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

Molecular biomarker research in periodontology: A roadmap for translation of science to clinical assay validation

The number of studies that aims to apply host- or microbe-derived biochemical biomarkers to periodontal disease diagnosis has increased significantly during the last three decades. The biochemical markers can reflect the presence, severity, and activity of periodontal diseases; however, heterogeneities in applied laboratory methods, data presentation, statistical analysis, and data interpretation prevent the translation of candidate host- or microbe-derived biochemical biomarkers to clinical assay validation. Here, we propose a roadmap for making the research outcomes comparable and re-analysable with the ultimate goal of translating research to clinical practice. This roadmap presents reporting recommendations for host- or microbe-derived biochemical biomarker studies in periodontology. We aim to make essential elements of the research work (including diagnostic criteria, clinical endpoint definitions, participant recruitment criteria, sample collection and storage techniques, biochemical and microbiological detection methods, and applied statistical analysis) visible and comparable

A critical role for suppressors of cytokine signaling 3 in regulating LPS-induced transcriptional activation of matrix metalloproteinase-13 in osteoblasts

Suppressor of cytokine signaling 3 (SOCS3) is a key regulator of cytokine signaling in macrophages and T cells. Although SOCS3 seems to contribute to the balance between the pro-inflammatory actions of IL-6 family of cytokines and anti-inflammatory signaling of IL-10 by negatively regulating gp130/Jak/Stat3 signal transduction, how and the molecular mechanisms whereby SOCS3 controls the downstream impact of TLR4 are largely unknown and current data are controversial. Furthermore, very little is known regarding SOCS3 function in cells other than myeloid cells and T cells. Our previous study demonstrates that SOCS3 is expressed in osteoblasts and functions as a critical inhibitor of LPS-induced IL-6 expression. However, the function of SOCS3 in osteoblasts remains largely unknown. In the current study, we report for the first time that LPS stimulation of osteoblasts induces the transcriptional activation of matrix metalloproteinase (MMP)-13, a central regulator of bone resorption. Importantly, we demonstrate that SOCS3 overexpression leads to a significant decrease of LPS-induced MMP-13 expression in both primary murine calvariae osteoblasts and a mouse osteoblast-like cell line, MC3T3-E1. Our findings implicate SOCS3 as an important regulatory mediator in bone inflammatory diseases by targeting MMP-13

Impact of fixed orthodontic appliances on blood count and high-sensitivity C-reactive protein levels: A prospective cohort study.

INTRODUCTION The aim was to elucidate the magnitude of alterations in systemic blood counts in healthy patients during the first 14 days after fixed orthodontic appliance placement. METHODS This prospective cohort study consecutively included 35 White Caucasian patients starting orthodontic treatment with fixed appliances. The mean age was 24.48 ± 6.68 years. All patients were physically and periodontally healthy. Blood samples were collected at 3 time points: (1) baseline (exactly before the placement of appliances), (2) 5 days after bonding, and (3) 14 days after baseline. Whole blood and erythrocyte sedimentation rates were analyzed in automated hematology and erythrocyte sedimentation rate analyzer. Serum high-sensitivity C-reactive protein levels were measured by the nephelometric method. Standardized sample handling and patient preparation procedures were adopted to reduce preanalytical variability. RESULTS A total of 105 samples were analyzed. All clinical and orthodontic procedures were performed without complications or side effects during the study period. All laboratory procedures were performed per protocol. Significantly lower white blood cell counts were detected 5 days after bracket bonding, compared with baseline (P <0.05). Hemoglobin levels were lower at 14 days than baseline (P <0.05). No other significant shifts or alteration patterns were observed over time. CONCLUSIONS Orthodontic fixed appliances led to a limited and transient change in white blood cell counts and hemoglobin levels during the first days after bracket placement. The fluctuation of high-sensitivity C-reactive protein levels was not significant, demonstrating a lack of association between systemic inflammation and orthodontic treatment

Impact of Orthodontic Forces on Plasma Levels of Markers of Bone Turnover and Inflammation in a Rat Model of Buccal Expansion.

Plasma levels of protein analytes might be markers to predict and monitor the kinetics of bone and tissue remodeling, including maximization of orthodontic treatment stability. They could help predict/prevent and/or diagnose possible adverse effects such as bone dehiscences, gingival recession, or root resorption. The objective of this study was to measure plasma levels of markers of bone turnover and inflammation during orthodontic force application in a rat model of orthodontic expansion. Two different orthodontic forces for bilateral buccal expansion of the maxillary arches around second and third molars were applied in 10 rats equally distributed in low-force (LF) or conventional force (CF) groups. Four rats served as the control group. Blood samples were collected at days 0, 1, 2, 3, 6, 13, 21, and 58. Longitudinal concentrations of osteoprotegerin (OPG), soluble receptor activator of nuclear factor kappaB ligand (sRANKL), interleukin-4 (IL-4), interleukin-6 (IL-6), interleukin-10 (IL-10), tumor necrosis factor α (TNF), and parathyroid hormone (PTH) were determined in blood samples by a multiplex immunoassay. CF and LF resulted in a significantly maxillary skeletal expansion while the CF group demonstrated significantly higher expansion than the LF group in the long term. Bone turnover demonstrated a two-phase response. During the "early phase" (up to 6 days of force application), LF resulted in more sRANKL expression and increased sRANKL/OPG ratio than the CF and control animals. There was a parallel increase in PTH levels in the early phase in response to LF. During the "late phase" (6-58 days), the markers of bone turnover were stable in both groups. IL-4, IL-6, and IL-10 levels did not significantly change the test groups throughout the study. These results suggest that maxillary expansion in response to different orthodontic forces follows different phases of bone turnover that may be force specific

Heritability of facial soft tissue growth in mono- and dizygotic twins at 12 and 17 years of age: A retrospective cohort study

OBJECTIVE The purpose of this investigation of untreated monozygotic and dizygotic twins was to identify the genetic and environmental components to the facial soft tissue growth. SETTINGS AND SAMPLE POPULATION The sample consisted of 52 untreated monozygotic twins (36 male and 16 female) and 46 untreated dizygotic twins (23 male and 23 female) from the Forsyth Moorrees Twin Study (1959-1975). MATERIALS AND METHODS Lateral cephalograms were taken at 12 and 17 years of age and traced to analyse facial convexity, nasolabial angle, upper and lower lip thickness, upper and lower lip profile and nose prominence. The genetic and environmental components of variance were analysed with structural equation modelling for multilevel mixed-effects model. RESULTS At 12 years of age, strong additive genetic influence was seen for facial convexity (70%), upper lip profile (66%) and nose prominence (65%), whereas strong dominant genetic components were found for upper lip thickness (56%). Nevertheless, under unique environment influence were nasolabial angle (58%), lower lip profile (51%) and lower lip thickness (64%). At 17 years of age, only upper lip thickness (55%) and nose prominence (84%) were under strong additive genetic control, while the rest of the variables were under strong dominant genetic control. The only exception was lower lip thickness (61%), which is still influenced by the unique environment. CONCLUSION Although monozygotic/dizygotic twins share at least part of their genome, at both times either additive, dominant or environmental components were found. Nevertheless, at 17 years of age most of the variables are either under additive or dominant genetic influence

An Antimicrobial Dental Light Curable Bioadhesive Hydrogel for Treatment of Peri-Implant Diseases.

Dental implants constitute the standard of care to replace the missing teeth, which has led to an increase in the number of patients affected by peri-implant diseases (PIDs). Here, we report the development of an antimicrobial bioadhesive, GelAMP, for the treatment of PIDs. The hydrogel is based on a visible light-activated naturally-derived polymer (gelatin) and an antimicrobial peptide (AMP). The optimized formulation of GelAMP could be rapidly crosslinked using commercial dental curing systems. When compared to commercial adhesives, the bioadhesives exhibited significantly higher adhesive strength to physiological tissues and titanium. Moreover, the bioadhesive showed high cytocompatibility and could efficiently promote cell proliferation and migration in vitro. GelAMP also showed remarkable antimicrobial activity against Porphyromonas gingivalis. Furthermore, it could support the growth of autologous bone after sealing calvarial bone defects in mice. Overall, GelAMP could be used as a platform for the development of more effective therapeutics against PIDs

RvE1 Impacts the Gingival Inflammatory Infiltrate by Inhibiting the T Cell Response in Experimental Periodontitis

Periodontitis is a chronic inflammatory disease associated with the formation of dysbiotic plaque biofilms and characterized by the progressive destruction of the alveolar bone. The transition from health to disease is characterized by a shift in periodontal immune cell composition, from mostly innate (neutrophils) to adaptive (T lymphocytes) immune responses. Resolvin E1 (RvE1) is a specialized pro-resolution mediator (SPMs), produced in response to inflammation, to enhance its resolution. Previous studies have indicated the therapeutic potential of RvE1 in periodontal disease; however, the impact of RvE1 in the microbial-elicited osteoclastogenic immune response remains uncharacterized in vivo. In the present study, we studied the impact of RvE1 on the gingival inflammatory infiltrate formation during periodontitis in a mouse model. First, we characterized the temporal-dependent changes of the main immune cells infiltrating the gingiva by flow cytometry. Then, we evaluated the impact of early or delayed RvE1 administration on the gingival immune infiltration and cervical lymph nodes composition. We observed a consistent inhibitory outcome on T cells -particularly effector T cells- and a protective effect on regulatory T cells (Tregs). Our data further demonstrated the wide range of actions of RvE1, its preventive role in the establishment of the adaptive immune response during inflammation, and bone protective capacity.publishedVersio

Resolvin E1 Reverses Experimental Periodontitis and Dysbiosis

Periodontitis is a biofilm-induced inflammatory disease characterized by dysbiosis of the commensal periodontal microbiota. It is unclear how natural regulation of inflammation affects the periodontal biofilm. Promoters of active resolution of inflammation including Resolvin E1 (RvE1) effectively treat inflammatory periodontitis in animal models. The goals of this study were 1) to compare periodontal tissue gene expression in different clinical conditions, 2) to determine the impact of local inflammation on the composition of subgingival bacteria, and 3) to understand how inflammation impacts these changes. Two clinically-relevant experiments were performed in rats: prevention and treatment of ligature-induced periodontitis with RvE1 topical treatment. The gingival transcriptome was evaluated by RNA-seq sequencing of mRNA. The composition of the subgingival microbiota was characterized by 16S rDNA sequencing. Periodontitis was assessed by bone morphometric measurements and histomorphometry of block sections. H&E and, tartrate resistant acid phosphatase staining were used to characterize and quantify inflammatory changes. RvE1 treatment prevented bone loss in ligature induced periodontitis. Osteoclast density and inflammatory cell infiltration in the RvE1 groups were lower than those in the placebo group. RvE1 treatment reduced expression of inflammation-related genes returning the expression profile to one more similar to health. Treatment of established periodontitis with RvE1 reversed bone loss, reversed inflammatory gene expression and reduced osteoclast density. Assessment of the rat subgingival microbiota after RvE1 treatment revealed marked changes in both prevention and treatment experiments. The data suggest that modulation of local inflammation has a major role in shaping the composition of the subgingival microbiota