The effect of low-dose aspirin on aspirin triggered lipoxin, interleukin 1 beta, and prostaglandin E2 levels in periapical fluid: a double-blind randomized clinical trial.

BACKGROUND: The role of pro-resolving mediators in inflammation is a new concern in research. The effect of low-dose aspirin on production of a special kind of these mediators named aspirin triggered lipoxin (ATL) has been studied on different tissues. This randomized clinical trial evaluated the effect of low-dose aspirin on ATL and pro-inflammatory mediators' level in periapical fluid of necrotic teeth with large lesions. METHODS: Twenty-four patients with necrotic pulp and periapical lesion were randomly assigned to low-dose aspirin and placebo groups. In the first appointment, canals were shaped up to F3 size and #40 K-file and cleaned with 10 milliliters 2.5% sodium hypochlorite and 17% Ethylenediaminetetraacetic acid. Periapical fluid was sampled by a paper cone. The tooth was temporized without any intracanal medication. Tablets were administered for 7 days, then the teeth were re-opened and the sampling were repeated. Interleukin-1 beta (IL-1ß), prostaglandin E2 (PGE2) and ATL were analyzed by enzyme-linked immunosorbent assay. Data were analyzed with paired t-test using SPSS statistical software, version 21 (α = 0.05). RESULTS: A significant reduction in PGE2 and IL-1ß was noted in the aspirin-treated group while an increase in ATL was observed (P < 0.001). There was no significant difference in the mediator scores before and after in the placebo-treated group (P > 0.05). CONCLUSION: Low-dose aspirin can influence the inflammatory process by reducing pro-inflammatory mediators such as PGE2 and IL-1ß, as well as increasing the pro-resolving mediators such as ATL. TRIAL REGISTRATION: IRCT20191211045702N1.

Application of specialized pro-resolving mediators in periodontitis and peri-implantitis: a review.

Scaling and root planning is a key element in the mechanical therapy used for the eradication of biofilm, which is the major etiological factor for periodontitis and peri-implantitis. However, periodontitis is also a host mediated disease, therefore, removal of the biofilm without adjunctive therapy may not achieve the desired clinical outcome due to persistent activation of the innate and adaptive immune cells. Most recently, even the resident cells of the periodontium, including periodontal ligament fibroblasts, have been shown to produce several inflammatory factors in response to bacterial challenge. With increased understanding of the pathophysiology of periodontitis, more research is focusing on opposing excessive inflammation with specialized pro-resolving mediators (SPMs). This review article covers the major limitations of current standards of care for periodontitis and peri-implantitis, and it highlights recent advances and prospects of SPMs in the context of tissue reconstruction and regeneration. Here, we focus primarily on the role of SPMs in restoring tissue homeostasis after periodontal infection.

Specialized pro-resolving lipid mediators in endodontics: a narrative review.

Endodontics is the branch of dentistry concerned with the morphology, physiology, and pathology of the human dental pulp and periradicular tissues. Human dental pulp is a highly dynamic tissue equipped with a network of resident immunocompetent cells that play major roles in the defense against pathogens and during tissue injury. However, the efficiency of these mechanisms during dental pulp inflammation (pulpitis) varies due to anatomical and physiological restrictions. Uncontrolled, excessive, or unresolved inflammation can lead to pulp tissue necrosis and subsequent bone infections called apical periodontitis. In most cases, pulpitis treatment consists of total pulp removal. Although this strategy has a good success rate, this treatment has some drawbacks (lack of defense mechanisms, loss of healing capacities, incomplete formation of the root in young patients). In a sizeable number of clinical situations, the decision to perform pulp extirpation and endodontic treatment is justifiable by the lack of therapeutic tools that could otherwise limit the immune/inflammatory process. In the past few decades, many studies have demonstrated that the resolution of acute inflammation is necessary to avoid the development of chronic inflammation and to promote repair or regeneration. This active process is orchestrated by Specialized Pro-resolving lipid Mediators (SPMs), including lipoxins, resolvins, protectins and maresins. Interestingly, SPMs do not have direct anti-inflammatory effects by inhibiting or directly blocking this process but can actively reduce neutrophil infiltration into inflamed tissues, enhance efferocytosis and bacterial phagocytosis by monocytes and macrophages and simultaneously inhibit inflammatory cytokine production. Experimental clinical application of SPMs has shown promising result in a wide range of inflammatory diseases, such as renal fibrosis, cerebral ischemia, marginal periodontitis, and cancer; the potential of SPMs in endodontic therapy has recently been explored. In this review, our objective was to analyze the involvement and potential use of SPMs in endodontic therapies with an emphasis on SPM delivery systems to effectively administer SPMs into the dental pulp space.

Understanding resolution of inflammation in periodontal diseases: Is chronic inflammatory periodontitis a failure to resolve?

Periodontitis is an infectious-inflammatory disease that results from loss of balance between the commensal microbiome and the host response. The hyper-inflammatory, uncontrolled inflammatory immune lesion promotes tissue damage and impedes effective bacterial clearance. In this review, the relationship between the microbiome and the inflammatory/immune response is explored in the context of a bi-directional pathogenesis; bacteria induce inflammation and inflammation modifies the growth environment causing shifts in the composition of the microbiome. Resolution of inflammation is an active, receptor-mediated process induced by specialized pro-resolving lipid mediators. Inflammatory disease may, therefore, be the result of failure of resolution. Failure to resolve inflammation coupled with resultant microbiome changes is hypothesized to drive development of periodontitis. Re-establishment of microbiome/host homeostasis by specialized pro-resolving lipid mediator therapy suggests that microbiome dysbiosis, the host hyperinflammatory phenotype, and periodontitis can be reversed.

Resolvin D2-induced reparative dentin and pulp stem cells after pulpotomy in a rat model.

Introduction: Vital pulp therapy (VPT) is performed to preserve dental pulp. However, the biocompatibility of the existing materials is of concern. Therefore, novel materials that can induce pulp healing without adverse effects need to be developed. Resolvin D2 (RvD2), one of specialized pro-resolving mediators, can resolve inflammation and promote the healing of periapical lesions. Therefore, RvD2 may be suitable for use in VPT. In the present study, we evaluated the efficacy of RvD2 against VPT using in vivo and in vitro models. Methods: First molars of eight-week-old male Sprague-Dawley rats were used for pulpotomy. They were then divided into three treatment groups: RvD2, phosphate-buffered saline, and calcium hydroxide groups. Treatment results were assessed using radiological, histological, and immunohistochemical (GPR18, TNF-α, Ki67, VEGF, TGF-ß, CD44, CD90, and TRPA1) analyses. Dental pulp-derived cells were treated with RvD2 in vitro and analyzed using cell-proliferation and cell-migration assays, real-time PCR (Gpr18, Tnf-α, Il-1ß, Tgf-ß, Vegf, Nanog, and Trpa1), ELISA (VEGF and TGF-ß), immunocytochemistry (TRPA1), and flow cytometry (dental pulp stem cells: DPSCs). Results: The formation of calcified tissue in the pulp was observed in the RvD2 and calcium hydroxide groups. RvD2 inhibited inflammation in dental pulp cells. RvD2 promoted cell proliferation and migration and the expression of TGF-ß and VEGF in vitro and in vivo. RvD2 increased the number of DPSCs. In addition, RvD2 suppressed TRPA1 expression as a pain receptor. Conclusion: RvD2 induced the formation of reparative dentin, anti-inflammatory effects, and decreased pain, along with the proliferation of DPSCs via the expression of VEGF and TGF-ß, on the pulp surface in pulpotomy models.

Polymer micelles for the protection and delivery of specialized pro-resolving mediators.

Specialized pro-resolving mediators (SPMs) are being considered for the treatment of chronic inflammatory diseases. However, these polyunsaturated fatty acids are prone to oxidation and as a result have a short biological half-life. It was reasoned that a micelle formulation would provide sustained delivery of SPMs while providing protection from oxidation. Thus, micelle formulations were prepared with poly(ethylene glycol) (PEG) as the hydrophilic block and poly(trimethylene carbonate) (PT) containing unsaturated pendant groups, specifically benzyloxy (BT) and sorbate (ST) groups, as the hydrophobic block. The potential of these micelles was assessed using linoleic acid as a model SPM. Loading into a micelle core reduced the extent of oxidation of the model SPM and a sustained release of non-oxidized model drug was achieved for up to 20 days in vitro from the PEG-P(T-BT) micelles. These micelles were also non-cytotoxic over a wide concentration range, demonstrating the potential of this formulation for effective SPM release in vivo.

Soluble epoxide hydrolase inhibition enhances production of specialized pro-resolving lipid mediator and promotes macrophage plasticity.

BACKGROUND AND PURPOSE: Epoxyeicosatrienoic acids (EETs) and other epoxy fatty acids (EpFA) are lipid mediators that are rapidly inactivated by soluble epoxide hydrolase (sEH). Uncontrolled and chronic inflammatory disorders fail to sufficiently activate endogenous regulatory pathways, including the production of specialized pro-resolving mediators (SPMs). Here, we addressed the relationship between SPMs and the EET/sEH axis and explored the effects of sEH inhibition on resolving macrophage phenotype. EXPERIMENTAL APPROACH: Mice were treated with a sEH inhibitor, EETs, or sEH inhibitor + EETs (combination) before ligature placement to induce experimental periodontitis. Using RT-qPCR, gingival samples were used to examine SPM receptors and osteolytic and inflammatory biomarkers. Maxillary alveolar bone loss was quantified by micro-CT and methylene blue staining. SPM levels were analysed by salivary metabolo-lipidomics. Gingival macrophage phenotype plasticity was determined by RT-qPCR and flow cytometry. Effects of sEH inhibition on macrophage polarization and SPM production were assessed with bone marrow-derived macrophages (BMDMs). KEY RESULTS: Pharmacological inhibition of sEH suppressed bone resorption and the inflammatory cytokine storm in experimental periodontitis. Lipidomic analysis revealed that sEH inhibition augmented levels of LXA4, RvE1, RvE2, and 4-HDoHE, concomitant with up-regulation of LTB4R1, CMKLR1/ChemR23, and ALX/FPR2 SPM receptors. Notably, there is an impact on gingival macrophage plasticity was affected suggesting an inflammation resolving phenotype with sEH inhibition. In BMDMs, sEH inhibition reduced inflammatory macrophage activation, and resolving macrophages were triggered to produce SPMs. CONCLUSION AND IMPLICATIONS: Pharmacological sEH inhibition increased SPM synthesis associated with resolving macrophages, suggesting a potential target to control osteolytic inflammatory disorders.

Roles of specialized pro-resolving mediators and omega-3 polyunsaturated fatty acids in periodontal inflammation and impact on oral microbiota.

Periodontitis is a chronic inflammatory disease induced by dysbiotic dental biofilms. Management of periodontitis is primarily anti-bacterial via mechanical removal of bacterial biofilm. The successful resolution requires wound healing and tissue regeneration, which are not always achieved with these traditional methods. The discovery of specialized pro-resolving mediators (SPMs), a class of lipid mediators that induce the resolution of inflammation and promote local tissue homeostasis, creates another option for the treatment of periodontitis and other diseases of chronic inflammation. In this mini-review, we discuss the host-modulatory effects of SPMs on periodontal tissues and changes in the taxonomic composition of the gut and oral microbiome in the presence of SPMs and SPM precursor lipids. Further research into the relationship between host SPM production and microbiome-SPM modification has the potential to unveil new diagnostic markers of inflammation and wound healing. Expanding this field may drive the discovery of microbial-derived bioactive therapeutics to modulate immune responses.

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

[This corrects the article DOI: 10.3389/fimmu.2021.664756.].

Developments of specialized pro-resolving mediators in periodontitis.

Resolution of inflammation plays an important part in maintaining homeostasis. It is an actively programmed progress involving multiple immune cells and mediators. Specialized pro-resolving mediators (SPMs) derived from Ω-3 polyunsaturated fatty acids include resolvins, protectins and maresins, and they exert abilities in the resolution of inflammation, host defense, organ protection, and tissue generation. Periodontitis is an inflammatory and destructive disease in the periodontal tissue initiated by dental plaque. Inadequate proinflammatory or proresolving responses, or the imbalance between the two, may contribute to the pathogenesis of the disease. Studies have shown that activating specialized receptors SPMs displayed multiple biological effects towards periodontitis, including resolution of inflammation, alveolar bone protection, periodontal tissue regeneration, and pathogen resistance. Thus, the relationship between SPM and periodontitis and the potentials and challenges in SPM application were reviewed.

Intersection between macrophages and periodontal pathogens in periodontitis.

Periodontitis is a chronic infectious disease characterized by loss of periodontal attachment and resorption of alveolar bone. Dysregulated oral microbial community is the initial factor of periodontitis and causes excessive infiltration of immune cells in periodontal tissues. Macrophage, as an important part of the innate immune system, interacts continually with oral pathogens. Macrophages can recognize and phagocytize pathogens and apoptotic neutrophils and produce the specialized pro-resolving mediators (SPMs) playing an important role in maintaining the homeostasis of tissue microenvironment. However, macrophages may also induce abnormal immune responses with the overstimulation from pathogens, leading to the destruction of periodontal tissues and alveolar bone. Looking for targeted drugs that can regulate the activities of oral pathogens and the functions of macrophages provides a new idea for periodontitis treatment. This review summarizes the interaction between macrophages and periodontal pathogens in periodontitis, focusing on the pro-inflammation and anti-inflammation phenotypes of macrophages, and briefly concludes potential new methods of periodontitis therapy targeted at oral pathogens and macrophages.

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.