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

Abstract

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.

Keywords: Apical periodontitis; Endodontics; Pulpitis; Resolution of inflammation; Specialized pro-resolving mediators; Therapeutic potential.

Fig. 1

Pulp and periapical inflammatory disease and their ideal outcomes. a Pulp and periapical inflammatory process. The pulp inflammatory process is linked to the infiltration of bacteria and toxins. Odontoblasts initiate the immune response. Without therapeutic intervention (upper and lower left panel), inflammation and bacteria cause chronic inflammation, which leads to total pulp necrosis and apical periodontitis. The objective of vital pulp therapies and root canal treatment is to obtain inflammation resolution (central panel). The resolution of inflammation occurs after the first vascular and cellular phases. The resolution of inflammation is coordinated by a large number of mediators termed SPMs. These mediators promote the switch from a proinflammatory (M1) to an anti-inflammatory macrophage phenotype (M2), and nonapoptotic cells ultimately return to the vasculature or lymph. b Healing and regeneration phase. Dental pulp has the capacity to produce tertiary dentin when inflammation is resolved. According to the intensity of the stimulus, reactionary or reparative dentinogenesis can be mediated by odontoblasts or odontoblast-like cells, respectively (upper panel). At the apical bone level, the resolution of inflammation allows bone healing and bone regeneration (lower panel)

Fig. 2

Specialized lipid mediator synthesis. SPMs are all derived from free PUFAs released at the onset of inflammation, including arachidonic acid and ω-3 fatty acids: eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and docosapentaenoic acid (DPA). COX, cyclooxygenase; HETE, hydroxyeicosatetraenoic acid; LO, lipoxygenase; LT, leukotriene; LX, lipoxin; H(p)EPE, hydroxyeicosapentaenoic acid; MaR, maresin; PD protectin; Rv, resolvin

Fig. 3

SPM delivery system strategy for endodontic applications. SPMs can be used as therapeutic agents for innovative clinical endodontic therapy for pulpitis or apical periodontitis. To improve SPM efficacy and stability, SPM encapsulation may be required, and different formulations and designs are under investigation (microspheres, fibers or hydrogels) to create new therapeutic devices. Before they can be used in humans, these SPM delivery systems must be characterized and assessed in vitro and in vivo (injectability, physical characterization, efficiency evaluation and animal model assessments) to validate that they fulfill clinical specifications. The clinical objectives are to use these SPM delivery systems for vital pulp therapy or in pulp tissue engineering