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1.  Oral Inflammatory Diseases and Systemic Inflammation: Role of the Macrophage 
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.
PMCID: PMC3353263  PMID: 22623923
innate immune system; macrophage; oral disease; inflammation; resolution
2.  The Management of Inflammation in Periodontal Disease 
Journal of periodontology  2008;79(8 Suppl):1601-1608.
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.
PMCID: PMC2563957  PMID: 18673016
Anti-inflammatory; lipoxins; Porphyromonas gingivalis; periodontal disease; resolvin E1
3.  Protein Biomarkers of Periodontitis in Saliva 
ISRN inflammation  2014;2014:593151.
Periodontitis is a chronic inflammatory condition of the tissues that surround and support the teeth and is initiated by inappropriate and excessive immune responses to bacteria in subgingival dental plaque leading to loss of the integrity of the periodontium, compromised tooth function, and eventually tooth loss. Periodontitis is an economically important disease as it is time-consuming and expensive to treat. Periodontitis has a worldwide prevalence of 5–15% and the prevalence of severe disease in western populations has increased in recent decades. Furthermore, periodontitis is more common in smokers, in obesity, in people with diabetes, and in heart disease patients although the pathogenic processes underpinning these links are, as yet, poorly understood. Diagnosis and monitoring of periodontitis rely on traditional clinical examinations which are inadequate to predict patient susceptibility, disease activity, and response to treatment. Studies of the immunopathogenesis of periodontitis and analysis of mediators in saliva have allowed the identification of many potentially useful biomarkers. Convenient measurement of these biomarkers using chairside analytical devices could form the basis for diagnostic tests which will aid the clinician and the patient in periodontitis management; this review will summarise this field and will identify the experimental, technical, and clinical issues that remain to be addressed before such tests can be implemented.
PMCID: PMC4040190  PMID: 24944840
4.  RNAi-Mediated Silencing of Atp6i and Atp6i Haploinsufficiency Prevents Both Bone Loss and Inflammation in a Mouse Model of Periodontal Disease 
PLoS ONE  2013;8(4):e58599.
Periodontal disease affects about 80% of adults in America, and is characterized by oral bacterial infection-induced gingival inflammation, oral bone resorption, and tooth loss. Periodontitis is also associated with other diseases such as rheumatoid arthritis, diabetes, and heart disease. Although many efforts have been made to develop effective therapies for this disease, none have been very effective and there is still an urgent need for better treatments and preventative strategies. Herein we explored for the first time the possibility that adeno-associated virus (AAV)-mediated RNAi knockdown could be used to treat periodontal disease with improved efficacy. For this purpose, we used AAV-mediated RNAi knockdown of Atp6i/TIRC7 gene expression to target bone resorption and gingival inflammation simultaneously. Mice were infected with the oral pathogen Porphyromonas gingivalis W50 (P. gingivalis) in the maxillary periodontium to induce periodontitis. We found that Atp6i depletion impaired extracellular acidification and osteoclast-mediated bone resorption. Furthermore, local injection of AAV-shRNA-Atp6i/TIRC7 into the periodontal tissues in vivo protected mice from P. gingivalis infection-stimulated bone resorption by >85% and decreased the T-cell number in periodontal tissues. Notably, AAV-mediated Atp6i/TIRC7 knockdown also reduced the expression of osteoclast marker genes and inflammation-induced cytokine genes. Atp6i+/− mice with haploinsufficiency were similarly protected from P. gingivalis infection-stimulated bone loss and gingival inflammation. This suggests that AAV-shRNA-Atp6i/TIRC7 therapeutic treatment may significantly improve the health of millions who suffer from P. gingivalis-mediated periodontal disease.
PMCID: PMC3618217  PMID: 23577057
5.  The Relationship Between Periodontal Disease (Pd) and Cardiovascular Disease (Cvd). 
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.
PMCID: PMC3033151  PMID: 21415980
6.  Periodontitis and diabetes: a two-way relationship 
Diabetologia  2011;55(1):21-31.
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.
PMCID: PMC3228943  PMID: 22057194
Diabetes; Diabetes complications; Periodontal diseases; Periodontitis; Type 1 diabetes mellitus; Type 2 diabetes mellitus
7.  Interrelationship between chronic periodontitis and anemia: A 6-month follow-up study 
In India, anemia is a common and serious health disorder among both sexes and all age groups, with anemia of chronic disease (ACD) being the second most prevalent anemia. Periodontitis is an inflammatory disease of the supporting tissues of the tooth caused by specific microorganisms. An immune response to bacteria and their products induces a major vascular response, offering explanatory mechanisms for the interactions between periodontal infection and a variety of systemic disorders. Therefore, periodontitis results in low-grade systemic inflammation, which may cause lower number of erythrocytes and, consequently, lower hemoglobin concentration.
Materials and Methods:
A total of 100 systemically healthy male patients visiting the outpatient department participated in the study. Of these, 50 patients had healthy periodontium and 50 patients had chronic periodontitis. Clinical parameters and red blood cell parameters of all the patients were assessed at baseline and 6 months after non-surgical periodontal therapy. Statistical analysis using Student's t-test was performed.
Data analysis revealed that patients with chronic periodontitis showed an improvement in both clinical and red blood cell parameters from baseline to 6 months after non-surgical periodontal therapy.
From the present study, it can be concluded that like any other chronic condition, chronic periodontitis can lead to ACD. It also provides evidence that non-surgical periodontal therapy can improve the anemic status of patients with chronic periodontitis.
PMCID: PMC3988635  PMID: 24744539
Anemia; chronic periodontitis; cytokines; hepcidin; red blood cells
8.  Effect of periodontal therapy on hemoglobin and erythrocyte levels in chronic generalized periodontitis patients: An interventional study 
Aims and Objectives:
Anemia of chronic disease (ACD) is one of the most common forms of anemia. It is defined as anemia occurring in chronic infections, inflammatory conditions or neoplastic disorders which are not due to marrow deficiencies or other diseases, and occurring despite the presence of adequate iron stores and vitamins. Periodontitis is one of the most prevalent chronic inflammatory diseases in humans. This study aimed at finding out if periodontitis, like other inflammatory conditions, could lead to anemia.
Materials and Methods:
Thirty chronic generalized periodontitis male patients with hemoglobin levels below 15 mg/dl and serum ferritin values above 30 ng/ml were selected. The various blood parameters recorded at baseline were hemoglobin levels(Hb), erythrocyte count (RBC), erythrocyte sedimentation rate (ESR), mean corpuscular volume(MCV), mean corpuscular hemoglobin (MCH) and mean corpuscular hemoglobin concentration (MCHC).
Periodontal parameters recorded at baseline included: plaque index, gingival index, probing pocket depth, clinical attachment level. Periodontal treatment including surgery if required was carried out in all the patients. Periodontal status of patients was monitored by repeating evaluation of periodontal indices at three months and at the end of one year. The hematological values were again measured at the end of one year.
The results showed that correction of periodontal inflammation resulted in a significant increase in hemoglobin levels and erythrocyte counts. The erythrocyte sedimentation rate showed a reduction indicating resolution of periodontal inflammation. There was a significant, but much lesser, improvement in MCV, MCH and MCHC values.
The results of this study showed that treatment of periodontitis leads to an improvement in hematocrit and other related blood parameters in chronic generalized periodontitis patients with anemia. This provides evidence that periodontitis like other chronic diseases may also cause anemia.
PMCID: PMC2846680  PMID: 20376233
ACD; anemia; hemoglobin; periodontitis
9.  Anti-inflammatory Actions of Adjunctive Tetracyclines and Other Agents in Periodontitis and Associated Comorbidities  
The Open Dentistry Journal  2014;8:109-124.
The non-antimicrobial properties of tetracyclines such as anti-inflammatory, proanabolic and anti-catabolic actions make them effective pharmaceuticals for the adjunctive management of chronic inflammatory diseases. An over-exuberant inflammatory response to an antigenic trigger in periodontitis and other chronic inflammatory diseases could contribute to an autoimmune element in disease progression. Their adjunctive use in managing periodontitis could have beneficial effects in curbing excessive inflammatory loading from commonly associated comorbidities such as CHD, DM and arthritis. Actions of tetracyclines and their derivatives include interactions with MMPs, tissue inhibitors of MMPs, growth factors and cytokines. They affect the sequence of inflammation with implications on immunomodulation, cell proliferation and angiogenesis; these actions enhance their scope, in treating a range of disease entities. Non-antimicrobial chemically modified tetracyclines (CMTs) sustain their diverse actions in organ systems which include anti-inflammatory, anti-apoptotic, anti-proteolytic actions, inhibition of angiogenesis and tumor metastasis. A spectrum of biological actions in dermatitis, periodontitis, atherosclerosis, diabetes, arthritis, inflammatory bowel disease, malignancy and prevention of bone resorption is particularly relevant to minocycline. Experimental models of ischemia indicate their specific beneficial effects. Parallel molecules with similar functions, improved Zn binding and solubility have been developed for reducing excessive MMP activity. Curbing excessive MMP activity is particularly relevant to periodontitis, and comorbidities addressed here, where specificity is paramount. Unique actions of tetracyclines in a milieu of excessive inflammatory stimuli make them effective therapeutic adjuncts in the management of chronic inflammatory disorders. These beneficial actions of tetracyclines are relevant to the adjunctive management of periodontitis subjects presenting with commonly prevalent comorbidities addressed here.
PMCID: PMC4073587  PMID: 24976875
Arthritis; cardiometabolic disorders; non-antimicrobial actions of tetracyclines; periodontitis.
10.  The Link Between Periodontitis and Rheumatoid Arthritis: A Periodontist’s Perspective 
In this review, we critically evaluate the case–control studies examining the relationship between rheumatoid arthritis (RA) and periodontitis, two common chronic inflammatory diseases with a similar host-mediated pathogenesis. We review the “two-hit” periodontitis model that our group previously proposed, in which we elucidate how a systemic disease such as RA can potentially exacerbate or initiate periodontitis. Furthermore, we discuss adjunctive host modulation therapy, originally developed for periodontitis (i.e., subantimicrobial-dose doxycycline alone or in combination with an anti-inflammatory agent), to simultaneously mitigate RA and periodontitis. Finally, we review studies describing periodontal treatment effects on both RA disease activity measures and systemic inflammation. Current evidence suggests that an association exists between periodontitis and RA. Well-designed multicenter longitudinal clinical trials and studies with sufficient sample sizes are needed to ascertain the temporal relationship between these two diseases and whether periodontal treatment can reduce the severity of RA or prevent its onset.
PMCID: PMC4312393  PMID: 25657894
Rheumatoid arthritis; Periodontitis; Alveolar bone loss; Case–control studies; Subantimicrobial dose doxycycline
11.  Usefulness of Self-Reported Periodontal Disease to Identify Individuals with Elevated Inflammatory Markers at Risk of Cardiovascular Disease 
The American journal of cardiology  2008;102(11):1509-1513.
Periodontal disease has been associated with cardiovascular disease (CVD) and inflammation may represent a common pathophysiology. Oral health screening in the context of CVD risk assessment represents a potential opportunity to identify persons at risk for CVD. The purpose of this study was to determine if self-reported oral health status is independently associated with inflammatory markers and if oral health assessment as part of CVD risk screening can identify at-risk persons without traditional CVD risk factors. A baseline analysis was conducted among participants in the NHLBI Family Intervention Trial for Heart Health (F.I.T. Heart) (n=421; mean age 48±13.5y; 36% non-white) without CVD or diabetes who underwent standardized assessment of oral health, lifestyle, CVD risk factors and inflammatory markers high sensitivity c-reactive protein (hsCRP) and lipoprotein-associated phospholipase A2 (Lp-PLA2). Statistical associations between oral health, risk factors and inflammatory markers were assessed and logistic regression was used to adjust for effects of lifestyle and potential confounders. Periodontal disease was independently associated with being in the top Lp-PLA2 quartile versus the lower three (OR=1.9; 95%CI=1.1–3.2) after adjustment for lifestyle and risk factors. History of periodontal disease was reported by 24% of non-overweight, non-hypertensive, non-hypercholesterolemic participants and among these participants, 37% had elevated hsCRP (≥ 3mg/L) or Lp-PLA2 (≥ 215ng/mL). In conclusion, self-reported periodontal disease is independently associated with inflammation and common in persons without traditional CVD risk-factors.
PMCID: PMC2640225  PMID: 19026305
Oral Health; Cardiovascular Disease; Inflammation; Lipoprotein-Associated Phospholipase A2
12.  Aberrant Mucin Assembly in Mice Causes Endoplasmic Reticulum Stress and Spontaneous Inflammation Resembling Ulcerative Colitis 
PLoS Medicine  2008;5(3):e54.
MUC2 mucin produced by intestinal goblet cells is the major component of the intestinal mucus barrier. The inflammatory bowel disease ulcerative colitis is characterized by depleted goblet cells and a reduced mucus layer, but the aetiology remains obscure. In this study we used random mutagenesis to produce two murine models of inflammatory bowel disease, characterised the basis and nature of the inflammation in these mice, and compared the pathology with human ulcerative colitis.
Methods and Findings
By murine N-ethyl-N-nitrosourea mutagenesis we identified two distinct noncomplementing missense mutations in Muc2 causing an ulcerative colitis-like phenotype. 100% of mice of both strains developed mild spontaneous distal intestinal inflammation by 6 wk (histological colitis scores versus wild-type mice, p < 0.01) and chronic diarrhoea. Monitoring over 300 mice of each strain demonstrated that 25% and 40% of each strain, respectively, developed severe clinical signs of colitis by age 1 y. Mutant mice showed aberrant Muc2 biosynthesis, less stored mucin in goblet cells, a diminished mucus barrier, and increased susceptibility to colitis induced by a luminal toxin. Enhanced local production of IL-1β, TNF-α, and IFN-γ was seen in the distal colon, and intestinal permeability increased 2-fold. The number of leukocytes within mesenteric lymph nodes increased 5-fold and leukocytes cultured in vitro produced more Th1 and Th2 cytokines (IFN-γ, TNF-α, and IL-13). This pathology was accompanied by accumulation of the Muc2 precursor and ultrastructural and biochemical evidence of endoplasmic reticulum (ER) stress in goblet cells, activation of the unfolded protein response, and altered intestinal expression of genes involved in ER stress, inflammation, apoptosis, and wound repair. Expression of mutated Muc2 oligomerisation domains in vitro demonstrated that aberrant Muc2 oligomerisation underlies the ER stress. In human ulcerative colitis we demonstrate similar accumulation of nonglycosylated MUC2 precursor in goblet cells together with ultrastructural and biochemical evidence of ER stress even in noninflamed intestinal tissue. Although our study demonstrates that mucin misfolding and ER stress initiate colitis in mice, it does not ascertain the genetic or environmental drivers of ER stress in human colitis.
Characterisation of the mouse models we created and comparison with human disease suggest that ER stress-related mucin depletion could be a fundamental component of the pathogenesis of human colitis and that clinical studies combining genetics, ER stress-related pathology and relevant environmental epidemiology are warranted.
Michael McGuckin and colleagues identify two mutations that cause aberrant mucin oligomerization in mice. The resulting phenotype, including endoplasmic reticulum stress, resembles clinical and pathologic features of human ulcerative colitis.
Editors' Summary
Inflammatory bowel diseases (IBD) are common disorders in which parts of the digestive tract become inflamed. The two main types of IBD are Crohn's disease, which mainly affects the small bowel, and ulcerative colitis (UC), which mainly affects the large bowel (colon). Both types tend to run in families and usually develop between 15 and 35 years old. Their symptoms include diarrhea, abdominal cramps, and unintentional weight loss. These symptoms can vary in severity, can be chronic (persistent) or intermittent, and may start gradually or suddenly. There is no cure for IBD (except removal of the affected part of the digestive tract), but drugs that modulate the immune system (for example, corticosteroids) or that inhibit “proinflammatory cytokines” (proteins made by the immune system that stimulate inflammation) can sometimes help.
Why Was This Study Done?
Although the clinical and pathological (disease-associated) features of Crohn's disease and UC are somewhat different, both disorders are probably caused by an immune system imbalance. Normally, the immune system protects the body from potentially harmful microbes in the gut but does not react to the many harmless bacteria that live there or to the food that passes along the digestive tract. In IBD, the immune system becomes overactive for unknown reasons, and lymphocytes (immune system cells) accumulate in the lining of the bowel and cause inflammation. In this study, the researchers use a technique called random mutagenesis (the random introduction of small changes, called mutations, into the genes of an organism using a chemical that damages DNA) to develop two mouse models that resemble human UC and that throw new light on to how this disorder develops.
What Did the Researchers Do and Find?
The researchers establish two mutant mouse strains—Winnie and Eeyore mice—that develop mild spontaneous inflammation of the colon and chronic diarrhea and that have more proinflammatory cytokines and more lymphocytes in their colons than normal mice. 25% and 40% of the Winnie and Eeyore mice, respectively, have severe clinical signs of colitis by 1 year of age. Both strains have a mutation in the Muc2 gene, which codes for MUC2 mucin, the main protein in mucus. This viscous substance (which coats the inside of the intestine) is produced by and stored in intestinal “goblet” cells. Mucus helps to maintain the intestine's immunological balance but is depleted in UC. The researchers show that the manufacture and assembly of Muc2 molecules is abnormal in Winnie and Eeyore mice, that less mucin is stored in their goblet cells than in normal mice, and that their intestinal mucus barrier is reduced. In addition, an incompletely assembled version of the molecule, called Muc2 precursor, accumulates in the endoplasmic reticulum (ER; the cellular apparatus that prepares newly manufactured proteins for release) of goblet cells, leading to overload with abnormal protein and causing a state of cellular distress known as the “ER stress response.” Finally, the researchers report that MUC2 precursor also accumulates in the goblet cells of people with UC and that even the noninflamed intestinal tissue of these patients shows signs of ER stress.
What Do These Findings Mean?
These findings indicate that mucin abnormalities and ER stress can initiate colitis in mice. Results from animal studies do not always reflect what happens in people, but these findings, together with those from the small study in humans, suggest that ER stress-related mucin depletion could be a component in the development of human colitis. The results do not identify the genetic changes and/or environmental factors that might trigger ER stress in human colitis, but suggest that once initiated, ER stress might interfere with MUC2 production, which would lead to a diminished mucus barrier, expose the lining of the intestine to more toxins and foreign substances, and trigger local mucosal inflammation. The release of inflammatory cytokines would then damage the intestine's lining and exacerbate ER stress, thus setting up a cycle of intestinal damage and inflammation. Clinical studies to look for genetic changes and environmental factors capable of triggering ER stress and for ER-stress related changes in human UC should now be undertaken to test this hypothesis.
Additional Information.
Please access these Web sites via the online version of this summary at
The MedlinePlus Encyclopedia has pages on Crohn's disease and on ulcerative colitis (in English and Spanish)
The US National Institute of Diabetes and Digestive and Kidney Diseases provides information on Crohn's disease and ulcerative colitis
Information and support for patients with inflammatory bowel disease and their caregivers is provided by the Crohn's and Colitis Foundation of America and by the UK National Association for Colitis and Crohn's Disease
Wikipedia has pages on mucins and on mucus (note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
PMCID: PMC2270292  PMID: 18318598
13.  Is immunesenescence a contributing factor for periodontal diseases? 
Current concept in periodontal diseases (PDs) states that it is the host's response toward the periodontal pathogens which leads to tissue destruction and attachment loss. Hence the role of immune response in the progression and resolution of PD must be considered vital. Any alteration in the immune system disturbs the homeostasis of the periodontium. Decline in immune system is the hallmark of aging, leading to increased susceptibility of elderly individuals to bacterial infections. The periodontal apparatus which is being constantly exposed to plaque biofilm is more vulnerable to destruction in aged individuals. Ageing related alterations in immune system has been discussed elsewhere as a contributor to various chronic inflammatory diseases like atherosclerosis, preterm, and low birth weight, etc. This paper reviews on the possible role of aging in periodontal destruction through altered immunity. Aging has long been associated with altered systemic inflammation. It has been discussed whether (1) this systemic inflammation is a consequence of increased occurrence of chronic inflammatory diseases upon aging or (2) aging associated systemic inflammation leads to such diseases. The immune responses which are protective at the first stages of life might result detrimental in the elderly. Hence it might be very difficult to individuate genetic profiles that might allow to identify individuals with a major risk for one or more age related diseases. Taking this into consideration, the cause of PDs in elderly is addressed with a systemic approach in order to understand the complex interplay between the aging immunity and PDs.
PMCID: PMC3713746  PMID: 23869121
Aging; immunesenescence; immunity; inflammaging; periodontal diseases
14.  Effect of periodontal treatment on the clinical parameters of patients with rheumatoid arthritis: study protocol of the randomized, controlled ESPERA trial 
Trials  2013;14:253.
Rheumatoid arthritis (RA) is a chronic inflammatory disorder that leads to joint damage, deformity, and pain. It affects approximately 1% of adults in developed countries. Periodontitis is a chronic oral infection, caused by inflammatory reactions to gram-negative anaerobic bacteria, and affecting about 35 to 50% of adults. If left untreated, periodontitis can lead to tooth loss. A significant association has been shown to exist between periodontitis and RA in observational studies. Some intervention studies have suggested that periodontal treatment can reduce serum inflammatory biomarkers such as C-reactive protein, or erythrocyte sedimentation rate. We hypothesize that periodontitis could be an aggravating factor in patients with RA, and that its treatment would improve RA outcomes. The aim of this clinical trial is to assess the effect of periodontal treatment on the biological and clinical parameters of patients with RA.
The ESPERA (Experimental Study of Periodontitis and Rheumatoid Arthritis) study is an open-label, randomized, controlled trial. Subjects with both RA and periodontitis will be recruited at two university hospitals in southwestern France. In total, 40 subjects will be randomized into two arms (intervention and control groups), and will be followed up for 3 months. Intervention will consist of full-mouth supra-gingival and sub-gingival non-surgical scaling and root planing, followed by systemic antibiotic therapy, local antiseptics, and oral hygiene instructions. After the 3-month follow-up period, the same intervention will be applied to the subjects randomized to the control group.
The primary outcome will be change of in Disease Activity Score in 28 Joints (DAS28) at the end of the follow-up period. Secondary outcomes will be the percentages of subjects with 20%, 50%, and 70% improvement in disease according to the American College of Rheumatology criteria. Health-related quality of life assessments (the Health Assessment Questionnaire and the Geriatric Oral Health Assessment Index) will also be compared between the two groups.
Evidence-based management of potential aggravating factors in subjects with active RA could be of clinical importance, yet there are few randomized controlled trials on the effect of periodontal treatment on the clinical parameters of RA. The ESPERA trial is designed to determine if non-surgical periodontal treatment could improve clinical outcomes in patients with active RA, and the quality of life of these patients.
Trial registration
The ESPERA Trial was registered in Current Controlled Trials [ISRCTN79186420] on 2012/03/20. The trial started recruiting on 2012/03/06.
PMCID: PMC3751435  PMID: 23945051
Rheumatoid arthritis; Periodontal diseases; Periodontitis; Randomized controlled trial; Protocol
15.  Salivary enzymes as diagnostic markers for detection of gingival/periodontal disease and their correlation with the severity of the disease 
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.
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.
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.
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.
PMCID: PMC3498704  PMID: 23162329
Enzymes; periodontal disease; saliva
Oral Diseases  2011;17(5):450-461.
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.
PMCID: PMC3373016  PMID: 21223455
Cardiovascular disease; atherosclerosis; periodontal diseases; infection; periodontal pathogens; bacteremia; inflammatory response; systemic biomarkers; C-reactive protein
17.  A comparative evaluation of antioxidant enzymes and selenium in the serum of periodontitis patients with diabetes mellitus type 2 
Contemporary Clinical Dentistry  2013;4(2):176-180.
Chronic periodontitis is an inflammatory disease with an aberrant response characterized by exaggerated inflammation, involving the release of excess proteolytic enzymes and reactive oxygen species (ROS). Diabetes mellitus is a group of complex multisystem metabolic disorders characterized by a relative or absolute insufficiency of insulin secretion and or concomitant resistance to the metabolic action of insulin on target tissues. Increased production of ROS necessitates elevated requirements for the nutrients involved in antioxidant defenses: Selenium, zinc, and copper. Inflammatory states promote a decrease in the amount of systemic glutathione levels. Catalase is a central antioxidant enzyme constituting the primary defense against oxidative stress.
This study has been designed to evaluate the comparison of glutathione, catalase, and selenium levels in the serum of diabetes mellitus type 2 patients and healthy individuals with and without periodontal disease.
Settings and Design:
This study is a case control study.
Materials and Methods:
The study was designed as a case - control study comprising of 150 subjects, inclusive of both sexes and were divided into three groups of 50 patients each. Group I: 50 subjects with type 2 diabetes mellitus and chronic periodontitis. Group II: 50 subjects who are systemically healthy with the chronic periodontitis. Group III: 50 subjects who are systemically healthy and not suffering from
Serum samples were taken for estimation of glutathione, catalase, and selenium from all groups, and Subjected to biochemical analysis after which atomic absorption spectrophotometry method was used to obtain their levels in serum.
Statistical Analysis Used:
ANOVA and Tukey HSD.
The serum levels of glutathione in diabetic patients with periodontitis were significantly lower with a mean of 61.36 + 8.054 when compared to healthy individuals with and without periodontitis with a mean of 56.93 + 6.874 and 90.36 + 6.564 respectively (P ≤ 0.005). The serum levels of catalase were significantly lower in diabetic patients with periodontitis with a mean of 19.30 + 7.355 when compared to healthy individuals with and without periodontitis with a mean of 20.71 + 6.472 and 36.09 + 5.108 respectively (P ≤ 0.005). The serum levels of selenium were significantly lower in diabetic patients with periodontitis with a mean of 81.41 + 55.419 when compared to healthy individuals with and without periodontitis with a mean of 161.44 + 84.787 and 193.84 + 66.713 respectively (P ≤ 0.005).
The findings from the study suggest that the levels of glutathione, catalase, and selenium are significantly lower in diabetic patients with periodontitis and also in healthy individuals with periodontitis, but are highest in healthy controls, showing that the serum levels are inversely proportional to inflammation and tissue destruction.
PMCID: PMC3757878  PMID: 24015005
Catalase; diabetes mellitus type 2; glutathione; periodontitis; selenium
18.  Effect of Non-Surgical Periodontal Therapy on Superoxide Dismutase Levels in Gingival Tissues of Chronic Periodontitis Patients: A Clinical and Spectophotometric Analysis 
Disease markers  2013;34(5):305-311.
BACKGROUND: Superoxide dismutase (SOD), an antioxidant acting against superoxide (oxygen radical, O2.-), it is released in inflammatory pathways and causes connective tissue breakdown. Increased SOD activity in inflamed gingiva may indicate increased O2.- radical generation by neutrophils and other inflammatory cells at the diseased site. The aim of the study was to evaluate the effects of non-surgical periodontal therapy (NSPT) on SOD levels in gingival tissues of chronic periodontitis patients.
METHODS: Forty subjects: 20 periodontally healthy (Control) and 20 chronic periodontitis (Test); age range 24–55 years were recruited. Gingival tissue samples were collected by excising the inner lining of the periodontal pocket at baseline (prior to non-surgical periodontal therapy) and 2 months post therapy. In controls, tissue samples were obtained immediately after tooth extraction scheduled for orthodontic reasons. Clinical parameters included probing depth, clinical attachment level, gingival index, bleeding index, plaque index. SOD activities were assessed spectrophotometrically at baseline and 2 months post NSPT, results were analysed statistically.
RESULTS: At baseline, patients with chronic periodontitis had higher mean SOD activity (2.73 ± 1.36) than the control subjects (1.12 ± 1.13) with p = 0.00003 (p < 0.05). At 2 months post NSPT median SOD level (1.00) had come close to median SOD value of control group (0.85); p = 0.99 (p > 0.05). The resolution of inflammation with successful NSPT resulted in decreased SOD levels as in control group. Clinical parameters in patients with chronic periodontitis showed a significant improvement 2 months post NSPT (p < 0.05).
CONCLUSION: Non-surgical periodontal therapy significantly improves the clinical parameters and restores previously increased SOD levels to normal in chronic periodontitis patients.
PMCID: PMC3809744  PMID: 23478273
Non-surgical periodontal therapy; superoxide dismutase; chronic periodontitis; gingiva; neutrophils
19.  Determination of levels of nitric oxide in smoker and nonsmoker patients with chronic periodontitis 
Cigarette smoking is a major risk factor in periodontal diseases. The pathogenesis of periodontal diseases may be affected by alterations of the inflammatory response by smoke. Nitric oxide (NO) is a gaseous, colorless, highly reactive, short-lived free radical with a pivotal role in the regulation of various physiological and pathological mechanisms in the body. It is important in host defense and homeostasis, on the one hand, whereas, on the other hand, it modulates the inflammatory response in periodontitis, leading to harmful effects. The aim of this study was to assess the levels of NO in both the serum and saliva of smokers and nonsmokers having chronic periodontitis and to compare them with periodontally healthy controls.
Sixty subjects participated in the study and were divided into three groups: group I, healthy nonsmoking subjects; group II, nonsmoking patients with chronic periodontitis; group III, smoking patients with chronic periodontitis. Each group consisted of twenty subjects. The biochemical estimation of NO in the collected serum and in the saliva was performed using the Griess colorimetric reaction.
The results showed that the mean value of the salivary and serum NO was greater in group II than in group I, and also greater in group III than in group II.
NO appears to play an important and rather complex role in the immuno-inflammatory process and in the remodeling and maintenance of osseous structures. It is therefore logical that modulation of this mediator has potential for the treatment of a number of inflammatory conditions including periodontal disease.
PMCID: PMC3825988  PMID: 24236243
Chronic periodontitis; Colorimetry; Nitric oxide; Smoking
20.  Effect of anti-rheumatic agents on periodontal parameters and biomarkers of inflammation: a systematic review and meta-analysis 
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.
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.
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.
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.
PMCID: PMC3296933  PMID: 22413068
Periodontitis; Rheumatoid arthritis; Tumor necrosis factor-alpha
21.  A New Inflammatory Cytokine on the Block: Re-thinking Periodontal Disease and the Th1/Th2 Paradigm in the Context of Th17 Cells and IL-17 
Journal of dental research  2008;87(9):817-828.
For almost two decades, the Th1/Th2 paradigm has offered a productive conceptual framework for investigating the pathogenesis of periodontitis. However, as with many other inflammatory diseases, the observed role of T-cell-mediated immunity in periodontitis did not readily fit this model. A new subset of CD4+ T-cells was recently discovered that explains many of the discrepancies in the classic Th1/Th2 model, and has been termed “Th17” based on its secretion of the novel pro-inflammatory cytokine IL-17. The identification of Th17 cells as a novel effector T-cell population compels re-examination of periodontitis in the context of the new subset and its signature cytokines. This review aims to offer a clarifying insight into periodontal pathogenesis under the extended Th1/Th2/Th17 paradigm, and is predicated on the principle that periodontal disease activity is determined by a complex interplay between the immune system and periodontal pathogens. The re-examination of existing periodontal literature and further studies in the light of these new discoveries may help explain how the inflammatory response results in damage to the periodontium while generally failing to control the pathogens. This knowledge is essential for the development of immunomodulatory intervention strategies for fine-tuning the host response to maximize the protective and minimize the destructive aspects of the periodontal host response. Moreover, with the advent of anti-cytokine biologic drugs that target the Th1 and Th17 pathways in autoimmunity, the potential consequences to periodontal disease susceptibility in humans need to be understood.
PMCID: PMC2692983  PMID: 18719207
cytokines; Th1/Th2/Th17; IL-17; periodontal disease
22.  Effect of periodontal treatment on adipokines in type 2 diabetes 
World Journal of Diabetes  2014;5(6):924-931.
The association between adipokines and inflammatory periodontal diseases has been studied over the last two decades. This review was intended to explore the observation that periodontal therapy may lead to an improvement of adipokines in diabetic patients. In summary, substantial evidence suggests that diabetes is associated with increased prevalence, extent and severity of periodontitis. Numerous mechanisms have been elucidated to explain the impact of diabetes on the periodontium. However, current knowledge concerning the role of major adipokines indicates only some of their associations with the pathogenesis of periodontitis in type 2 diabetes. Conversely, treatment of periodontal disease and reduction of oral inflammation may have positive effects on the diabetic condition, although evidence for this remains somewhat equivocal.
PMCID: PMC4265882  PMID: 25512798
Adipokines; Diabetes; Periodontal disease; Periodontal therapy
23.  The effect of a periodontal intervention on cardiovascular risk markers in Indigenous Australians with periodontal disease: the PerioCardio study 
BMC Public Health  2011;11:729.
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.
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.
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
PMCID: PMC3189892  PMID: 21943132
24.  Utility of PDL progenitors for in vivo tissue regeneration: a report of 3 cases 
Oral diseases  2010;16(1):20-28.
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.
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.
This study demonstrated clinical and experimental evidences supporting a potential efficacy and safety of utilizing autologous PDL cells in the treatment of human periodontitis.
PMCID: PMC2848819  PMID: 20355278
periodontal ligament progenitors; regeneration; periodontitis
25.  Pathologic crossroads: cardio–vascular diseases, periodontal diseases and calcium antagonists  
RationaleDuring the last decennium t a more focused attention has been directed to the presence of chronic inflammation in cardiovascular diseases (CVD), but mainly to the high impact that this one has in generating and fastening the atherosclerotic process.
ObjectiveTo highlight the causal relationship between periodontal diseases (PD) and CVD. One of the most important chronic inflammations, present in the modern societies in the vast majority of the population, is represented by the periodontal diseases (PD). Both types of diseases are characterized by a high and continuously increasing prevalence. It is now clear that they share some common risk factors, but it would be of great interest, not only for a scientific purpose, but also from a possible health benefit, as PD can be prevented and treated efficiently, to prove that there is a causal link between these two pathologies.
MethodsWe will present a review of the actual data concerning their relationship
DiscussionThe study of this causal relationship is made more difficult due to the increased utilization, due to the guides' recommendations of the calcium antagonists (CA) in treating CVD.
Abreviations: AE = adverse effect; AMI = acute myocardial infarction; CA = calcium antagonists; CHD = coronary heart disease; COI = chronic oral infection; CsA = cyclosporine A; CVD = cardio-vascular diseases; DM = diabetes mellitus; DNA = deoxyribonucleic acid; GH = gingival hypertrophy; GO = gingival overgrowth; hs-CRP = high-sensitivity C reactive protein; IL = interleukine; ICAM = intracellular adhesion molecule; JE/MCP–1 = macrophage chemotactic protein; LPS– lipopolisaccharides; MIP–2 = macrophage inflammatory protein–2; MMP = matrix metalloproteinases; mRNA = messenger–ribonucleic acid; NOS = nitric oxide synthase; PAI–1 = plasminogen activator inhibitor–1; PD = periodontal diseases; TIMP = tissue inhibitor of metalloproteinase; TNF = tumor necrosis factor; USA = United States of America; UFC = units forming cultures; WHO= World Health Organization.
PMCID: PMC3056418  PMID: 21505569
cardiovascular diseases; periodontal diseases; atherosclerosis; gingival overgrowth; calcium antagonists

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