Periodontal Disease and Overall Health: A Clinician's Guide

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CHAPTER 3 Infection and Inflammation 37maintained, tissue destruction continues andinflammation persists. If pro-resolution signalsare weak, neutrophils are not removedand monocytes/macrophages maintain aphlogistic phenotype. This results in furtherproduction of inflammatory cytokines andperpetuation of the inflamed state.New Treatment ParadigmsIt is reasonable to suggest that the understandingand ability to manipulate resolutionof inflammation may provide a newtreatment paradigm for inflammatory diseases,local and systemic. Although humandata are not yet available, there is a growingand promising literature from in vitro workand animal models that supports the bene -ficial actions of resolution agonists both onperio dontal and other systemic diseases. 5The Role of Pro-Resolution MediatorsExamples of the actions of therapeuticpro-resolution mediators in periodontal diseaseinclude over-expression of lipoxin A 4intransgenic rabbits protecting against perio -dontitis and atherosclerosis. 43 In anotherstudy, topical treatment with resolvins (-3fatty acid derived resolution agonists, videinfra) prevented more than 95% of alveolarbone destruction in rabbits. Moreover, histologicalanalysis revealed few, if any, neutrophils in the tissue and little tissue damage.At the same time, the numbers of osteoclastswere also found to be reduced. In addition,treatment of periodontitis with resolvins systemicallyreversed the observed increase inCRP and IL-1 levels. Finally, in establishedperiodontal disease, resolvins prevented furthertissue destruction, and both gingival andosseous tissues that were lost during diseasewere regenerated. 44Resolvins, lipoxins, and protectins havealso been shown in animal models to havebeneficial impact on a variety of other inflammatorydiseases. For example, lipoxinsstopped neutrophil recruitment and promotedlymphatic removal of phagocytes in perio -tonitis. 42 Moreover, in cystic fibrosis, lipoxinsdecreased neutrophil inflammation, pulmo -nary bacterial burden, and disease severity. 45Resolvins in a colitis model in mice decreasedneutrophil recruitment and pro-inflammatorygene expression, improved survival, andreduced weight loss. 46 In addition, resolvinsprotected against neovascularization inretinopathy. 47 Finally, in an asthma model,protectins protected against lung damage,airway inflammation, and airway hyperresponsiveness.48 Table 2 lists the impact oflipoxins, resolvins, and protectins on variousinflammatory disease models.It is conceivable that the use of proresolutionmediators in managing periodontaland other inflammatory diseases mayprove to be beneficial in humans as well.Mechanical debridement, which aims at thereduction of the bacterial load in the gingivalpocket, may help the host/patient to clearthe infection. In addition, it is possible thatthe use of locally applied pro-resolution mediatorscould prevent further tissue damage,enhance the resolution of inflammation(which would lead to healthy gingiva), andideally result in periodontal tissue regenerationrather than scarring and repair. Moreover,resolution of inflammation at the gingi -val level may minimize systemic inflammationinduced by periodontal disease, therebyattenuating the possible negative effects ofperio dontal disease on systemic diseases.Origins of Pro-Resolution MediatorsIn order to manipulate resolution ofinflammation more effectively, it is imperativeto understand the biological origin of the proresolutionmediators. Lipoxins (e.g., lipoxinA 4) derive from arachidonic acid after acti -vation of the 12-/5-LO or the 15-/5-LO pathways.Resolvins and protectins are bio synthesizedfrom omega-3 essential poly -unsaturatedfatty acids (-3 PUFAs), such as eicosapentanoicacid (EPA) and docosahexanoic acid
38 Periodontal Disease and Overall Health: A Clinician's GuideTable 2. Impact of Lipoxins, Resolvins, and Protectins on Various Inflammatory Disease ModelsDisease Model Species Action(s)Lipoxin A4/ATLPeriodontitis Rabbit –Reduces neutrophil infiltration–Prevents connective tissue and bone lossPeritonitis Mouse Stops neutrophil recruitment and lymphatic removal of phagocytesDorsal air pouch Mouse Stops neutrophil recruitmentDermal inflammation Mouse Stops neutrophil recruitment and vascular leakageColitis Mouse –Attenuates pro-inflammatory gene expression–Reduces severity of colitis–Inhibits weight loss, inflammation, pulmonary dysfunctionAsthma Mouse Inhibits airway hyper-responsiveness and pulmonary inflammationCystic fibrosis Mouse Decreases neutrophilic inflammation, pulmonary bacterial burden, and disease severityIschemia-reperfusion injury Mouse –Attenuates hind-limb ischemia-reperfusion lung injury–Causes detachment of adherent leukocytes in mesenteric ischemia-reperfusion injuryCorneal disorders Mouse –Accelerates cornea re-epithilialization–Limits sequelae of thermal injury (such as neovascularization and opacity)–Promotes host defenseAngiogenesis Mouse Reduces angiogenic phenotype: endothelial-cell proliferation and migrationBone-marrow transplant Mouse Protects against bone-marrow-transplant-induced graft-versus-host diseasesGlomerulonephritis Mouse –Reduces leukocyte rolling and adherence–Decreases neutrophil recruitmentHyperalgesia Rat –Prolongs paw withdraw latency and reduces hyperalgesic index–Reduces paw oedemaPleuritis Rat Shortens the duration of pleural exudationResolvin E1Periodontitis Rabbit –Reduces neutrophil infiltration–Prevents connective tissue and bone loss–Promotes healing of diseased tissues–Regenerates lost soft tissue and bonePeritonitis Mouse –Stops neutrophil recruitment–Regulates chemokine and/or cytokine production–Promotes lymphatic removal of phagocytesDorsal air pouch Mouse Stops neutrophil recruitmentRetinopathy Mouse Protects against neovascularizationColitis Mouse –Decreases neutrophil recruitment and pro-inflammatory gene expression–Improves survival–Reduces weight lossResolvin D1Peritonitis Mouse Stops neutrophil recruitmentDorsal skin air pouch Mouse Stops neutrophil recruitmentKidney ischemia- Mouse –Protects from ischemia-reperfusion kidney damage and loss of functionreperfusion injury Mouse Regulates macrophageRetinopathy Mouse Protects against neovascularizationProtectin D1Peritonitis Mouse –Inhibits neutrophil recruitment–Regulates chemokine and/or cytokine production–Promotes lymphatic removal of phagocytes–Regulates T-cell migrationAsthma Mouse Protects from lung damage, airway inflammation, and airway hyper-responsivenessAsthma Human Protectin D1 is generated in humans and appears to be diminished in asthmaticsKidney ischemia- Mouse Protects from ischemia-reperfusion kidney damage and loss of functionreperfusion injuryRegulates macrophages functionRetinopathy Mouse Protects against neovascularizationIschemic stroke Rat –Stops leukocyte infiltration–Inhibits nuclear factor-kB and cyclo-oxygenase-2 inductionAlzheimer’s disease Human Diminishes protecting D1 production in human Alzheimer’s disease
Page 5: ivCONTRIBUTORSSrividya Kidambi, MDA
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