Resolution of inflammation: Intervention strategies and future applications.

Chronic inflammatory diseases are the major cause of morbidity and mortality in the aging population worldwide. Chronic inflammation reflects a deficiency in the resolution phase of the acute inflammatory response, which then fails to engage the adaptive immune system accordingly. Resolution of inflammation is a tightly regulated biological pathway that sequentially aids in eliminating the inducing agent and orchestrates clearance of effete immune cells to promote the return to tissue homeostasis. The lipid mediators of resolution of inflammation comprise a family of specialized pro-resolving mediators (SPMs). The synthesis of SPMs occurs via enzymatic conversion of essential omega-6 (n-6) and omega-3 (n-3) fatty acids. SPMs have anti-inflammatory, pro-resolving and tissue regenerating properties. A large number of in vitro and in vivo studies have unveiled the mechanism of action of many SPMs. Here, we focus on the actions of SPMs in health and chronic disease models as well as their potential as therapeutic agents in ongoing and future clinical trials.

Distinct Profiles of Specialized Pro-resolving Lipid Mediators and Corresponding Receptor Gene Expression in Periodontal Inflammation.

Polyunsaturated fatty acid-derived specialized pro-resolving lipid mediators (SPMs) play an important role in modulating inflammation. The aim of the study was to compare profiles of SPMs, SPM related lipid mediators and SPM receptor gene expression in gingiva of subjects with periodontitis to healthy controls. A total of 28 subjects were included; 13 periodontally healthy and 15 periodontitis before or after non-surgical periodontal therapy. Gingival tissues were collected from two representative posterior teeth prior to and 8 weeks after scaling and root planning; only once in the healthy group. Lipid mediator-SPM metabololipidomics was performed to identify metabolites in gingiva. qRT-PCR was performed to assess relative gene expression (2-ΔΔCT) of known SPM receptors. Intergroup comparisons were made using Wilcoxon tests. Thirty-six omega-6 or omega-3 fatty acid-derived lipid mediators and seven receptor genes were identified in gingiva. Profiles of lipid mediators and receptor gene expression were significantly different between the three groups. Levels of six lipid mediators, 5-HETE, 15-HETE, 15(S)-HEPE, 4-HDHA, 7-HDHA, and 17-HDHA in periodontitis before treatment were significantly higher than in periodontitis after treatment. The expression of BLT1 in the healthy group was significantly higher than periodontitis subjects before and after treatment. The expression of GPR18 in periodontitis before treatment was significantly higher than in periodontitis after treatment while the expression of GPR32 in periodontitis before treatment was significantly lower than in periodontitis after treatment. Elevated levels of SPM biosynthetic pathway markers in periodontitis subjects before treatment indicated inflammation induced pro-resolution activity in gingiva, but receptors for these molecules were deficient in periodontitis pre-treatment suggesting that failure of resolution of inflammation contributes to excess, chronic inflammation in periodontitis.

Omega-3 PUFA and aspirin as adjuncts to periodontal debridement in patients with periodontitis and type 2 diabetes mellitus: Randomized clinical trial.

BACKGROUND: Supplementation with omega-3 polyunsaturated fatty acids (ω-3 PUFA) and low-dose aspirin (ASA) have been proposed as a host modulation regimen to control chronic inflammatory diseases. The aim of this study was to investigate the clinical and immunological impact of orally administered ω-3 PUFA and ASA as adjuncts to periodontal debridement for the treatment of periodontitis in patients type 2 diabetes. METHODS: Seventy-five patients (n = 25/group) were randomly assigned to receive placebo and periodontal debridement (CG), ω-3 PUFA + ASA (3 g of fish oil/d + 100 mg ASA/d for 2 months) after periodontal debridement (test group [TG]1), or ω-3 PUFA + ASA (3 g of fish oil/d + 100 mg ASA/d for 2 months) before periodontal debridement (TG2). Periodontal parameters and GCF were collected at baseline (t0), 3 months after periodontal debridement and ω-3 PUFA + ASA or placebo for TG1 and CG (t1), after ω-3 PUFA + ASA (before periodontal debridement) for TG2 (t1), and 6 months after periodontal debridement (all groups) (t2). GCF was analyzed for cytokine levels by multiplex ELISA. RESULTS: Ten patients (40%) in TG1 and nine patients (36%) in TG2 achieved the clinical endpoint for treatment (less than or equal to four sites with probing depth ≥ 5 mm), as opposed to four (16%) in CG. There was clinical attachment gain in moderate and deep pockets for TG1. IFN-γ and interleukin (IL)-8 levels decreased over time for both test groups. IL-6 levels were lower for TG1. HbA1c levels reduced for TG1. CONCLUSION: Adjunctive ω-3 and ASA after periodontal debridement provides clinical and immunological benefits to the treatment of periodontitis in patients with type 2 diabetes.

Omega-3 Fatty Acids Effects on Inflammatory Biomarkers and Lipid Profiles among Diabetic and Cardiovascular Disease Patients: A Systematic Review and Meta-Analysis.

The purpose of this systematic review and meta-analysis was to investigate omega-3 fatty acids' influence on 12 inflammatory biomarkers-LDL, HDL, total cholesterol, TG, HbA1c, Apo AI, Apo AII, Apo B, CRP, TNF-α, glucose, and fasting blood glucose among diabetic and cardiovascular disease (CVD) patients. We searched articles in six database engines, and 16 of the 696 articles reviewed met the inclusion criteria. Among these, lipid and inflammatory biomarkers investigated commonly included total cholesterol (11 studies), LDL, and TG (10 studies each). Overall, omega-3 was associated with a significant reduction in Apo AII among diabetic patients, as compared to different controls (-8.0 mg/dL 95% CI: -12.71, -3.29, p = 0.0009), triglycerides (-44.88 mg/dL 95% CI: -82.6, -7.16, p < 0.0001), HDL (-2.27 mg/dL 95% CI: -3.72, -0.83, p = 0.002), and increased fasting blood glucose (16.14 mg/dL 95% CI: 6.25, 26.04, p = 0.001). Omega-3 also was associated with increased LDL among CVD patients (2.10 mg/dL 95% CI: 1.00, 3.20, p = 0.0002). We conclude that omega-3 fatty acids may be associated with lower inflammatory biomarkers among diabetic and cardiovascular patients. Clinicians should be aware of these potential benefits; however, it is essential to recommend that patients consult with clinicians before any omega-3 intake.

Resolvin E1 Promotes Bone Preservation Under Inflammatory Conditions.

Resolvins are endogenous lipid mediators derived from omega-3 fatty acids. Resolvin E1 (RvE1), derived from eicosapentaenoic acid (EPA), modulates osteoclasts and immune cells in periodontal disease models. The direct role of RvE1 in bone remodeling is not well understood. The objective of this study was to determine the impact of RvE1 on bone remodeling under inflammatory conditions. Our working hypothesis is that RvE1 downregulates bone resorption through direct actions on both osteoblast and osteoclast function in inflammatory osteoclastogenesis. A tumor necrosis factor-α induced local calvarial osteolysis model with or without the systemic administration of RvE1 was used. To evaluate osteoclastogenesis and NFκB signaling pathway activity, murine bone tissue was evaluated by Micro CT (µCT) analysis, TRAP staining, and immunofluorescence analysis. Mechanistically, to evaluate the direct role of RvE1 impacting bone cells, primary calvarial mouse osteoblasts were stimulated with interleukin (IL)-6 (10 ng/ml) and IL-6 receptor (10 ng/ml) and simultaneously incubated with or without RvE1 (100 nM). Expression of receptor activator of NFκB ligand (RANKL) and osteoprotegerin (OPG) was measured by ELISA. RNA sequencing (RNA-Seq) and differential expression analysis was performed to determine signaling pathways impacted by RvE1. The systemic administration of RvE1 reduced calvarial bone resorption as determined by µCT. Histologic analysis of calvaria revealed that osteoclastogenesis was reduced as determined by number and size of osteoclasts in TRAP-stained sections (p < 0.05). Immunofluorescence staining of calvarial sections revealed that RvE1 reduced RANKL secretion by 25% (p < 0.05). Stimulation of osteoblasts with IL-6 increased RANKL production by 30% changing the RANKL/OPG to favor osteoclast activation and bone resorption. The ratio changes were reversed by 100 nM RvE1. RvE1 decreased the production of RANKL maintaining an RANKL/OPG more favorable for bone formation. RNA-Seq and transcriptomic pipeline analysis revealed that RvE1 significantly downregulates osteoclast differentiation mediated by differential regulation of NFκB and PI3K-AKT pathways. RvE1 reduces inflammatory bone resorption. This action is mediated, at least in part, by direct actions on bone cells promoting a favorable RANKL/OPG ratio. Mediators of resolution in innate immunity also directly regulate bone cell gene expression that is modulated by RvE1 through at least 14 specific genes in this mouse model.

Propolis Improves Periodontal Status and Glycemic Control in Patients With Type 2 Diabetes Mellitus and Chronic Periodontitis: A Randomized Clinical Trial.

BACKGROUND: Propolis is a natural resin made by bees from various plant sources and exerts antimicrobial, anti-inflammatory, immunomodulatory, antioxidant, and antidiabetic properties. The purpose of this study is to assess adjunctive benefit of propolis supplementation in individuals with chronic periodontitis (CP) and type 2 diabetes mellitus (DMt2) receiving scaling and root planing (SRP). METHODS: A 6-month masked, randomized clinical trial comparing SRP with placebo (placebo + SRP group, n = 26) or SRP combined with a 6-month regimen of 400 mg oral propolis once daily (propolis + SRP group, n = 24) was performed in patients with long-standing DMt2 and CP. Treatment outcomes included changes in hemoglobin (Hb) A1c (primary outcome), fasting plasma glucose (FPG), serum N€-(carboxymethyl) lysine (CML), and periodontal parameters (secondary outcomes). RESULTS: After 3 and 6 months, average HbA1c levels in the propolis group decreased significantly by 0.82% and 0.96% units, respectively (P <0.01); however, there were no significant differences in the placebo group. Likewise, FPG and CML levels were significantly reduced in the propolis group, but not in the placebo group. After therapy, periodontal parameters of CP were significantly improved in both groups. The propolis group showed significantly greater probing depth reduction and clinical attachment level gain than the control group after 3 and 6 months. CONCLUSION: A 6-month regimen of 400 mg propolis once daily is a potentially viable adjunct to SRP that significantly reduces levels of HbA1c, FPG, and CML, and improves periodontal therapy outcome in people with DMt2 and CP.

Intracanal delivery of Resolvin E1 controls inflammation in necrotic immature rat teeth.

INTRODUCTION: Pulp necrosis in immature teeth and the resulting periodontal apical inflammation negatively affect root formation. Resolvin E1 (RvE1) is a lipid-derived endogenous pro-resolution molecule that controls inflammation. The aim of this investigation was to evaluate the impact of RvE1 applied as an intracanal medication on root formation in nonvital immature teeth. METHODS: To arrest root development, pulpectomy was performed in the lower first molars of 4-week-old Wistar rats. After 3 weeks, irrigation with 2.5% sodium hypochlorite and 0.9% sterile saline was performed, and either a triple antibiotic paste (TAP) or RvE1 in saline was applied into the root canals. In the control group, access openings drilled into molars were left exposed to the oral environment. Root development and periapical repair were evaluated radiographically and histologically at 3 and 6 weeks after treatment. RESULTS: RvE1 reduced periapical lesion size compared with the control at 3 weeks, which was similar to TAP. Inflammatory response in the RvE1-treated group was markedly reduced compared with both TAP and control specimens. At 6 weeks, root development was observed in both groups, but RvE1 treatment produced less cellularity with more regular calcified tissue deposition. CONCLUSIONS: RvE1 and TAP had a positive impact on reducing inflammation and promoting root formation. RvE1 was more effective in reducing inflammation at earlier stages. RvE1 has potential to be used as root canal dressing to control inflammation in endodontically compromised teeth before complete root formation. Stability of RvE1 within the root canal and its delivery are issues to be addressed before its clinical use.

High-dose atorvastatin reduces periodontal inflammation: a novel pleiotropic effect of statins.

OBJECTIVES: The purpose of this study was to test whether high-dose statin treatment would result in a reduction in periodontal inflammation as assessed by (18)F-fluorodeoxyglucose positron emission tomography (FDG-PET)/computed tomography (CT). BACKGROUND: Periodontal disease (PD) is an independent risk factor for atherosclerosis. METHODS: Eighty-three adults with risk factors or with established atherosclerosis and who were not taking high-dose statins were randomized to atorvastatin 80 mg vs. 10 mg in a multicenter, double-blind trial to evaluate the impact of atorvastatin on arterial inflammation. Subjects were evaluated using FDG-PET/CT at baseline and at 4 and 12 weeks. Arterial and periodontal tracer activity was assessed while blinded to treatment allocation, clinical characteristics, and temporal sequence. Periodontal bone loss (an index of PD severity) was evaluated using contrast-enhanced CT images while blinded to clinical and imaging data. RESULTS: Seventy-one subjects completed the study, and 59 provided periodontal images for analysis. At baseline, areas of severe PD had higher target-to-background ratio (TBR) compared with areas without severe PD (mean TBR: 3.83 [95% confidence interval (CI): 3.36 to 4.30] vs. 3.18 [95% CI: 2.91 to 3.44], p = 0.004). After 12 weeks, there was a significant reduction in periodontal inflammation in patients randomized to atorvastatin 80 mg vs. 10 mg (ΔTBR 80 mg vs. 10 mg group: mean -0.43 [95% CI: -0.83 to -0.02], p = 0.04). Between-group differences were greater in patients with higher periodontal inflammation at baseline (mean -0.74 [95% CI: -1.29 to -0.19], p = 0.01) and in patients with severe bone loss at baseline (-0.61 [95% CI: -1.16 to -0.054], p = 0.03). Furthermore, the changes in periodontal inflammation correlated with changes in carotid inflammation (R = 0.61, p < 0.001). CONCLUSIONS: High-dose atorvastatin reduces periodontal inflammation, suggesting a newly recognized effect of statins. Given the concomitant changes observed in periodontal and arterial inflammation, these data raise the possibility that a portion of that beneficial impact of statins on atherosclerosis relate to reductions in extra-arterial inflammation, for example, periodontitis. (Evaluate the Utility of 18FDG-PET as a Tool to Quantify Atherosclerotic Plaque; NCT00703261).

Paradigm shift in the pharmacological management of periodontal diseases.

It is becoming clear that variations in inflammatory response are a major determinant in susceptibility to periodontitis. However, our understanding of the relationship of the causal agents in periodontitis to the pathogenesis is not as clear as we once thought, and thus therapies based on etiopathogenesis are similarly in question. We are entering a new era of therapeutic discovery that may have a major impact on our management of the periodontal diseases. Fundamentally, periodontitis is an irreversible condition and once both soft and hard tissues are lost, the healthy periodontal architecture cannot be completely or predictably rebuilt. The discovery of new families of lipid mediators of resolution of inflammation (the lipoxins) and eicosapentaenoic-acid- and docosahexaenoic-acid-derived chemical mediators (the resolvins and protectins) opens new avenues to designing resolution-targeted therapies to control the unwanted side effects of excessive inflammation. The novel protective and therapeutic actions of pro-resolution lipid mediators following microbial challenge are mediated by regulation of the local and systemic inflammatory response that has a direct impact on the organization of the biofilm (plaque) and suggests a new paradigm in clinical periodontal therapeutics.

Adjunctive treatment of chronic periodontitis with daily dietary supplementation with omega-3 Fatty acids and low-dose aspirin.

BACKGROUND: Host modulatory therapy has been proposed as a treatment for periodontal diseases. Omega-3 (ω-3) polyunsaturated fatty acids (PUFAs), including docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), were shown to have therapeutic anti-inflammatory and protective actions in inflammatory diseases including periodontitis. The goal of this study was to test an innovative strategy for periodontal treatment in a clinical experiment. METHODS: Eighty healthy subjects (40 in each group) with advanced chronic periodontitis were enrolled in Mansoura, Egypt, in a parallel-design, double-masked clinical study. The control group was treated with scaling and root planing (SRP) and a placebo, whereas the ω-3 group was treated with SRP followed by dietary supplementation of fish oil (900 mg EPA + DHA) and 81 mg aspirin daily. Saliva samples were obtained from all patients at baseline and 3 and 6 months for evaluation of receptor activator of nuclear factor-kappa B ligand (RANKL) and matrix metalloproteinase-8 (MMP-8). Plaque and gingival indices, bleeding on probing, probing depths, and attachment levels were recorded at the same time points. RESULTS: Statistical analyses demonstrated a significant reduction in probing depths and a significant attachment gain after 3 and 6 months in the ω-3 group compared to baseline and the control group (P <0.05). Salivary RANKL and MMP-8 levels showed significant reductions in the ω-3 group in response to treatment at 3 and 6 months and compared to the control group at 6 months (P <0.01). Supplementation with ω-3 + aspirin resulted in a significant shift in the frequency of pockets with probing depths <4 mm (P <0.05). CONCLUSION: The results of this preliminary clinical study suggest that dietary supplementation with ω-3 PUFAs and 81 mg aspirin may provide a sustainable, low-cost intervention to augment periodontal therapy.

The management of inflammation in periodontal disease.

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.

Sequential chemotactic and phagocytic activation of human polymorphonuclear neutrophils.

Human polymorphonuclear neutrophils (PMN) chemotax to a foreign entity. When the chemoattractants' origins are reached, specific receptors bind to the invader's surface, initiating phagocytosis, phagosome formation, and fusion with granule membranes, generating the bactericidal oxidative burst, and releasing lytic enzymes, specific peptides, and proteins. We explored the initial signaling involved in these functions by observing naïve, unprimed PMN in suspension using fluorescent indicators of cytoplasmic signals (Delta[Ca(2+)](i) and DeltapH(i)) and of bactericidal entities (oxidative species and elastase) exposed to N-formyl-methionyl-leucyl-phenylalanine (fMLP) and/or multivalent immune complexes (IC). fMLP and IC each initiate a rapid transient rise in [Ca(2+)](i), mostly from intracellular stores, simultaneously with a drop in pH(i); these are followed by a drop in [Ca(2+)](i) and a rise in pH(i), with the latter being due to a Na(+)/H(+) antiport. The impact of a second stimulation depends on the order in which stimuli are applied, on their dose, and on their nature. Provided that [Ca(2+)](i) is restored, 10(-7) M fMLP, previously shown to elicit maximal Delta[Ca(2+)](i) but no bactericidal functions, did not prevent the cells' responses with Delta[Ca(2+)](i) to a subsequent high dose of fMLP or IC; conversely, cells first exposed to 120 mug/ml IC, previously shown to elicit maximal Delta[Ca(2+)](i) and bactericidal functions, exhibited no subsequent Delta[Ca(2+)](i) or DeltapH(i) to either stimulus. While exposure to 10(-7) M fMLP, which saturates the PMN high-affinity receptor, did not elicit bactericidal release from these naïve unprimed PMN in suspension, 10(-5) M fMLP did, presumably via the low-affinity receptor, using a different Ca(2+) source.

Subantimicrobial dose doxycycline enhances the efficacy of scaling and root planing in chronic periodontitis: a multicenter trial.

BACKGROUND: Previous studies have shown that subantimicrobial dose doxycycline (SDD) is of clinical benefit in the treatment of chronic periodontitis (CP). The aim of this study was to further assess the role of SDD as an adjunct to scaling and root planing (SRP) in the treatment of CP. METHODS: A double-blind, randomized, placebo-controlled, multicenter clinical study was conducted to test the efficacy of SDD (20 mg doxycycline B.I.D.) in combination with SRP in subjects with moderate to severe CP. Two-hundred ten subjects were treated with a standardized episode of SRP and randomized to receive either adjunctive SDD or placebo for 9 months. Efficacy parameters included per-subject mean changes in clinical attachment level (CAL) and probing depth (PD) from baseline, and the total number of sites with attachment gains and probing depth reductions > or = 2 mm and > or = 3 mm from baseline. RESULTS: In periodontal sites with PD 4 to 6 mm and > or = 7 mm (N = 209, intent-to-treat population), mean improvements in CAL and PD were greater following SRP with adjunctive SDD than SRP with placebo, achieving statistical significance in all baseline disease categories at month 9 (P < 0.05). At month 9, 42.3% of sites in the SDD group demonstrated CAL gain > or = 2 mm compared to 32.0% of sites in the placebo group (P < 0.01). CAL gain > or = 3 mm was seen in 15.4% of sites in the SDD group compared to 10.6% of sites in the placebo group (P < 0.05). When considering the same thresholds of change in PD, 42.9% of sites in the SDD group compared to 31.1% of sites in the placebo group demonstrated PD reduction > or = 2 mm (P < 0.01), and 15.4% of sites in the SDD group compared to 9.1% of sites in the placebo group demonstrated PD reduction > or = 3 mm (P < 0.01). CONCLUSION: Adjunctive subantimicrobial dose doxycycline enhances scaling and root planing. It results in statistically significant attachment gains and probing depth reductions over and above those achieved by scaling and root planing with placebo.

Change of antibiotic susceptibility following periodontal therapy. A pilot study in aggressive periodontal disease.

BACKGROUND: The hypothesis was tested that bacterial susceptibilities in aggressive periodontitis change upon administration of systemic antibiotics as adjuncts to periodontal therapy. METHODS: In 23 subjects (average age 38.9+/-6.7 years) with aggressive periodontitis, microbial parameters were assessed prior to and 1 year after completion of comprehensive mechanical/surgical and systemic antimicrobial therapy. Following identification of five selected pathogens with the Rapid ID 32 A system, their susceptibilities towards amoxicillin/clavulanate potassium, metronidazole, and tetracycline were examined with the E-test. Antibiotics were administered according to the test results, and the minimal inhibitory concentrations (MIC90) were reevaluated after 1 year. Statistical analysis was performed on a patient basis, with the site data used for evaluation of the MIC levels. RESULTS: Bacterial MIC levels remained constant among the three antibiotic treatment groups compared with baseline. Mean MIC90 values ranged from <0.02 to 0.11 microg/ml (amoxicillin/clavulanate potassium), <0.02 to 0.27 microg/ml (metronidazole), and <0.02 to 0.11 microg/ml (tetracycline). Observed changes in susceptibility were attributed to the elimination of single bacterial taxa in the subgingival environment after antibiotic therapy. There were no statistically significant differences in clinical parameters among the treatment groups. Single tetracycline MICs were 1.5- to 6-fold enhanced compared to amoxicillin/clavulanate potassium and metronidazole. CONCLUSION: The periodontal pathogens investigated prior to and 1 year after periodontal therapy are tested sensitive to the antimicrobial agents. In aggressive periodontitis, changes in bacterial susceptibility upon the administration of systemic antibiotics are associated with the limited number of isolates tested following therapy.

Neutrophil-mediated tissue injury in periodontal disease pathogenesis: findings from localized aggressive periodontitis.

Neutrophils play a major role in the host response against invading periodontopathogenic microorganisms. Localized aggressive periodontitis (LAgP) is associated with various functional abnormalities of neutrophils. Based on the recent findings, LAgP neutrophils are not "hypofunctional" or "deficient." They are "hyperfunctional," and their amplified activity is responsible for the tissue destruction in periodontal disease. Several signal transduction abnormalities are associated with elevated neutrophil function in LAgP. There is a strong correlation between defective chemotaxis and decreased intracellular Ca2+ levels; total calcium-dependent protein Kinase C (PKC) activity of neutrophils is significantly lower than healthy subjects; and there is a marked increase in diacylglycerol (DAG) accompanied by a pronounced decrease in DAG kinase activity. In a separate set of experiments on the involvement of the inducible cyclooxygenase isoform (COX-2) and the role of novel lipid mediators in the pathogenesis of periodontal disease, crevicular fluid samples from LAgP patients were found to contain prostaglandin E2 (PGE2) and 5-LO-derived products, leukotriene B4 (LTB4), and the biosynthesis interaction product, lipoxin LXA4. Neutrophils from peripheral blood of LAgP patients, but not from healthy volunteers, also generated LXA4, suggesting that this immunomodulatory molecule may have a role in periodontal disease. Lipoxin generation and its relationship to PGE2 and LTB4 can be visualized as an important marker for the pathogenesis of periodontal disease. Thus, major advances in our understanding of the role of the neutrophil in host defense against periodontal organisms have been made through studies of LAgP. LAgP is used as an example of a severe periodontal disease that is related to abnormal neutrophil function. In this model, it appears that a hyperresponsiveness of the neutrophil, due to cell priming/predisposition, results in enhanced tissue damage.

Aggressive periodontitis: 5-year follow-up of treatment.

BACKGROUND: The hypothesis that in subjects with aggressive periodontitis, a long-term stability of periodontal health can be achieved following comprehensive mechanical/surgical and systemic antimicrobial therapy was tested in this prospective study. METHODS: Thirteen patients (36.9+/-7.4 years) with aggressive periodontitis were monitored before and up to 5 years following periodontal therapy. Clinical attachment levels (CAL) were assessed pretherapy, and at 3 months following completion of active periodontal therapy supplemented by amoxicillin plus metronidazole. All subjects were subsequently enrolled in a maintenance program and provided with supportive periodontal therapy with 3 to 4 appointments annually. Reexaminations were performed after 6 months and 1, 2, 3, 4, and 5 years. The data were analyzed using the method of generalized estimating equations (GEE) for CAL changes from baseline to the 3-month visit, and from completion of periodontal therapy to each annual visit up to the 5-year follow-up reappointment. RESULTS: During the 5-year study, all subjects strongly benefited from periodontal treatment. Between baseline and the 3-month reexamination, the CAL levels revealed a significant decrease of 2.23 mm (95% confidence interval [CI]: 1.77 to 2.69 mm; P < or =0.001). At the 5-year maintenance visit, the CAL changes ranged from -0.04 to +0.29 mm with no further statistically significant periodontal breakdown (P >0.05). Five years after surgery, 3.2% of the treated sites demonstrated a further CAL gain > or =3 mm. A stabilization (CAL -2 to +2 mm) occurred in 94.6% of the cases. The number of periodontal sites experiencing a breakdown varied from 5.3% at 6 months to 2.2% at 5 years. CONCLUSIONS: In aggressive periodontitis, comprehensive mechanical/surgical and antimicrobial therapy is an appropriate treatment regimen for long-term stabilization of periodontal health. In this study, periodontal disease progression was successfully arrested in 95% of the initially compromised lesions, while 2% to 5% experienced discrete or recurrent episodes of loss of periodontal support.