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  • Braz Dent J 18(4) 2007

    Bacterial pathogenesis of apical periodontitis 267Braz Dent J (2007) 18(4): 267-280

    Correspondence: Prof. Dr. Jos F. Siqueira Jr, Faculdade de Odontologia, Universidade Estcio de S, Avenida Alfredo Baltazar da Silveira,580/cobertura, Recreio, 22790-701 Rio de Janeiro, RJ, Brazil. Tel: +55-21-8874-1022. Fax: +55-21-2199-2204. e-mail:jf_siqueira@yahoo.com; siqueira@estacio.br

    ISSN 0103-6440

    Bacterial Pathogenesis and Mediatorsin Apical Periodontitis

    Jos F. SIQUEIRA JrIsabela N. RAS

    Department of Endodontics, Estcio de S University, Rio de Janeiro, RJ, Brazil

    Apical periodontitis is a group of inflammatory diseases caused by microorganisms (mainly bacteria) infecting the necrotic root canalsystem. The pathogenesis of different types of apical periodontitis and even the same type in different individuals is unlikely to follow astereotyped fashion with regard to the involved bacterial mediators. Disease pathogenesis is rather complex and involves a multitude ofbacteria- and host-related factors. This review article discusses the bacterial pathogenesis of acute and chronic apical periodontitis, withthe main focus on the bacterial mediators conceivably involved in the different stages of the infectious process, including secreted products(enzymes, exotoxins, N-formyl-methionyl-leucyl-phenylalanine peptides, heat-shock proteins and metabolic end-products) and struc-tural components (lipopolysaccharide, peptidoglycan, lipoteichoic acid, lipoproteins, fimbriae, flagella, outer membrane proteins andvesicles, DNA, and exopolysaccharides). Knowledge of the bacterial factors involved in the pathogenesis of apical periodontitis is importantto the understanding of the disease process and to help establishing proper therapeutic measures to inactivate this bacterial artillery.

    Key Words: endodontic infection, bacterial pathogenicity, virulence factors, apical periodontitis.

    INTRODUCTION

    Apical periodontitis is a group of inflammatorydiseases caused by microorganisms (mainly bacteria)infecting the necrotic root canal system. The processstarts after pulp necrosis as a result of caries, trauma oriatrogenic procedures, when bacteria invade and colo-nize the root canal system. As a consequence ofnecrosis, the endodontic environment becomes a selec-tive habitat for the establishment of a mixed microbiotaconspicuously dominated by anaerobic bacteria (1). Inlate stages of the infectious process, bacterial organiza-tions resembling biofilms can be observed adhered tothe canal walls (2-4). Thus, there is a current trend toconsider apical periodontitis as a biofilm-induced dis-ease. Bacteria colonizing the necrotic root canal comeinto contact with the periodontal ligament via apical orlateral foramens, induce damage and give rise to inflam-matory changes. The host defenses, in turn, can eliminatebacteria egressing from the canal, but are unable to

    eradicate bacteria entrenched in the sanctuary of thenecrotic root canal, which lacks an active microcircu-lation and is consequently beyond the reaches of bodydefenses. Disease pathogenesis is rather complex andinvolves a multitude of bacteria- and host-related factors.This review article discusses the bacterial pathogenesisof apical periodontitis, with the main focus on thebacterial mediators (or virulence factors) involved in thedifferent stages of the disease process.

    ENDODONTIC PATHOGENS AND MECHANISMS OFPATHOGENICITY

    Bacteria involved in the pathogenesis of apicalperiodontitis may have participated in the early stages ofpulp inflammation and necrosis or they may have gainedentry into the canal space any time after pulpal necrosis.In the former situation, involved bacteria are usuallythose present in the advanced front of caries lesions andfrom saliva bathing the affected area. Bacteria impli-

  • Braz Dent J 18(4) 2007

    268 J. F. Siqueira Jr and I. N. Ras

    cated in pulp disease first adhere to the dentinal walls andcolonize this surface, forming authentic biofilms. Diffu-sion of bacterial products through dentinal tubulesinduces pulpal inflammation long before the tissue isexposed. After pulp exposure, the surface of the tissuecan also be colonized and covered by bacteria present inthe caries biofilm. The exposed pulp tissue is in directcontact with bacteria and their products, and respondswith severe inflammation. Some tissue invasion bysome bacteria may also occur. Bacteria in the battlefront have to survive the attack from the host defensesand at the same time have to acquire nutrients to keepthemselves alive. In this bacteria-pulp clash, the latterinvariably is defeated and becomes necrotic. Therefore,bacteria move forward and occupy the territory, i.e.,colonize the necrotic tissue. These events occur pertissue compartments, which coalesce and move to-wards the apical part of the canal until virtually the entireroot canal is necrotic and infected. At this stage,involved bacteria can be regarded as the early root canalcolonizers or pioneer species.

    Bacteria colonizing the necrotic root canal startinducing damage to the periradicular tissues and giverise to inflammatory changes. In fact, periradicularinflammation can be observed even before the entireroot canal is necrotic (5-7). Therefore, the early colo-nizers play an important role in the initiation of the apicalperiodontitis disease process. The environmental condi-tions in the canal are modified by pioneer species and thedisease process, and may now be conducive to theestablishment of bacterial groups different from theearly colonizers. Once the pulp is necrotic, species otherthan those that participated in the initial infectiousprocess may also have access to the canal via coronalexposure or exposed dentinal tubules. In fact, a shift inthe microbiota is observed and is resultant of re-arrangements in the proportions of the pioneer speciesand arrival of latecomers. Some early colonizers areexpected to no longer participate in the consortium inadvanced disease. As time passes, the endodonticmicrobiota becomes more and more structurally andspatially organized. Some virulence attributes requiredfor pathogens to thrive in other sites may be of no valuefor bacteria that reach the root canal after necrosis as,for instance, the ability to evade the host defenses. Thisis because latecomers face no significant oppositionfrom host defenses, which are no longer active in thecanal after necrosis. Although colonization may appear

    an easy task for late colonizers, other environmentalfactors, such as interaction with pioneer species, oxygentension and nutrients availability, will determine whetherthe new species entering the canal will succeed inestablishing therein. Thus, latecomers will join the earlycolonizers to make up a dynamic mixed community inthe root canal. Ultimately, the root canals of teethevincing radiographically detectable apical periodontitislesions harbor early colonizers that managed to stay inthe canals and late colonizers that managed to adapt tothe new, but propitious, environmental conditions.

    The usual sequential stages for bacterial infec-tions in several body sites include a) attachment to andcolonization of host surfaces; b) invasion of hosttissues; c) survival within the tissue by acquiring nutri-ents and evading host defense mechanisms; d) andinduction of direct or indirect damage to the hosttissues. The process of early pulp infection is likely tofollow similar events, even though it should be assumedthat the sequence of events is more didactic than real andsome phases may overlap or swap positions. Severalbacterial mediators (virulence factors) are involved ineach of these events.

    Bacteria exert their pathogenicity by wreakinghavoc to the host tissues through direct and/or indirectmechanisms. Bacterial factors that cause direct tissueharm include those that damage host cells and/or theintercellular matrix of the connective tissue. Thesefactors usually involve secreted products, includingenzymes, exotoxins and metabolic end-products (8).Furthermore, bacterial structural components, includ-ing peptidoglycan, lipoteichoic acid, fimbriae, flagella,outer membrane proteins and vesicles, DNA,exopolysaccharides and lipopolysaccharide, are shedinto the periradicular tissues and act as modulins bystimulating the development of host immune reactionscapable not only of defending the host against infectionbut also of causing severe tissue destruction (9, 10). Forinstance, inflammatory and non-inflammatory host cellscan be stimulated by bacterial components to releasechemical mediators such as cytokines and prostaglan-dins, which are involved in the induction of boneresorption characteristically observed in chronic apicalperiodontitis lesions (11). Pro-inflammatory cytokinesstimulate osteoclastic bone resorption by either enhanc-ing the proliferation and differentiation of osteoclastprecursors or promoting activation of mature osteo-clasts, or both (12). Another example of indirect dam-

  • Braz Dent J 18(4) 2007

    Bacterial pathogenesis of apical periodontitis 269

    age caused by bacteria is the formation of purulentexudate in acute apical abscesses. Host defense mecha-nisms against bacteria emanating from the root canalappear to be the most important factor involved in pusformation associated with abscesses. Formation ofoxygen-derived free radicals, such as superoxide andhydrogen peroxide, alongside the release of lysosomalenzymes by polymorphonuclear leukocytes, gives riseto destruction of the connective extracellular matrix,leading to pus formation (13). Therefore, bacteria canexert indirect destructive effects, which seem to be evenmore significant in the tissue damage associated withacute and chronic apical periodontitis lesions.

    Depending on several factors, apical periodonti-tis can be chronic or acute. A chronic disease is usuallyassociated w

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