A review of the literature on obesity and periodontal disease suggested that they both confound each other and obesity itself has been recognized as a major risk factor for periodontal disease. It has been found that adverse effects of obesity on the periodontium may be mediated through pro-inflammatory cytokines and various other bioactive substances. This article tries to focus on the possible role of obesity and obesity-related diseases like diabetes and coronary heart diseases (CHD), as a potential contributor to periodontal disease and vice versa. The meanings of these associations can be useful for various diagnostic and treatment planning purposes.

Summary

Lactoferrin (Lf), an iron-binding glycoprotein able to chelate two ferric ions per molecule, is a component of human secretions synthesized by exocrine glands and neutrophils in infection/inflammation sites. Lactoferrin in saliva represents an important defence factor against bacterial injuries including those related to Streptococcus mutans and periodontopathic bacteria through its ability to decrease bacterial growth, biofilm development, iron overload, reactive oxygen formation and inflammatory processes.

A growing body of research suggests that inflammatory periodontal disease involves a failure of resolution pathways to restore tissue homeostasis. There is an important distinction between anti-inflammation and resolution; anti-inflammation is pharmacologic intervention in inflammatory pathways, whereas resolution involves biologic pathways restoring inflammatory homeostasis. An appropriate regulation of pro-inflammatory cytokine synthesis might be useful in reducing periodontal tissue destruction. Recently, the multi-functional IL-6 is emerging as an important factor able to modulate bone, iron and inflammatory homeostasis.

Here, we report an overview of Lf functions as well as for the first time Lf anti-inflammatory ability against periodontitis in in vitro model and observational clinical study. In in vitro model, represented by gingival fibroblasts infected with Prevotella intermedia, Lf exerted a potent anti-inflammatory activity. In the observational clinical trial performed through bovine Lf (bLf) topically administered to volunteers suffering from periodontitis, bLf decreased cytokines, including IL-6 in crevicular fluid, edema, bleeding, pocket depth, gingival and plaque index, thus improving clinical attachment levels.

Even if other clinical trials are required, these results provide strong evidence for a instead of an therapeutic potential of this multifunctional natural protein.

Periodontitis is a periodontal tissue infectious disease and the most common cause for tooth loss in adults. It has been linked to many systemic disorders, such as coronary artery disease, stroke, and diabetes. At present, there is no ideal therapeutic approach to cure periodontitis and achieve optimal periodontal tissue regeneration. In this study, we explored the potential of using autologous periodontal ligament stem cells (PDLSCs) to treat periodontal defects in a porcine model of periodontitis. The periodontal lesion was generated in the first molars area of miniature pigs by the surgical removal of bone and subsequent silk ligament suture around the cervical portion of the tooth. Autologous PDLSCs were obtained from extracted teeth of the miniature pigs and then expanded ex vivo to enrich PDLSC numbers. When transplanted into the surgically created periodontal defect areas, PDLSCs were capable of regenerating periodontal tissues, leading to a favorable treatment for periodontitis. This study demonstrates the feasibility of using stem cell-mediated tissue engineering to treat periodontal diseases.

Purpose

Anti-rheumatic agents target common molecular pathways of inflammation in rheumatoid arthritis (RA) and periodontitis. The purpose of this study was to determine the relative effect of anti-rheumatic agents on the levels of inflammatory biomarkers and periodontal inflammation in RA patients with periodontitis.

Methods

A systematic review and meta-analysis were conducted of studies comparing periodontal parameters of inflammation, such as bleeding on probing, and biomarkers of inflammation in RA patients with periodontitis and healthy adults with and without periodontitis. The search included the electronic databases MEDLINE, Cochrane Database of Systematic Reviews, and Google Scholar, inclusive through October 2011, with no language restrictions. Hand searches were conducted of the bibliographies of related journals and systematic reviews. Observational and interventional studies assessing the effects of antirheumatic therapy qualified for inclusion. Two reviewers performed independent data extraction and risk-of-bias assessment. Of the 187 identified publications, 13 studies fulfilled the inclusion criteria.

Results

When compared to healthy adults without periodontitis, RA subjects were found to have significantly higher levels of bleeding on probing and limited evidence of higher levels of interleukin-1β and tumor necrosis factor-α (TNF-α) in gingival crevicular fluid and saliva. No consistent differences were found in periodontal parameters and inflammatory biomarkers between RA subjects and adults with periodontitis. Studies evaluating the effect of anti-TNF-α therapy in RA subjects with periodontitis have yielded inconsistent results.

Conclusions

There are limited data, however, to suggest that anti-TNF-α agents can reduce local production of inflammatory cytokines and periodontal inflammation in RA patients with periodontitis.

Inflammation when unchecked is associated with many prevalent disorders such as the classic inflammatory diseases arthritis and periodontal disease, as well as the more recent additions that include diabetes and cardiovascular maladies. Hence mechanisms to curtail the inflammatory response and promote catabasis are of immense interest. In recent years, evidence has prompted a paradigm shift whereby the resolution of acute inflammation is a biochemically active process regulated in part by endogenous PUFA (polyunsaturated fatty acid)-derived autacoids. Among these are a novel genus of SPMs (specialized proresolving mediators) that comprise novel families of mediators including lipoxins, resolvins, protectins and maresins. SPMs have distinct structures and act via specific G-protein seven transmembrane receptors that signal intracellular events on selective cellular targets activating proresolving programmes while countering pro-inflammatory signals. An appreciation of these endogenous pathways and mediators that control timely resolution opened a new terrain for therapeutic approaches targeted at stimulating resolution of local inflammation. In the present review, we provide an overview of the biosynthesis and actions of resolvin E1, underscoring its protective role in vascular systems and regulating platelet responses. We also give an overview of newly described resolution circuitry whereby resolvins govern miRNAs (microRNAs), and transcription factors that counter-regulate pro-inflammatory chemokines, cytokines and lipid mediators.

Background

Rheumatoid arthritis (RA) and periodontitis (PD) are common chronic inflammatory conditions. Recent studies have shown a beneficial effect of periodontal treatment on reducing the severity of active RA. This study was undertaken to further examine the effect of non-surgical periodontal treatment on signs and symptoms of RA in patients treated with or without anti-Tumor Necrosis Factor (TNF)-α medications. The effect of anti-TNF-α therapy on periodontitis also was assessed.

Methods

Forty participants diagnosed with moderate/severe RA (under treatment for RA) and severe periodontitis were randomly assigned to receive initial non-surgical periodontal therapy with scaling/root planing and oral hygiene instructions (n=20) or no periodontal therapy (n=20). To control RA, all participants had been using disease-modifying anti-rheumatic drugs (DMARDs), and 20 had been using anti-TNF-α in addition to DMARDs before randomization. Periodontal probing depth (PD), clinical attachment loss (CAL), bleeding on probing (BOP), gingival (GI) and plaque (PI) indices, RA disease activity score (DAS-28) and erythrocyte sedimentation rate (ESR) were measured at baseline and six weeks afterwards. Linear mixed models were used to identify significant differences between subjects receiving periodontal treatment and those who did not.

Results

Patients receiving periodontal treatment showed a significant decrease in the mean DAS28, ESR (p < 0.001) and serum TNF-α (p < 0.05). There was no statistically significant decrease in these parameters in those patients not receiving periodontal treatment. Anti- TNF-α therapy resulted in a significant improvement in CAL, PD, BOP and GI.

Conclusions

Non-surgical periodontal therapy had a beneficial effect on signs and symptoms of RA regardless of the medications used to treat this condition. Anti-TNF-α therapy without periodontal treatment has no significant effect on the periodontal condition.

Diabetes mellitus is a systemic disease characterized by increased blood glucose levels and abnormalities of lipid metabolism due to absence or decreased level of insulin. It affects all the body organs and their functions either directly or indirectly. Every dentist should have a basic understanding of the etiopathogenesis, oral and systemic manifestations of this disease. The periodontal diseases are a consequence of extension of the gingival inflammation into the underlying supporting structures of the periodontium, initiated by the presence of plaque and its products on the surfaces of the teeth and the adjoining structures. The progression of periodontal disease is influenced by variety of factors like microorganisms, host response, systemic background, and genetic makeup of the host. Amongst them, diabetes mellitus tops the list. Diabetes and periodontitis influence the clinical outcome of each other and control of both influences the clinical improvement of each.

Context:

Host responses to periodontal disease include the production of different enzymes released by stromal, epithelial or inflammatory cells. Important enzymes associated with cell injury and cell death are aspartate aminotransferase, alanine aminotransferase (AST, ALT), alkaline phosphatase, acidic phosphatase (ALP, ACP), and gama glutamyl transferase (GGT). Changes in enzymatic activity reflect metabolic changes in the gingiva and periodontium, in the inflammation.

Aims:

In this article we examined the activity of AST, ALT, GGT, ALP, and ACP in the saliva from patients with periodontal disease, before and after periodontal treatment (experimental group — 20 gingivitis patients and 20 periodontitis patients), and in the saliva from healthy subjects (control group — 20 samples).

Settings and Design:

Periodontal disease was determined based on the clinical parameters (gingival index (GI), probing depth (PD), and clinical attachment loss (CAL)). Patients with periodontal disease were under conventional periodontal treatment.

Materials and Methods:

The stimulated saliva of the patient was collected in a sterile test tube and analyzed using the Automatic Analyzer.

Results:

The obtained results showed statistically significant increased activity of AST, ALT, GGT, ALP, and ACP in the saliva from patients with periodontal disease, in relation to the control group. A significant reduction in the enzyme levels was seen after conventional periodontal therapy.

Conclusions:

Based on these results, it can be assumed that the salivary enzymes (AST, ALT, GGT, ALP, and ACP) can be considered as biochemical markers for evaluating the diagnosis and prognosis of the functional condition of periodontal tissues in disease and health, and in the evaluation of the therapy effects in periodontal disease.

Recently, it has been recognized that oral infection, especially periodontitis, may affect the course and pathogenesis of a number of systemic diseases, such as cardiovascular disease, bacterial pneumonia, diabetes mellitus, and low birth weight. The purpose of this review is to evaluate the current status of oral infections, especially periodontitis, as a causal factor for systemic diseases. Three mechanisms or pathways linking oral infections to secondary systemic effects have been proposed: (i) metastatic spread of infection from the oral cavity as a result of transient bacteremia, (ii) metastatic injury from the effects of circulating oral microbial toxins, and (iii) metastatic inflammation caused by immunological injury induced by oral microorganisms. Periodontitis as a major oral infection may affect the host's susceptibility to systemic disease in three ways: by shared risk factors; subgingival biofilms acting as reservoirs of gram-negative bacteria; and the periodontium acting as a reservoir of inflammatory mediators. Proposed evidence and mechanisms of the above odontogenic systemic diseases are given.

Periodontal disease is associated with diabetes, heart disease, and chronic kidney disease (CKD), an effect postulated to be due in part to endovascular inflammation. While a bidirectional relationship between CKD and periodontal disease is plausible, it has not been previously reported in the literature. Over 11 200 adults 18 years or older were identified in the Third National Health and Nutrition Examination Survey. Analyses were conducted in two stages. First, multivariable logistic regression models were fitted to test the hypothesis that periodontal disease was independently associated with CKD. Given the potential that the periodontal disease and CKD relationship may be bidirectional, a two-step analytic approach was used that involved 1) tests for mediation, and 2) structural equation models to examine more complex direct and indirect effects of periodontal disease on CKD, and vice versa. In two separate models periodontal disease (ORAdj =1.62 (95% CI: 1.17-2.26) and edentulism (ORAdj = 1.83 (1.31-2.55) and periodontal disease score (ORAdj = 1.01 (1.01-1.02) were associated with CKD, when simultaneously adjusting for 14 other factors. Three of four structural equation models were most plausible suggesting bidirectional relationships. Collectively, these analyses provide for the first time empirical support for a bidirectional relationship between CKD and periodontal disease, and mediation of that relationship by diabetes duration and hypertension.

Obesity in humans might increase the risk of periodontitis. The aim of the present study was to examine the relationship between body composition of males and their periodontal status. AS total of 150 males (aged 30–60) were selected: 31 were periodontally healthy, 45 had gingivitis, 39 had initial periodontitis, and 35 suffered from established periodontitis. BMI (body mass index), WC (waist circumference), and body composition parameters (consisting of body water, body fat, and skeletal muscle and bone mass) were measured. After adjusting for age, history of diabetes, smoking, physical activity status, and socioeconomic status, statistically significant correlations were found between periodontitis and BMI, WC, and body composition. There was only a statistically significant difference between the periodontal health and established periodontitis; that is, periodontal disease in mild forms (gingivitis) and initial periodontitis do not influence these variables (BMI, WC, and body composition parameters) and only the severe form of the disease influences the variables. These data suggest that there is a considerable association between severe forms of periodontal disease in males and their body composition, but this preliminary finding needs to be confirmed in more extensive studies.

Many epidemiological evidences have proven the association between smoking and periodontal disease. The causality can be further established by linking findings of traditional epidemiological studies with the developments in molecular techniques that occurred in the last decade. The present article reviews recent studies that address the effect of smoking on molecular and genetic factors in periodontal disease. Most findings support the fact that tobacco smoking modulates destruction of the periodontium through different pathways: microcirculatory and host immune systems, connective tissue, and bone metabolism. Although smokers experience an increased burden of inflammatory responses to microbial challenges compared to non-smokers, understanding the association between smoking and periodontal diseases involves substantial problems with respect to accuracy of measurements, and particularly, sampling of many subjects. It remains unclear whether genetic susceptibility to periodontal disease is influenced by exposure to smoking or the effect of smoking on periodontal disease is influenced by genetic susceptibility. Employment of molecular techniques may play a key role in further elucidation of mechanisms linking smoking and periodontal destruction, the direct relationship as environmental factors and indirect relationship through genetic factors.

Insulin resistance (IR) is now considered as a chronic and low level inflammatory condition. It is closely related to altered glucose tolerance, hypertriglyceridemia, abdominal obesity, and coronary heart disease. IR is accompanied by the increase in the levels of inflammatory cytokines like interleukin-1 and 6, tumor necrosis factor-α. These inflammatory cytokines also play a crucial part in pathogenesis and progression of insulin resistance. Periodontitis is the commonest of oral diseases, affecting tooth investing tissues. Pro-inflammatory cytokines are released in the disease process of periodontitis. Periodontitis can be attributed with exacerbation of IR. Data in the literature supports a "two way relationship" between diabetes and periodontitis. Periodontitis is asymptomatic in the initial stages of disease process and it often escapes diagnosis. This review presents the blurred nexus between periodontitis and IR, underlining the pathophysiology of the insidious link. The knowledge of the association between periodontitis and IR can be valuable in planning effectual treatment modalities for subjects with altered glucose homeostasis and diabetics. Presently, the studies supporting this association are miniscule. Further studies are mandatory to substantiate the role of periodontitis in the deterioration of IR.

Objective

Periodontal disease is an inflammatory disorder with widespread morbidities involving both oral and systemic health. The primary goal of periodontal treatment is the regeneration of the lost or diseased periodontium. In this study, we retrospectively examined feasibility and safety of reconstructing the periodontal intrabony defects with autologous periodontal ligament progenitor (PDLP) implantation in three patients.

Materials and Methods

In this retrospective pilot study, we treated 16 teeth with at least one deep intrabony defect of probing depth (PD) ≥ 6 mm with PDLP transplantation and evaluated clinical outcome measures in terms of probing depth, gingival recession and attachment gain for a duration of 32–72 months. Furthermore, we compare PDLPs with standard PDL stem cells (PDLSCs) and confirmed that PDLPs possessed progenitor characters.

Results

Clinical examination indicated that transplantation of PDLPs may provide therapeutic benefit for the periodontal defects. All treated patients showed no adverse effects during the entire course of follow up. We also found that PDLPs were analogous to PDLSCs in terms of high proliferation, expression of mesenchymal surface molecules, multipotent differentiation, and in vivo tissue regain. However, PDLPs failed to express scleraxis, a marker of tendon, as seen in PDLSCs.

Conclusions

This study demonstrated clinical and experimental evidences supporting a potential efficacy and safety of utilizing autologous PDL cells in the treatment of human periodontitis.

Both lesions of endodontic origin and periodontal diseases involve the host response to bacteria and the formation of osteolytic lesions. Important for both is the upregulation of inflammatory cytokines that initiate and sustain the inflammatory response. Also important are chemokines that induce recruitment of leukocyte subsets and bone-resorptive factors that are largely produced by recruited inflammatory cells. However, there are differences also. Lesions of endodontic origin pose a particular challenge since that bacteria persist in a protected reservoir that is not readily accessible to the immune defenses. Thus, experiments in which the host response is inhibited in endodontic lesions tend to aggravate the formation of osteolytic lesions. In contrast, bacteria that invade the periodontium appear to be less problematic so that blocking arms of the host response tend to reduce the disease process. Interestingly, both lesions of endodontic origin and periodontitis exhibit inflammation that appears to inhibit bone formation. In periodontitis, the spatial location of the inflammation is likely to be important so that a host response that is restricted to a subepithelial space is associated with gingivitis, while a host response closer to bone is linked to bone resorption and periodontitis. However, the persistence of inflammation is also thought to be important in periodontitis since inflammation present during coupled bone formation may limit the capacity to repair the resorbed bone.

Periodontal disease is a bacterially mediated chronic inflammatory disease that results in destruction of the periodontal ligament (PDL) and alveolar bone that surround and support the dentition. While their precise roles are not well understood, periodontal pathogens, including Treponema denticola, are believed to initiate the destructive inflammatory responses and dysregulation of tissue homeostasis that characterize the disease. These responses are believed to result from both proinflammatory effects of acylated bacterial membrane components (lipopolysaccharides and lipoproteins) and degradative effects of secreted bacterial proteases. Host-derived matrix metalloproteinases (MMPs) are key enzymes both in tissue homeostasis and tissue destruction. MMP expression is modulated in part by specific proteolytic fragments of fibronectin (FN), which are associated with periodontal disease. FN is a predominant extracellular matrix component in the periodontium. We examined the ability of Treponema denticola and its acylated outer membrane PrtP protease complex to induce both activation of MMP-2 and generation of FN fragments in human PDL cell culture supernatants. T. denticola parent and isogenic mutant strains, as well as MMP-2 small interfering RNA and specific inhibitors of MMP-2 and PrtP activity, were used to examine protein expression, gelatinolytic activity, and FN fragmentation in culture supernatants. T. denticola and its purified protease induced both MMP-2 activation and FN fragmentation. Here, we demonstrate that PrtP proteolytic activity induces the activation of MMP-2 and that active MMP-2 is required for FN fragmentation. These results suggest a specific mechanism by which the T. denticola protease may disrupt homeostatic processes required for the maintenance of periodontal health.

Periodontitis is a destructive inflammatory disease of the supporting tissues of the teeth and is caused by specific microorganisms or a group of specific microorganisms. Association of periodontal infection with organ systems like cardiovascular system, endocrine system, reproductive system, and respiratory system makes periodontal infection a complex multiphase disease. Inflamed periodontal tissues produce significant amounts of pro-inflammatory cytokines, mainly interleukin 1 beta (IL-1β), IL-6, prostaglandin E2 (PGE2), and tumor necrosis factor alpha (TNF-α), which may have systemic effects on the host. Low birth weight, defined as birth weight less than 2500 g, continues to be a significant public health issue in both developed and developing countries. Research suggests that the bacteria that cause inflammation in the gums can actually get into the bloodstream and target the fetus, potentially leading to premature labor and low birth weight (PLBW) babies. One reasonable mechanism for this is the deleterious effect of endotoxin released from gram-negative bacteria responsible for periodontal disease. Hence, periodontal disease appears to be an independent risk factor for PLBW and there is a need to expand preventive measures for pregnant women in coordination with the gynecological and dental professions.

Background

Indigenous Australians experience an overwhelming burden of chronic disease, including cardiovascular diseases. Periodontal disease (inflammation of the tissues surrounding teeth) is also widespread, and may contribute to the risk of cardiovascular diseases via pathogenic inflammatory pathways. This study will assess measures of vascular health and inflammation in Indigenous Australian adults with periodontal disease, and determine if intensive periodontal therapy improves these measures over a 12 month follow-up. The aims of the study are: (i) to determine whether there is a dose response relationship between extent and severity of periodontal disease and measures of vascular health and inflammation among Indigenous Australian adults with moderate to severe periodontal disease; and (ii) to determine the effects of periodontal treatment on changes in measures of vascular health and inflammation in a cohort of Indigenous Australians.

Methods/Design

This study will be a randomised, controlled trial, with predominantly blinded assessment of outcome measures and blinded statistical analysis. All participants will receive the periodontal intervention benefits (with the intervention delayed 12 months in participants who are randomised to the control arm). Participants will be Indigenous adults aged ≥25 years from urban centres within the Top End of the Northern Territory, Australia. Participants assessed to have moderate or severe periodontal disease will be randomised to the study's intervention or control arm. The intervention involves intensive removal of subgingival and supragingival calculus and plaque biofilm by scaling and root-planing. Study visits at baseline, 3 and 12 months, will incorporate questionnaires, non-fasting blood and urine samples, body measurements, blood pressure, periodontal assessment and non-invasive measures of vascular health (pulse wave velocity and carotid intima-media thickness). Primary outcome measures are pulse wave velocity and carotid intima-media thickness.

Discussion

The study will assess the periodontal-cardiovascular disease relationship among Indigenous Australian adults with periodontal disease, and the effectiveness of an intervention aimed at improving periodontal and cardiovascular health. Efforts to understand and improve Indigenous oral health and cardiovascular risk may serve as an important means of reducing the gap between Indigenous and non-Indigenous health in Australia.

Trial Registration

Australia and New Zealand Clinical Trials Register (ANZCTR): ACTRN12610000817044