Introduction
The dental pulp is a connective tissue enclosed within a mineralized hard tissue. As I.B. Bender said “Pulp is a small tissue with Big Issue”, it can trigger an immune response by different stimuli such as dental caries, trauma and operative procedure. Progressive pulp inflammation may lead to pulp necrosis because of the low compliance environment and lack of collateral circulation.1 Absence of therapeutic tools to limit the inflammatory process is the rationale behind performing endodontic procedures. But actually, the resolution of the inflammation is regulated and well coordinated by a number of mediators called SPMs including Lipoxins, Resolvins, Maresins and Protectins. 2
Pulp Inflammation
Bacteria are the primary cause of pulp infection to elicit an inflammatory response. Odontoblasts are first involved in fighting bacterial invasion and activate innate defence mechanisms. These mechanisms secrete various Pro inflammatory cytokines and chemokines to recruit other immune cells to the site of infections. If innate immune system exceeds its capacity, adaptive immune system gets activated and facilitate pathogen clearance through specific T and B cells. If the inflammation becomes uncontrolled, it may lead to pulp necrosis. This in turn stimulates a secondary immune response in periapical region. Apical periodontitis results as a defence mechanism to confine bacteria to the infected tooth and prevents its spread to other sites. But it may also be aggressive and may lead to bone destruction. 3
Resolution of the Inflammation
The extent of the inflammation can be counter regulated by promoting the active termination or resolution of the inflammation to re-establish homeostasis. This process mainly depends on actions of several anti inflammatory and Pro resolving mediators. The first evidence that the resolution of the inflammation is an active rather than a passive process came with the discovery of the pro resolution biochemical signalling circuits. The new genus of pro resolving mediators include Lipoxins (LXs) and Aspirin triggered lipoxins (ATL) (Levey et al., 2001; Serhan, 2005), Resolvins as well as the recently discovered Protectins and Maresins (Serhan et al.,2000;2008). 4 The five pillars of the resolution are Removal of the microorganism, dead cells and debris, Restoration of the vascular integrity and perfusion, Tissue regeneration, Remission of the fever and Relief of inflammatory pain. 5
Specialized Pro Resolving Lipid Mediators
They are the derivatives of the poly unsaturated fatty acids which are produced during the endogenous activation of resolution phase of inflammation. They are derived from both w-6 poly-unsaturated fatty acids (Arachidonic acid) and w-3 polyunsaturated fatty acids [Eicosapentaenoic acid (EPA) and Docosahexaenoic acid (DHA)]. Functions of the SPMs are 1) down regulation of the cell adhesion molecules molecule on both endothelial cells and leukocytes 2) reduction in activation of neutrophils and trans-endothelial migration 3) inhibition of formation and activation of pro inflammatory mediators. 6
Lipoxins
Lipoxins are formed by transcellular biosynthesis via multiple distinct pathways. These pathways include conversion of AA by 5-LOX, 15-LOX and aspirin/COX2.7 They modulate adaptive immune system by inducing M2 phenotype. They are called anti edemogenic mediators because they stimulate the return of the vascular homeostasis.8
Resolvins
Resolvins are the endogenous mediators synthesized from Omega 3 PUFA. Either by acetylation of the COX2 or by cytochrome p450, Eicosapentaenoic acid (EPA) produce E series Resolvins (RvE1, RvE2, RvE3) and Docosahexaenoic acid (DHA)produce D series Resolvins (RvD1-RvD2). Resolvin E1 stimulates the production of IL 10 to reduce the pro inflammatory cytokine. D series Resolvin gives protection against PMN mediated re-perfusion induced organ injury. RvD2 help in clearance of microbes. 9
Maresins and Protectins
The biosynthesis of Maresins and Protectins involves the formation of the epoxide intermediate of Docosahexaenoic acid DHA) by oxygenation through LOX. They reduce Pro inflammatory cytokines, activates M2 macrophages. They are also involved in pain reducing mechanism and tissue regeneration.10
SPMs in Endodontics
Xu H et al stated that the application of RvE1 in pathogen induced disease model of rat incisors and molars showed reduced inflammation and also induced pulpal alteration by producing less degeneration of the pulp tissue. It also down regulated the expression of chemR23, a transmembrane receptor to which RvE1 can bind, explaining the inhibition of leukocyte infiltration.11 Azuma MM et al proved that supplementation with Omega 3 regimen showed reduction in inflammatory symptoms of aphthous stomatitis. 12 Van DTE et al proved that the application of RvE1 in a rat model of immature tooth with apical periodontitis produced greater radiological root lengths and greater thickness of the dentinal walls which leads to increased fracture resistance of the root. 13 Siddiqui et al proved that the application of RvD2 in a tooth revascularization model allowed calcification around the root apex and reversed apical periodontitis. They also resulted in tissue regeneration and apical root closure.14
Therapeutic Role
Even though SPMs are highly potent and efficacious ligands they are delicate in their physicochemical nature, require complex chemical synthesis and are prone to metabolic inactivation. In an invitro study conducted by Van dyke et al, incorporation of SPM in the form of microparticles and nano particles have been effective in resolving periodontitis.15 Despite its advantages these particles have drawbacks such as non-specific bio distribution, poor water solubility and limited bio availability.16 Implanting a preformed scaffold into the root canal space is difficult because of the narrow and small volume of the pulp.17 Therefore, drug delivery systems such as microspheres, fibres and hydrogels must be considered for a sustained drug release. But hydrogels are limited carrying only hydrophilic drugs.18 In order to improve their drug loading capacity, different formulations had been tested in invitro studies using polyisocyanopeptide gel and poloxamer 407(P407). Wang B et al indicated that the PIC-PLGA vehicle exhibited suitable injectability and long-term structural stability.19
Conclusion
SPMs can dampen excess inflammation without compromising the host defence mechanism. They act locally to halt leukocyte recruitment by not impairing with the endogenous healing pathways. Only limited studies had explored the endodontic role of SPMs, but showed promising results in the form of control of pulp inflammation, resolution of inflammation and by reversing excessive bone destruction. If the above mentioned scientific and technical barriers have been resolved SPM will show promising result in the revolution of conventional endodontic procedures. Further clinical studies should be carried to formulate the specific drug delivery system for their application in the treatment of pulpitis and apical periodontitis.
Abbreviations
AA-arachidonic acid, IL-Interleukin, LT-leukotriene LOX-Lipoxygenase, COX-Cyclooxygenase, LX-Lipoxin, ATL-aspirin triggered lipoxin, EPA-Eicosapentaenoic acid, DHA-Docosahexaenoic acid, RvE-Resolvin E series, RvD-Resolvin D series, PIC-Polyisocyapeptide, PLGA-Polylactic co-glycolic acid, H(p) EPE-hydroxy eicosapentaenoic acid.
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