Clinical relevance of the host responses of periodontitis.
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Animals↗
Biomedical subjects
Denis F Kinane
Publications and source records attributed to Denis F Kinane.
Differential activation of human gingival epithelial cells and monocytes by Porphyromonas gingivalis fimbriae.
Humans develop periodontitis in response to challenge by microbial dental plaque. Inflammation begins after perturbation of gingival epithelial cells by subgingival bacteria interacting through pattern-recognition receptors, including the Toll-like receptors (TLR). Porphyromonas gingivalis is a major periodontopathogen that interacts with epithelial cells through its cell surface fimbriae (FimA), leading to colonization and/or invasion. Previous work by our group has established membrane CD14 as an essential coreceptor for TLR2-mediated activation of transfected cell lines by P. gingivalis FimA. We have shown that gingival epithelial cells express TLR2 but not CD14 on their cell surfaces. We thus speculated that P. gingivalis FimA does not readily activate epithelial innate immune responses but rather functions to promote P. gingivalis colonization in the absence of a vigorous FimA-induced response. This hypothesis was verified by the findings that primary human gingival epithelial cells responded poorly to FimA in terms of interleukin (IL)-6, IL-8, granulocyte-macrophage colony-stimulating factor, and tumor necrosis factor alpha responses, in stark contrast to the marked response to other TLR2 agonists (Pam3Cys, FSL-1) that are not strictly dependent on CD14. On the other hand, CD14-expressing human primary monocytes responded with high levels of the same cytokines to both FimA and the control TLR2 agonists. The gingival epithelial cells failed to respond to FimA even in the presence of exogenously added soluble CD14. These data indicate that the gingival epithelial cell hyporesponsiveness to FimA is attributable to the lack of membrane-expressed but not soluble CD14. In conclusion, P. gingivalis FimA differentially activates human monocytes and epithelial cells, perhaps reflecting different tactics used by P. gingivalis when interacting with different host cell types or a host strategy to limit inflammation.
Cells, Cultured↗
Porphyromonas gingivalis enhances FasL expression via up-regulation of NFkappaB-mediated gene transcription and induces apoptotic cell death in human gingival epithelial cells.
The interaction between epithelial cells and micro-organisms is often a crucial initiating event in infectious diseases. Infection with Porphyromonas gingivalis, a Gram-negative anaerobe, is strongly associated with severe periodontal disease. This bacterium possesses an array of virulence factors, some of which can induce apoptosis. The tumour necrosis factor (TNF) receptor family is involved in the regulation of cellular homeostasis, cell surface molecules involved in phagocytosis, Fas ligand (L) expression and activation of the caspase cascade resulting in DNA fragmentation and cell blebbing. The current study examined the role of nuclear factor-kappaB (NFkappaB) in FasL-mediated apoptotic cell death in primary human gingival epithelial cells (HGEC) induced by heat-killed P. gingivalis, probably through TLR signalling pathways. A marked up-regulation of TLR2 and Fas-FasL was detected in HGEC stimulated with P. gingivalis. Activation of NFkappaB by P. gingivalis in HGEC was demonstrated by an NFkappaB promoter luciferase assay as well as by phosphorylation of p65 as detected by Western blotting. Activation of cleaved caspase-3 and caspase-8 resulted in apoptotic cell death of HGEC. The survival proteins c-IAP-1/c-IAP-2 were decreased in HGEC exposed to P. gingivalis. HGEC apoptosis induced by P. gingivalis was inhibited by an anti-human FasL monoclonal antibody. Blockade of NFkappaB by helenalin resulted in down-regulation of FasL whereas a caspase-8 inhibitor did not decrease FasL. Taken together, these studies show that P. gingivalis can induce epithelial cell apoptosis through Fas-FasL up-regulation and activation of caspase-3 and caspase-8.
Apoptosis↗
Effects of smoking and gingival inflammation on salivary antioxidant capacity.
AIM: This study evaluated possible effects of smoking and gingival inflammation on salivary antioxidants in gingivitis patients. METHODS: Twenty otherwise healthy gingivitis patients (10 self-reported smokers) and 20 periodontally and systemically healthy volunteer subjects were enrolled in the study. Whole saliva samples and full-mouth clinical periodontal recordings were obtained at baseline and one month following initial phase of treatment in gingivitis patients. Salivary cotinine, glutathione and ascorbic acid concentrations, and total antioxidant capacity were determined, and the data generated were tested by non-parametric tests. RESULTS: Salivary cotinine measurements resulted in re-classification of three self-reported non-smokers as smokers. Smoker patients revealed significantly higher probing depths but lower bleeding values than non-smoker patients (p=0.044 and 0.001, respectively). Significant reductions in clinical recordings were obtained in non-smoker (all p<0.05) and smoker (all p<0.01) patients following periodontal treatment. Salivary total glutathione concentrations were reduced following therapy in gingivitis patients who smoke (p<0.01). Otherwise, no statistically significant differences were found between the groups in biochemical parameters at baseline or following treatment (p>0.05). CONCLUSIONS: Within the limits of this study, neither smoking nor gingival inflammation compromised the antioxidant capacity of saliva in systemically healthy gingivitis patients.
Adult↗
Environmental and other modifying factors of the periodontal diseases.
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Biofilms↗
Effects of selective cyclooxygenase-2 inhibitor and omega-3 fatty acid on serum interleukin-1beta, osteocalcin, and C-reactive protein levels in rats.
BACKGROUND: The aim of this study was to evaluate the effects of selective cyclooxygenase-2 inhibitor, celecoxib, and omega-3 fatty acid on serum levels of interleukin 1-beta (IL-1beta), osteocalcin (OC), and C-reactive protein (CRP) in experimental periodontitis. METHODS: Experimental periodontitis in rats was induced by repeated injection of purified lipopolysaccharide (LPS) derived from Escherichia coli endotoxin. Forty-seven adult male Sprague-Dawley rats were divided into five study groups as follows: saline control, LPS, LPS + celecoxib, LPS + omega-3 fatty acid, and LPS + celecoxib + omega-3 fatty acid. Celecoxib and omega-3 fatty acid were given alone or in combination during 14 days of the experimental study period. At the end of the 2-week protocol, serum samples were obtained, and the rats were sacrificed. Serum samples were analyzed for IL-1beta, OC, and CRP concentrations by enzyme-linked immunosorbent assay. Defleshed jaws were analyzed morphometrically for alveolar bone loss. Data were evaluated statistically by non-parametric tests. RESULTS: According to the morphometric measurements, the LPS and drug treatment groups showed significantly higher bone loss than the saline control group (P <0.05). Omega-3 fatty acid, both alone and in combination with celecoxib, revealed significantly higher IL-1beta levels than LPS and celecoxib groups (P <0.05). Individual and combined administration of celecoxib and omega-3 fatty acid significantly increased OC levels compared to the LPS group (P <0.05). There were no significant differences in serum CRP levels. CONCLUSIONS: Celecoxib and/or omega-3 fatty acid administration does not significantly influence circulating levels of CRP. The significantly increased serum OC level observed after individual and combination administration suggests that celecoxib and omega-3 fatty acid may influence bone remodeling and thereby inhibit the progression of alveolar bone resorption. However, the failure to observe any significant inhibition of bone loss in celecoxib- and/or omega-3 fatty acid-treated rats compared to the LPS group suggests that their therapeutic effect may be reduced by other factors, such as increases in serum IL-1beta promoting osteoclast activity.
Alveolar Bone Loss↗
Dietary supplementation of omega-3 fatty acid and circulating levels of interleukin-1beta, osteocalcin, and C-reactive protein in rats.
BACKGROUND: In this study, we evaluated the effects of two different regimes of dietary supplementation of omega-3 fatty acid on serum levels of interleukin-1 beta (IL-1beta), osteocalcin (OC), and C-reactive protein (CRP) in experimental periodontitis. METHODS: Experimental periodontitis was induced by repeated injections of Escherichia coli lipopolysaccharide (LPS). Thirty-nine adult male Sprague-Dawley rats were divided into four study groups as follows: an LPS positive control group; a saline (negative) control group; and two different groups with omega-3 fatty acid dietary supplementation, one in which we gave the supplement subsequent to disease induction (TO3) and the other in which the agent was started prior to and continued subsequent to LPS injections (P + TO3). In the TO3 group, omega-3 fatty acid administration was performed for 14 days following induction of experimental periodontitis. In the P + TO3 group, omega-3 fatty acid was given for 14 days prior to the start of LPS injections and was continued for another 14 days subsequent to the induction of experimental periodontitis. On day 15 of the first LPS injection, serum samples were obtained and rats were sacrificed. Serum samples were analyzed for IL-1beta, OC, and CRP concentrations by enzyme-linked immunosorbent assay. Defleshed jaws were analyzed morphometrically for alveolar bone loss. Data were evaluated statistically by non-parametric tests. RESULTS: LPS injection resulted in statistically significantly more bone loss compared to the saline control group (P <0.05). None of the omega-3 fatty acid administration groups showed evidence that this fatty acid was effective in preventing LPS-induced alveolar bone loss. TO3 and P + TO3 groups revealed significantly higher IL-1beta and OC levels than the LPS group (P <0.05). The study groups exhibited no significant differences in the serum CRP levels. CONCLUSIONS: Omega-3 fatty acid administration does not seem to influence circulating levels of CRP. The significantly increased serum OC level observed in both omega-3 fatty acid regimes is curious and could have an effect on bone turnover, as could the further significant increase in serum IL-1beta, which could counteract any osteoblastic induction by OC through promotion of osteoclast activity. The lack of a therapeutic benefit of omega-3 fatty acid in this study, despite the effects on OC and IL-1beta, is difficult to explain, and further studies are required to more fully assess the potential role of this fatty acid in periodontal treatment.
Alveolar Bone Loss↗
Plasminogen activator system in smokers and non-smokers with and without periodontal disease.
BACKGROUND: The present study assessed levels of plasminogen activator (PA) system proteins in gingival crevicular fluid (GCF) and serum of chronic gingivitis, chronic periodontitis patients and periodontally healthy subjects and evaluated how smoking influenced these levels. METHODS: Twenty chronic gingivitis; 20 chronic periodontitis patients and 20 periodontally healthy volunteers were consecutively recruited according to the inclusion criteria so that exactly half of the subjects in each category were smokers. GCF samples from four sites together with serum samples were obtained from each subject. GCF levels of tissue type PA (t-PA), urokinase type PA (u-PA), PA inhibitor-1 (PAI-1) and PA inhibitor-2 (PAI-2) and serum concentrations of cotinine, u-PA and PAI-1 were analysed by enzyme-linked immunosorbent assay. RESULTS: The only statistically significant difference between smokers and non-smokers was a lower GCF PAI-2 concentrations in healthy smokers compared with healthy non-smokers (p<0.01). Gingivitis and periodontitis patients had higher GCF concentrations of PAI-2 than healthy subjects (p<0.002 and p<0.02 respectively). The ratio of u-PA:PAI-1 and t-PA:PAI-1 were significantly higher in GCF of smokers with periodontitis compared with "healthy" smokers, whereas the ratio of t-PA:PAI-2 was significantly lower in smokers with periodontal disease (p<0.05). CONCLUSIONS: GCF levels of the PA system proteins are increased in chronic gingivitis and periodontitis compared with healthy gingiva. Smoking had only subtle effects on the GCF PA system proteins with the exception of PAI-2, and the balance of activators and inhibitors. These findings suggest one mechanism whereby smoking may exert detrimental effects on the periodontal tissues.
Adult↗
Bacteraemia following periodontal procedures.
INTRODUCTION: Transient bacteraemias are frequently detected following dental manipulation. Infective endocarditis (IE) can arise in susceptible individuals and antibiotic prophylaxis is routinely performed for certain procedures considered to be "at risk" of IE. Evidence is emerging that periodontal disease may be a significant risk factor for the development of certain systemic diseases such as cardiovascular disease. These systemic conditions could be initiated or detrimentally influenced by the repeated entry of bacteria into the bloodstream. MATERIALS AND METHODS: The present study comprised a single blind parallel study of 2 weeks duration. A baseline blood sample was obtained from 30 volunteers with untreated periodontal disease following which a periodontal probing depth chart was collected. A further blood sample was taken following this procedure, and each subject was recalled 2 weeks later. A blood sample was collected, the subject carried out toothbrushing and a further blood sample taken. Full-mouth ultrasonic scaling was then performed and a final blood sample taken. Blood samples were analysed for bacteraemia using conventional microbiological culture and polymerase chain reaction (PCR) using universal bacterial primers that target the 16S ribosomal RNA gene of the vast majority of bacteria. RESULTS: Using culture methods, the incidence of bacteraemias was as follows: following ultrasonic scaling (13%), periodontal probing (20%) and toothbrushing (3%). PCR analysis revealed bacteraemia incidences following ultrasonic scaling, periodontal probing and toothbrushing of 23%, 16% and 13%, respectively. CONCLUSION: These findings suggest that detectable dental bacteraemias induced by periodontal procedures are at a lower level than previously reported.
Adult↗
Reducing variability and choosing ideal subjects for experimental gingivitis studies.
INTRODUCTION: This study was undertaken to test the hypothesis that male, non-smokers, aged 25-50 years, with a proven track record of developing gingivitis would provide suitable subjects for experimental gingivitis studies because the inter-subject variation would be greatly reduced. MATERIALS AND METHODS: Subjects were required to be men aged between 25 and 50 years, in good general health with at least four sound teeth in one posterior quadrant of the mandible. Subjects who were smokers, taking antibiotics, anti-inflammatory drugs or had any other medical, surgical or social condition making participation in the study inadvisable, were excluded. Subjects had previously participated in a 21-day experimental gingivitis study. Subjects with the most gingivitis at the end of the previous study were invited to participate first, moving down the list until the required number of subjects had been achieved. Subjects were randomly assigned to one of three toothpastes: Crest Gum Care, Mentadent P or a placebo (UK Signal). Subjects were asked to brush their teeth twice daily for 1 min., with the tooth-shield in place and containing 1 ml of their assigned toothpaste. RESULTS: Thirty-five subjects completed the study using the placebo, 36 used Mentadent P and 39 completed the study using Crest Gum Care. Both toothpastes containing active gum health ingredients (Triclosan and Zinc Citrate in Mentadent P and Stannous Fluoride in Crest Gum Care) resulted in statistically significant reductions in gingival bleeding and inflammation. Although a directional reduction, there was no statistically significant reduction in plaque scores. No significant differences between the two active groups were established. CONCLUSION: The factors that were controlled or measured and analyzed in these studies were: gender, smoking status, age and chronic gingivitis level. The results add support to the hypothesis that male subjects show less variation, however there is limited evidence linking the female menstrual cycles to variations in gingivitis status. Further research in this area is required before definitive conclusions can be made. Selecting a subject population in order to decrease variation must be undertaken with caution. A subject population selected for particular attributes can be extremely valuable when assessing the anti-gingivitis potential of new agents, but this population would be as biased if used for large efficacy clinical trials. The data obtained will not necessarily be able to be generalized, that is, applicable to the whole population. However there is sufficient evidence to justify balancing for (or excluding) smokers from subject populations in experimental gingivitis studies.
Adult↗
Single-visit, full-mouth ultrasonic debridement: a paradigm shift in periodontal therapy?
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Dental Scaling↗
Effect of genetic variability on the inflammatory response to periodontal infection.
AIM: To review the association between genetic variability and the inflammatory response induced by periodontal infection. MATERIAL AND METHODS: A search of MEDLINE-PubMed was performed from January 2000 up to and including March 2005. The search included all types of publications, published in English without other limitations. The following search terms were used: "cytokine polymorphism", "gene polymorphism", "periodontitis", "gingivitis", "inflammation" and "host-response". The papers resulting from the above search were used as an additional source for relevant articles. RESULTS: Genetic variability was examined for the correlation to clinical indicators of inflammation such as bleeding on probing (BOP), gingival inflammation, cytokine in gingival crevicular fluid (GCF) and cytokine production by inflammatory cells. According to the current literature, most of the studies found no association between genetic variability and BOP, gingival inflammation or cytokine concentrations in the GCF. These studies were hampered by inappropriate study designs and the use of inflammatory parameters as secondary rather than primary outcome variables. The data suggest that the production of inflammatory mediators by inflammatory cells may be affected by different genetic traits but further studies are needed in order to establish this association. CONCLUSIONS: To date, there is no clear correlation between any of the gene polymorphisms and clinical indicators of inflammation. The powering of studies to reveal associations between single or multiple nucleotide polymorphisms and inflammatory parameters will need to involve a much larger number of subjects than were used in the past. The available data (including the interleukin-1 composite genotype) do not currently support the utility of such tests in the diagnosis and prognostic assessments of periodontal diseases.
Bacteria, Anaerobic↗
The genetic basis of periodontitis.
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Family Health↗
Parotid secretory protein is expressed and inducible in human gingival keratinocytes.
BACKGROUND: Parotid secretory protein (PSP) is a major salivary protein that is thought to possess both antibacterial and anti-inflammatory activity. A major question is whether PSP expression can be regulated by humoral factors and bacteria. Periodontitis is an inflammatory lesion initiated by interaction between gingival keratinocytes and periodontopathogenic microorganisms such as the Gram-negative anaerobe Porphyromonas gingivalis. Cytokines and sex hormones have been implicated in the progression of various forms of periodontal diseases. MATERIALS AND METHODS: We investigated the expression of PSP and its regulation in primary cultures of human gingival keratinocytes (HGK). HGK at the third or fourth passage were exposed to heat-killed P. gingivalis, tumor necrosis factor-alpha (TNF-alpha) and 17beta-estradiol. The PSP mRNA levels were examined by real-time polymerase chain reaction (PCR). The protein expression of PSP was confirmed by immunofluorescence. RESULTS: Heat-killed P. gingivalis, TNF-alpha and 17beta-estradiol all resulted in increased HGK levels of mRNA for PSP as determined by real-time PCR analysis. Immunofluorescence demonstrated increased PSP localized within the cytoplasm of HGK following exposure to killed P. gingivalis. CONCLUSION: The present study has demonstrated for the first time that PSP is expressed in keratinocytes and that it can be up-regulated by bacteria and humoral factors. Thus PSP may have a role in the innate defense system at the gingival epithelial surface.
Cell Culture Techniques↗
Systemic low-dose doxycycline and alendronate administration and serum interleukin-1beta, osteocalcin, and C-reactive protein levels in rats.
BACKGROUND: The aim of the present study was to evaluate the effects of systemic administration of low-dose doxycycline and a bisphosphonate, alendronate, on serum levels of interleukin-1beta (IL-1beta), osteocalcin (OC), and C-reactive protein (CRP) in experimental periodontitis in rats. METHODS: Experimental periodontitis was induced by repeated injection of purified lipopolysaccharide (LPS) derived from Escherichia coli endotoxin. Forty-seven adult male Sprague-Dawley rats were divided into five study groups and given LPS, LPS + doxycycline, LPS + alendronate, LPS + doxycycline + alendronate, and saline control. At the end of the 1-week protocol, blood samples were obtained, and the rats were sacrificed. Serum samples were analyzed for IL-1beta, OC, and CRP concentrations by enzyme-linked immunosorbent assay (ELISA). The jaws were defleshed, and alveolar bone loss was assessed morphometrically. Data were evaluated statistically by non-parametric tests. RESULTS: Morphometric measurements revealed significantly more bone loss in the LPS group compared to the saline control group (P <0.05). Alendronate revealed slight inhibition on alveolar bone loss either alone or in combination with doxycycline (alveolar bone loss: 0.41 mm in alendronate and combined drug treatment groups versus 0.45 mm in LPS and doxycycline groups). Significantly higher IL-1beta levels were observed with alendronate either alone or in combination with doxycycline than in the LPS group (P <0.05). Combined administration of doxycycline and alendronate showed significantly higher levels of OC than all of the other groups (P <0.01). Serum CRP levels did not exhibit significant differences between the study groups. CONCLUSIONS: Alendronate either alone or in combination with doxycycline provided slight inhibition on LPS-induced alveolar bone resorption. The significantly increased serum OC level observed in the combined drug treatment group suggests that combined administration of alendronate and doxycycline might increase bone remodeling and thereby inhibit the progression of alveolar bone resorption in rats.
Alendronate↗
Macrophage inflammatory protein-3alpha and beta-defensin-2 stimulate dentin sialophosphoprotein gene expression in human pulp cells.
Macrophage inflammatory protein (MIP)-3alpha and beta-defensin (BD)-2 have antimicrobial activity and chemotactic activity for immature dendritic cells, natural killer cells, and memory T cells. However, it remains unknown if the widespread effects of these peptides also include an influence on the differentiation of mesenchymal cells. Pulp cells have the capacity to differentiate into odontoblasts and to form dentin. The aim of this study was to determine if inflammatory leukocyte products influence the capacity of pulp cells to differentiate. Dentin sialophosphoprotein (DSPP) is a tooth-specific protein being expressed mostly by odontoblast cells. In the present study, we investigated effects of MIP-3alpha and BD-2 on the DSPP and osteopontin (OPN) gene expression in cultures of human pulp-derived fibroblastic cells (HP cells). HP cells expressed mRNA for the CC chemokine receptor (CCR) 6 to which both MIP-3alpha and BD-2 can bind. Real-time PCR showed that MIP-3alpha and BD-2 significantly increased DSPP mRNA levels, although BD-2 increased DSPP mRNA levels less than MIP-3alpha. MIP-3alpha and BD-2 increased OPN mRNA levels very slightly. MIP-3alpha and BD-2 possessed antibacterial activity against Streptococcus mutans and Lactobacillus casei, which are involved in caries, although the antibacterial activity of MIP-3alpha was lower than that of BD-2. These findings suggest the MIP-3alpha and BD-2 have the ability to stimulate odontoblast differentiation in addition to their more traditional role in inflammation and have potential in the removal of bacteria in infected soft dentin and pulp tissues.
Cell Differentiation↗
Nutrition, inflammation, and periodontal disease.
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Antioxidants↗
Gingival crevicular fluid collagenase-2 (MMP-8) test stick for chair-side monitoring of periodontitis.
BACKGROUND: A rapid chair-side test based on the immunological detection of elevated levels of collagenase-2 (matrix metalloproteinase-8, MMP-8) in gingival crevicular fluid (GCF) was developed to identify and monitor the course and treatment of adult periodontitis. METHODS: MMP-8 was determined in GCF from periodontitis (11 patients, 90 sites), gingivitis (10 patients, 58 sites) and healthy control (8 patients, 59 sites) sites (i) by a test stick incorporating monoclonal antibodies to two epitopes on MMP-8 and (ii) by measuring MMP-8 concentration by a quantitative immunofluorometric assay. Patients with adult periodontitis were treated by scaling and root planing (SRP) and received oral hygiene instructions. GCF MMP-8 testing and clinical measurements were done before and after SRP. RESULTS: MMP-8 GCF levels and chair-side test differentiated periodontitis from gingivitis and healthy control sites. MMP-8 GCF levels > 1 mg/l and positive chair-side test identified especially severe periodontitis sites. A positive and negative test stick result, the outcome of which was rapidly detectable in 5 mins, in GCF correlated well with MMP-8 immunofluorometric assay analysis from the collected GCF samples and the severity of periodontitis. Scaling and root planing reduced the MMP-8 levels in severe periodontitis sites with positive MMP-8 test and gingival probing pocket depth (PD) > 5 mm before treatment. The test stick result and the quantitative assay were discrepant in only 18 of the 207 sites tested, thus agreement was very good (kappa = 0.81). With a threshold of 1 mg/l MMP-8 activity the chair-side test provided a sensitivity of 0.83 and specificity of 0.96 (n = 207). CONCLUSION: The MMP-8 test can be used to differentiate periodontitis from gingivitis and healthy sites as well as to monitor treatment of periodontitis. A reduction in GCF MMP-8 levels and a change in test stick result provide a means to optimize patient control during maintenance of periodontal treatment.
Adult↗