Periodontal Disease and Overall Health: A Clinician's Guide

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CHAPTER 3 Infection and Inflammation 35phospholipids. Once free arachidonic acidis available, two different pathways can beinitiated: (a) the cyclo-oxygenase (COX)pathway that leads to the production ofprostaglandins (e.g., PGE 2), and (b) the lipoxygenase(LO) pathways that lead to the productionof a series of hydroxyl acids characterizedby the 5-LO products, the leukotrienes(e.g., LTB 4). There are three cell type-specificLOs; the 5-LO from myeloid cells, the 12-LOfrom platelets, and the 15-LO of epithelial andendothelial cells. PGE 2is a potent activator ofosteoclast-mediated bone resorption, and withother eicosanoids mediates inflammation andperiodontal tissue destruction. LTB 4attractsneutrophils, stimulates the release of granuleassociatedenzymes from neutro phils, and contributesto pro-inflammatory processes and tofurther tissue damage.Returning to HomeostasisOnce the bacteria have been removedby phagocytosis, resolution of inflammationoccurs with the reduction or removal ofleukocytes and debris from inflamed siteswith a return to homeostasis. 5 Until recently,resolution of inflammation was considered tobe a passive process in which the lack ofbacterial stimuli decreased the production ofinflammatory mediators, which in turn reducedthe inflammatory response, therebyreturning to normal function. New data suggestthat resolution of inflammation is an activebiochemical and metabolic process thatis initiated by a newly identified class of receptoragonists that emerge temporally asthe inflammatory lesion matures. 5 Althoughprostaglandins and leukotrienes secreted byneutrophils have pro-inflammatory properties,as inflammation proceeds the sameprostaglandins (PGE 2and PGD 2) may promoteexpression of the 15-LO gene, leadingto a switch in the expression of biosyntheticenzymes by infiltrating neutrophils (Figure2). Binding of lipoxin A4 to neutrophils leadsto a phenotypic change, stopping all proinflammatoryactivity of neutrophils andleading to apoptosis. As a result, they stopsecreting the chemo-attractant LTB 4andseveral cellular pathways are activated, producing,at a local level, other dual-actinganti- inflammatory and proresolution lipidmediators, including resolvins and protectins.Mechanisms of Inflammation ResolutionResolvins and protectins provide potentsignals that orchestrate and accelerate mechanismsthat promote resolution of inflammationand homeostasis. Specifically, as depictedin Figure 3, pro-resolution mediatorsstop neutrophil infiltration and drive neutrophilsto apoptosis, while at the same timeattracting monocytes to the lesion. 41 Lipoxinstimulatedmonocytes/macrophages obtaina nonphlogistic phenotype, which resultsin phagocytosis of apoptotic neutrophilsand enhanced mucosal clearance of bacteriawithout concomitant secretion of pro- inflam -matory mediators that could contribute totissue damage. 42 Moreover, pro-resolutionlipid molecules increase the exit of phagocytesfrom the inflamed site through the lymphatics.Finally, some of these moleculesmay also stimulate the uptake and clearanceof local cytokines by apoptotic neutrophils.After neutrophils and debris are removed,homeostasis returns and repair mechanismsare initiated; lipoxins are antifibrotic andallow for complete tissue healing withoutscarring.Hence, it can be argued that the persistenceof an inflammatory disease, such asperiodontal disease, may be caused by toomuch pro-inflammatory signal or not enoughproresolution signal. In other words, a “hyperinflammatoryphenotype” due to a particulargenetic background of the host mayresult in oversecretion of inflammatory mediatorsin response to bacterial stimuli, whichin turn contributes to periodontal disease susceptibility,or a failure of resolution pathways.As high levels of inflammatory cyto kines are
36 Periodontal Disease and Overall Health: A Clinician's GuideFigure 2. Progression and Biosynthesis of Lipid Mediators During Inflammation ResolutionChemical mediators involved in the initiation of acute inflammation, such as prostaglandins (PGs) and leukotrienes(LTs), induce “class switching” toward pro-resolving lipid mediators. The pro-resolving mediators include -6PUFAs, AA- derived LXs, ATLs, -3 PUFA EPA-derived RvEs, docosahexanoic acid (DHA)-derived RvDs, andprotectins (PDs) (or neuroprotectins in neural tissues).Reprinted by permission from Wiley-Blackwell: Br J Pharmacol 2008;153(Suppl)S200–S215.Figure 3. Dual Anti-Inflammatory and Pro-Resolution Actions of Specific Lipoxins,Figure 3. Resolvins and ProtectinsReprinted by permission from Macmillan Publishers Ltd: Nat Rev Immunol 2008;8:349-361. 5
Page 5: ivCONTRIBUTORSSrividya Kidambi, MDA
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