|Year : 2015 | Volume
| Issue : 1 | Page : 10-14
Resolvins: A novel theraputic approach in treating periodontal disease
H Nilofer Farjana, Nithya Anand, SC Chandrasekaran
Department of Periodontology, Sree Balaji Dental College and Hospital, Chennai, Tamil Nadu, India
|Date of Web Publication||26-Aug-2015|
Dr. H Nilofer Farjana
Department of Periodontology, Sree Balaji Dental College and Hospital, Chennai, Tamil Nadu
Source of Support: None, Conflict of Interest: None
Unresolved inflammation is associated with several widely occurring diseases such as arthritis, periodontal diseases, cancer, and atherosclerosis. Endogenous mechanisms are that which curtail excessive inflammation. A newly emerging chemical mediators derived from polyunsaturated fatty acids were identified that controls the acute inflammatory response by activating local resolution. They are specialized pro-resolving lipid mediators that includes lipoxins (LXs), resolvins (Rv), protectins, and maresins, because they are enzymatically biosynthesized during resolution of self-limited inflammation. They have anti-inflammatory and pro-resolution actions of Rv of the D1 with up regulation of arachidonic acid-derived endogenous resolution pathways (LXA4). A novel therapeutic host modulating are for resolution of inflammation.
Keywords: Anti-inflammation; host modulation; inflammation; lipid mediators; resolvins
|How to cite this article:|
Farjana H N, Anand N, Chandrasekaran S C. Resolvins: A novel theraputic approach in treating periodontal disease. Indian J Multidiscip Dent 2015;5:10-4
|How to cite this URL:|
Farjana H N, Anand N, Chandrasekaran S C. Resolvins: A novel theraputic approach in treating periodontal disease. Indian J Multidiscip Dent [serial online] 2015 [cited 2020 May 30];5:10-4. Available from: http://www.ijmdent.com/text.asp?2015/5/1/10/163649
| Introduction|| |
Periodontitis is a host-mediated chronic inflammatory disease causing leukocyte-mediated inflammation and bone loss.  It is the host response to the biofilm that destroys the periodontium in the pathogenesis of the periodontal diseases. Periodontal diseases progresses in periodic, relatively short episodes of rapid tissue destruction followed by some repair and prolonged intervening periods of disease remission.
Chronic periodontitis is also associated with impaired phagocytosis as well as other hyper-inflammatory traits. Localized aggressive periodontitis (LAP) is characterized by functional abnormalities of host cells, particularly neutrophils that possess a hyper-activated or primed phenotype.  The functional consequences of neutrophil priming include dysregulated chemotaxis, phagocytic abnormalities, and heightened pro-inflammatory activity including increased oxidative stress and secretion of inflammatory mediators. Hence, in LAP polymorphonuclear neutrophil yields its inability to clear bacteria resulting in tissue damage and chronic lesions.
| Definition|| |
Resolvins (Rv) are a new family of bioactive products of omega-3 fatty acid transformation circuits initiated by aspirin treatment. It is now increasingly apparent that local inflammation plays a critical role in many diseases, including cardiovascular disease, atherosclerosis, and asthma, experiments were undertaken to evaluate the actions of the newly described eicosapentaenoic acid (EPA)-derived Rv of the E1 (RvE1) in regulation of neutrophil tissue destruction and resolution of inflammation.  The actions of an aspirin-triggered lipoxin (LX) analogue and RvE1 in a human disease, LAP, were determined.
| History|| |
The 87 th General Session of the International Association for Dental Research, scientists from Boston University are reporting on the discovery of Rv, a new family of biologically active products of omega-3 fatty acids with the therapeutic potential to resolve periodontal inflammation and restore the gingiva to health.
| Chemistry|| |
The omega-3 essential fatty acids are the focus of considerable interest among nutritionists, because of the perceived beneficial effects for the health of consumers. It is likely that oxygenated metabolites derived from EPA and docosahexaenoic acid (DHA), the Rv and (neuro) protectins, plays a significant part as they have potent anti-inflammatory and immunoregulatory actions at concentrations in the nanomolar and picomolar ranges.  The term "Rv" or "resolution-phase" interaction products was coined by Prof. Charles N. Serhan and colleagues because these compounds were first encountered in resolving inflammatory exudates. Compounds are derived from EPA are designated as RvE series, while those formed from the precursor DHA are denoted as either Rv or protectins (PD) ("neuroprotectins") of the D-series [Figure 1].
| Aspirin Resolvin Interaction|| |
Aspirin is commonly administered at one of three doses, 81, 325 or 650 mg daily (Chiang N et al., 2004; Furst and Hillson, 2001). The 17-HDHA is present in blood of healthy individuals (Mas et al., 2012; Psychogios et al., 2011) and is bioactive in animal disease models (Bento et al., 2011; Lima-Garcia et al., 2011) likely as a result of its local transformation by leukocytes to D-series Rv (Serhan et al., 2002).
When aspirin is taken concurrently with omega-3 fatty acids in our diet, omega-3 is metabolized into new resolving molecules that are more stable and long acting.  The potent anti-inflammatory properties of aspirin recognized in 1900 and first introduced by Sir John Vane that inhibits the prostaglandin (PG) synthesis. Recently, it is also suggested that part of action of aspirin is the result of derivatization of LXs and Rv. Aspirin directly modifies the action of cyclooxygenase-2, changing the activity to a lipoxygenase. The products of aspirin modified cyclooxygenase-2 are epimers of the normal lipoxygenase products that, when acted again by second lipoxygenases, yield aspirin-triggered LX and resolving compounds that long lasting and more potent than endogenous Rv and LXs. 
In addition, the 17R aspirin-triggered lipid mediators such as aspirin-triggered RvD1 remain elevated in tissues longer because they are less susceptible to local inactivation via dehydrogenation (Serhan, 2007). Thus, aspirin-triggered RvD3 also proved to be a potent mediator in blocking neutrophil transmigration as well as enhancing pro-resolving responses, (Serhan and Petasis, 2011) and enhance bacterial clearance in sepsis (Spite et al., 2009) and infections (Chiang et al., 2012).
| Resolvins in Inflammation|| |
The novel lipid mediators produced from DHA, an abundant omega-3 fatty acid in neural tissues, are now coined as docosatrienes, and 17S series Rv were found to be both anti-inflammatory and tissue protective. Although intended for host defense, phagocytes can amplify injury via release of pro-inflammatory mediators. This explains the pathophysiology observed in many clinical as well as chronic inflammatory diseases. Acute inflammation and its timely resolution play central roles in the body's response to trauma, tissue injury, ischemia-reperfusion, and surgical interventions, as well as in microbial host defense. Lipid-derived mediators such as the eicosanoids, particularly classic PGs, and leukotrienes (LT) play pivotal roles in orchestrating inflammation.  These are autacoids or local-acting mediators within the innate acute inflammatory response. Nonsteroidal anti-inflammatory drugs such as, aspirin and cyclooxygenase inhibitors (both COX-1 and -2) are used to block PG biosynthesis. The major routes and biological actions of LX, aspirin-triggered 15-epi-lipoxins (ATLs), Rv, docosatrienes, and neuroprotectins can have therapeutic potential in regulating inflammation and diseases.
The local response to acute inflammation is an active rather than a passive process that triggers specific biochemical and cellular programs of resolution. The first "pro-resolution" pathway involves novel lipid mediators that possess endogenous anti-inflammatory and pro-resolution properties that are termed as Rv. In addition, novel lipid mediators produced from DHA, an abundant omega-3 fatty acid in neural tissues, are now coined as docosatrienes, and 17S series Rv were found to be both anti-inflammatory and tissue protective. 
Rv stimulate the resolution of inflammation through multiple mechanisms, including preventing neutrophil penetration, phagocytosing apoptotic neutrophils to clear the lesion, and enhancing clearance of inflammation within the lesion to the promote tissue regeneration. Such pro-resolving functions result in a shift in inflammatory response to a shorter resolution interval, which may help to prevent progression of an acute inflammatory response to chronic inflammation. The more rapid resolution of acute inflammation associated with Rv and PD function may underlie the beneficial effects of dietary consumption of the omega-3 polyunsaturated fatty acids (PUFAs), EPA and DHA, in some inflammatory human diseases. ,
| Lipoxin and Resolvin|| |
Lipid mediators of platelet activating factor lysolipids, and many known eicosanoids from arachidonic acid, including prostanoids, LT, and related compounds, play an important roles in initiation and progression of inflammations and are thus termed "pro-inflammatory mediators." Interactions between cells and at the transcellular level amplify and generate lipid-derived mediators, particularly those produced by lipoxygenases. In addition to the pro-inflammatory mediators, "anti-inflammatory mediators" are also produced during these interactions. For example, LXs are formed from endogenous sources of arachidonate across many species, from fish to humans, in vivo. Thus, the major routes and biological actions of LX, ATLs, Rv, docosatrienes, and neuroprotectins can have therapeutic potential in regulating inflammation and diseases. 
| Systemic Effects|| |
Recently, lymph nodes were found to produce 17-HDHA, where it enhances antibody production, and the D-series Rv and metabolome are also present in other lymphoid tissues of the mouse such as spleen (Ramon et al., 2012). Hence, it is likely that in addition to the role of specialized pro-resolving mediators in bringing acute inflammation to homeostasis, preventing a potential for chronicity, these mediators may also play a role in acquired immunity. Although the levels in mice of n-3 essential fatty acids (e.g., EPA, DHA) and n-6 (e.g., arachidonic acid) (Weldon and Whelan, 2011) are different from those in human tissues (De Caterina, 2011), there is still a prevailing notion that n-3 fatty acids such as DHA have important actions in maintaining human health and preventing disease (Calder, 2012) including cardiovascular diseases (De Caterina, 2011).
| Resolvins in Periodontal Disease|| |
The bioactive local mediators or autacoids, that requires enzymatic generation from the omega-3 essential fatty acids EPA resolving inflammatory exudates in vivo and carry potent stereoselective biological actions. They were termed as RvE series derived from EPA.  Those derived from DHA were termed as RvD series. The other family of bioactive chemical signals from DHA (i.e., docosanoids, oxygenated products from DHA),  which specifically possess a conjugated triene double-bond system in their structures, are denoted PD. The PD demonstrate anti-inflammatory and neuroprotective actions in vivo.
Oxygenated compounds identified earlier from omega-3 PUFAs such as PGs and LT (LT B5) were found to be far less potent than their AA-derived counterparts, or completely devoid of bioactivity. Rv and PD evoke biological actions in the nanogram range in vivo and are natural exudate products. The term Rv (resolution-phase interaction products) was first introduced to signify that these new structures were endogenous mediators, biosynthesized in the resolution phase of inflammatory exudates, possessing very potent anti-inflammatory and immunoregulatory actions. These actions include reducing neutrophil traffic, regulating cytokine and reactive oxygen species, and lowering the magnitude of the response [Figure 2].
| Resolvin Prevents Inflammation and Bone Loss in Experimental Periodontitis|| |
In the Porphyromonas gingivalis-induced rabbit model of periodontitis RvE1 prepared by total organic synthesis was topically applied to P. gingivalis ligatured teeth (4 μg/tooth) 3 times a week in the rabbit model over a 6-week study period. Control groups received the same frequency of topical application of vehicle (ethanol) together with P. gingivalis application to ligatured teeth or placement of ligature alone. 
Macroscopic evaluation at the end of the 6-week period demonstrated inflammation, as well as tissue and bone loss, in the buccal and lingual mandibular region of rabbits receiving non-RvE1 vehicle control, suggesting significant progression of periodontal disease. In addition, a profound increase in bone-resorbing osteoclasts was observed histologically, with osteoclast proliferation increasing with closer proximity to the ligature, as well as prominent leukocyte infiltrates and collagen loss. 
This was in contrast to findings with RvE1 application, in which the development and progression of periodontal disease seems to be prevented, with essentially no neutrophils or tissue damage observed. There was a remarkable absence of inflammatory changes and osteoclast proliferation, and bone remained largely intact. Correspondingly, mean alveolar bone loss was significantly reduced with RvE1 treatment or ligature alone compared to vehicle controls. Radiographic evidence also demonstrated a significantly reduced percentage of bone loss associated with RvE1 treatment (<5%) over the 6-week period compared to vehicle controls (<35%) or ligature alone (<12%), P < 0.05 [Figure 3].
| Conclusion|| |
The primary etiologic agent is the bacterial biofilm and excessive host immune response, inadequate resolution is critical to the pathogenesis of periodontitis. Earlier it has been placed on the deleterious actions of lipid mediators, such as prostanoids and LT, in propagating the inflammatory response and enhancing tissue destruction. However, a class shift is now apparent that results in the production of pro-resolving compounds, such as LXs, Rv and PD seems to be important for stimulating resolution pathways and restoring tissues to homeostasis.
The pro-resolving functions of these lipid mediators in stimulating the restoration of homeostasis through agonist actions on neutrophils differs from the traditional pharmacologic approach of antagonizing select pro-inflammatory pathways. In a P. gingivalis-induced rabbit model of experimental periodontitis, RvE1 was potent when topically applied, demonstrating remarkable efficacy in the prevention and treatment of periodontal disease. Thus the targeted agents, such as RvE1, that stimulate the resolution of inflammation may offer some therapeutic advantage in the treatment of periodontitis compared to more traditional pharmacologic interventions.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Van Dyke TE, Serhan CN. Resolution of inflammation: A new paradigm for the pathogenesis of periodontal diseases. J Dent Res 2003;82:82-90.
Kornman KS. Mapping the pathogenesis of periodontitis: A new look. J Periodontol 2008;79:1560-8.
Hasturk H, Kantarci A, Goguet-Surmenian E, Blackwood A, Andry C, Serhan CN, et al.
Resolvin E1 regulates inflammation at the cellular and tissue level and restores tissue homeostasis in vivo
. J Immunol 2007;179:7021-9.
Serhan CN. Resolution phase of inflammation: Novel endogenous anti-inflammatory and proresolving lipid mediators and pathways. Annu Rev Immunol 2007;25:101-37.
El-Sharkawy H, Aboelsaad N, Eliwa M, Darweesh M, Alshahat M, Kantarci A, et al.
Adjunctive treatment of chronic periodontitis with daily dietary supplementation with omega-3 Fatty acids and low-dose aspirin. J Periodontol 2010;81:1635-43.
Serhan CN. Systems approach to inflammation resolution: Identification of novel anti-inflammatory and pro-resolving mediators. J Thromb Haemost 2009;7 Suppl 1:44-8.
Smith WL, DeWitt DL, Garavito RM. Cyclooxygenases: Structural, cellular, and molecular biology. Annu Rev Biochem 2000;69:145-82.
Serhan CN, Chiang N. Novel endogenous small molecules as the checkpoint controllers in inflammation and resolution: Entrée for resoleomics. Rheum Dis Clin North Am 2004;30:69-95.
Hong S, Lu Y, Yang R, Gotlinger KH, Petasis NA, Serhan CN. Resolvin D1, protectin D1, and related docosahexaenoic acid-derived products: Analysis via electrospray/low energy tandem mass spectrometry based on spectra and fragmentation mechanisms. J Am Soc Mass Spectrom 2007;18:128-44.
Yang R, Chiang N, Oh SF, Serhan CN. Metabolomics-lipidomics of eicosanoids and docosanoids generated by phagocytes. Curr Protoc Immunol 2011;Chapter 14:Unit 14.26.
Wallace JL, Fiorucci S. A magic bullet for mucosal protection and aspirin is the trigger! Trends Pharmacol Sci 2003;24:323-6.
Requirand P, Gibert P, Tramini P, Cristol JP, Descomps B. Serum fatty acid imbalance in bone loss: Example with periodontal disease. Clin Nutr 2000;19:271-6.
Pouliot M, Clish CB, Petasis NA, Van Dyke TE, Serhan CN. Lipoxin A(4) analogues inhibit leukocyte recruitment to Porphyromonas gingivalis
: A role for cyclooxygenase-2 and lipoxins in periodontal disease. Biochemistry 2000;39:4761-8.
Bannenberg GL, Chiang N, Ariel A, Arita M, Tjonahen E, Gotlinger KH, et al.
Molecular circuits of resolution: Formation and actions of resolvins and protectins. J Immunol 2005;174:4345-55.
[Figure 1], [Figure 2], [Figure 3]