periradicular lesions (chapter 5)

As a consequence ofpathologic changes in the dentalpulp,the root canal system can harbor numerous irri-tants.Egress ofthese irritants from infected rootcanals into the periradicular tissues can initiate forma-tion and perpetuation ofperiradicular lesions.Depending on the nature and quantity ofthese irri-tants,as well as the duration ofexposure ofthe peri-radicular tissues,a variety oftissue changes can occur.When the irritants are transient in nature,the inflam-matory process is short-lived and self-limiting.However,with an excessive amount ofirritants or per-sistent exposure,the nonspecific and specificimmunologic reactions can cause destruction ofperi-radicular tissues.

1

Radiographically,these lesionsappear as radiolucent areas around the portal(s) of exit ofthe main canal or lateral and/or accessory canals.Histologically,depending on their stage of development,the lesions contain numerous inﬂam-matory cells such as polymorphonuclear neutrophilleukocytes (PMNs),macrophages,lymphocytes,plas-ma cells,mast cells,basophils,and eosinophils.Theinteraction between the irritants and the host defen-sive mechanisms results in release ofnumerous medi-ators that curtail progression ofinfection and devel-opment ofsevere local infection

(osteomyelitis)

andsystemic complication such as septicemia.Numerousstudies,conducted within the past 30 years,elucidatethe reactions and mediators ofpathogenesis ofhumanperiradicular lesions.This chapter contains informa-tion about the etiologic factors involved in the devel-opment ofperiradicular lesions,mediators that partic-ipate in the pathogenesis ofthe changes,a classi

ﬁ

ca-tion ofperiradicular pathosis with emphasis on theirclinical and histologic features,and repair ofperi-radicular lesions following root canal therapy.In addi-tion,some nonendodontic lesions with clinical and/orradiographic signs and appearances similar toendodontic lesions ofpulpal origin will be discussed.

PERIRADICULAR LESIONS OF PULPAL ORIGINIrritants

Irritation ofpulpal or periradicular tissues results inin

ﬂ

ammation.The major irritants ofthese tissues canbe divided into living and nonliving irritants.The liv-ing irritants are various microorganisms and viruses.The nonliving irritants include mechanical,thermal,and chemical irritants.Mild to moderate injuries of short duration cause

reversible

tissue damage and

recovery

ofthese tissues.Persistent and/or severeinjuries usually cause

irreversible

changes in the pulpand development ofperiradicular lesions.

Microbial Irritants

Microbial irritants ofpulp and periradicular tissuesinclude bacteria,bacterial toxins,bacterial fragments,and viruses.These irritants egress apically from theroot canal system into the periradicular tissues andinitiate in

ﬂ

ammation and tissue alterations.A num-ber ofstudies have shown that pulpal and/or peri-radicular pathosis do not develop without the pres-ence ofbacterial contamination.Kakehashi and asso-ciates created pulpal exposures in conventional andgerm-free rats.

1

Pulpal necrosis and abscess formationoccurred by the eighth day in the conventional rats.Incontrast,the germ-free rats showed only minimalin

ﬂ

ammation throughout the 72-day investigation.M

ö

ller and coworkers made pulpal exposures in mon-keys and lacerated the pulp tissue with endodonticinstruments.

2

In one group,all procedures were car-ried out in a sterile environment and the access cavi-ties were sealed.In the other group,after pulp expo-sure the teeth were left open to intraoral contamina-tion.Six months later,only mild in

ﬂ

ammation wasapparent in the periradicular tissues in the

ﬁ

rst group.In contrast,the periradicular tissues in the secondgroup were severely in

ﬂ

amed.

Chapter 5

PERIRADICULAR LESIONS

Mahmoud Torabinejad and Richard E.Walton

Other investigators examined the

ﬂ

ora ofpreviously traumatized teeth with necrotic pulps with and with-out periradicular pathosis.

3,4

Teeth without apicallesions were aseptic,whereas those with periradicularlesions had positive bacterial cultures.Korzen et al.demonstrated the importance ofthe amount ofmicro-bial inoculum in the pathogenesis ofpulpal and peri-radicular lesions.

5

They showed that higher levels of contamination lead to greater in

ﬂ

ammatory responses.In addition to bacterial irritation,the periradiculartissues can be mechanically irritated and in

ﬂ

amed.Physical irritation ofperiradicular tissues can alsooccur during root canal therapy ifthe canals are instru-mented or

ﬁ

lled beyond their anatomic boundaries.Periradicular tissues can be irritated by impact trauma,hyperocclusion,endodontic procedures and accidents,pulp extirpation,overinstrumentation,root perfora-tion,and overextension of

ﬁ

lling materials.Chemicals are used as adjuncts for better d

é

bride-ment and disinfection ofthe root canal system.An invitro study,however,has shown that many ofthesechemicals are highly concentrated and not biocompat-ible.

6

Irrigating solutions such as sodium hypochloriteand hydrogen peroxide,intracanal medications,andchelating agents such as ethylenediaminetetraaceticacid (EDTA) can also cause tissue injury and in

ﬂ

am-mation ifinadvertently extruded into the periradiculartissues.Some components in obturation materials canirritate the periradicular tissues when extruded beyondthe root canal system.

Periradicular Reaction to Irritation

The periradicular tissues consist ofapical root cemen-tum,periodontal ligament,and alveolar bone.The apicalperiodontium is also richly endowed with cellular andextracellular components containing blood and lymphat-ics,as well as sensory and motor nerve

ﬁ

bers supplyingboth pulp and periodontium.Other structural elementsofthe periodontal ligament include ground substance,various

ﬁ

bers,

ﬁ

broblasts,cementoblasts,osteoblasts,osteoclasts,histiocytes,undifferentiated mesenchymalcells,and the epithelial cell rests ofMalassez.Irritation ofperiradicular tissues results in in

ﬂ

am-matory changes taking place.The vascular response toan injury includes vasodilation,vascular stasis,andincreased vascular permeability.The latter leads toextravasation of

ﬂ

uid and soluble components into thesurrounding tissues.These vascular changes cause red-ness,heat,swelling,and pain,which are the cardinalsigns ofin

ﬂ

ammation.The in

ﬂ

ammatory cells involvedin various stages oftissue injury and repair includeplatelets,PMNs,mast cells,basophils,eosinophils,

176

Endodonticsmacrophages,and lymphocytes,

7

all ofwhich have spe-ci

ﬁ

c roles in in

ﬂ

ammatory responses.

Mediators ofPeriradicular Lesions

The in

ﬂ

ammatory process is not completely under-stood,but a number ofsubstances have been implicat-ed as mediators ofin

ﬂ

ammation.They include neu-ropeptides,

ﬁ

brinolytic peptides,kinins,complementfragments,arachidonic acid metabolites,vasoactiveamines,lysosomal enzymes,cytokines,and mediatorsofimmune reactions.

Neuropeptides.

These are proteins generated fromsomatosensory and autonomic nerve

ﬁ

bers followingtissue injury.They include substance P (SP),calcitoningene

–

related peptide (CGRP),dopamine hydrolase,neuropeptide Y originating from sympathetic nerve

ﬁ

bers,and vasoactive intestinal polypeptides generatedfrom parasympathetic nerve

ﬁ

bers.

8

Substance P is a neuropeptide present in both theperipheral and central nervous systems.The release of SP can cause vasodilation,increased vascular perme-ability,and increased blood

ﬂ

ow during in

ﬂ

ammation.In addition,it can cause the release of

histamine frommast cells

and potentiate in

ﬂ

ammatory responses.Calcitonin gene

–

related peptide has been localizedin small to medium sensory nerve

ﬁ

bers.Like SP,it is apotent vasodilator and may play a role in the regulationofblood

ﬂ

ow in bone,periosteum,and other sites.Substance P and CGRP have been found in pulp andperiradicular tissues.

9

Fibrinolytic Peptides.

The

ﬁ

brinolytic cascade istriggered by the Hageman factor,which causes activa-tion ofcirculating plasminogen,previously known as

ﬁ

brinolysin and digestion ofblood clots.This results inrelease of

ﬁ

brinopeptides and

ﬁ

brin degradation prod-ucts that cause increased vascular permeability andleukocyte chemotaxis.

10

Kinins.

Release ofkinins causes many signs of in

ﬂ

ammation.

11

They include chemotaxis ofin

ﬂ

am-matory cells,contraction ofsmooth muscles,dilationofperipheral arterioles,increased vascular permeabili-ty,and pain.The kinins are produced by proteolyticcleavage ofkininogen by trypsin-like serine proteases,the kallikreins.The kinins are subsequently inactivatedby removal ofthe last one or two C-terminal aminoacids by the action ofpeptidase.

12

The kallikreins arealso able to react with other systems,such as the com-plement and coagulation systems,to generate othertrypsin-like serine proteases.

13

Elevated levels of

kinins

have been detected in

human periapical lesions

.

14

Complement System.

The complement system con-sists ofa number ofdistinct plasma proteins capable of

Periradicular Lesions

177

interacting with each other and with other systems toproduce a variety ofeffects.

15

Complement is able tocause cell lysis ifactivated on the cell membrane andalso to enhance phagocytosis through interaction withcomplement receptors on the surface ofphagocyticcells.Complement can also increase vascular perme-ability and act as a chemotactic factor for granulocytesand macrophages.The complement system is a com-plex cascade that has two separate activation pathwaysthat converge to a single protein (C3) and complete thecascade in a

ﬁ

nal,common sequence.Complement canbe activated through the classic pathway by antigen-antibody complexes or through the alternative pathway by directly interacting with complex carbohydrates onbacterial and fungal cell walls or with substances suchas plasmin.Several investigators have found

C3 complement

components in human

periradicularlesions

.

10

Activators ofthe classic and alternative pathways ofthecomplement system include immunoglobulin (Ig) M,IgG,bacteria and their by-products,lysosomal enzymesfrom PMNs,and clotting factors.Most ofthese activa-tors are present in periradicular lesions.Activation of the complement system in these lesions can contributeto bone resorption either by destruction ofalready existing bone or by inhibition ofnew bone formationvia the production ofprostaglandins (PGs).

Arachidonic Acid Metabolites.

Arachidonic acid isformed from membrane phospholipid as a result ofcellmembrane injury and phospholipase A

2

activity and isfurther metabolized.

Prostaglandins

are produced as a result ofthe acti-vation ofthe cyclooxygenase pathway ofthe arachi-donic acid metabolism.Their pathologic functionsinclude increased vascular permeability and pain.Torabinejad and associates demonstrated in an animalmodel that periradicular bone resorption could beinhibited by administration of

indomethacin(Indocin),an antagonist ofPGs.

16

High levels ofPGE

2

were found in periradicularlesions

ofpatients with

symptomatic apical periodontitis (SAP)

.

17

Takayamaet al.

18

and Shimauchi and coworkers

19

con

ﬁ

rmedthese

ﬁ

ndings by demonstrating lower levels ofPGE

2

associated with asymptomatic large lesions or cessationofsymptoms subsequent to emergency cleaning andshaping ofroot canals.Miyauchi et al.used immuno-histochemical staining and found PGE

2

,PGF

2

α

,and6-keto-PGF

1

α

in the experimentally induced periapi-cal lesions in rats.

20

Leukotrienes (LTs)

are produced as a result oftheactivation ofthe lipoxygenase pathway ofthe arachi-donic acid metabolism.Polymorphonuclear neutrophilleukocytes and mast cells are the major sources for pro-duction ofLTs.

21

Leukotriene B

4

is a powerful chemo-tactic agent from PMNs.Increased levels of

LTB

4

havebeen found in

symptomatic

human

periapicallesions

.

22

Other leukotrienes such as LTC

4

,LTD

4

,andLTE

4

are chemotactic for eosinophil and macrophage,cause increased vascular permeability,and stimulatelysozyme release from PMNs and macrophages.

15

Vasoactive Amines.

Vasoactive amines are presentin mast cells,basophils,and platelets.

Histamine,

themajor one ofthese substances,is found in all three celltypes,whereas

serotonin

is present only in platelets.

21

Release ofthese materials causes increased vascularpermeability,as well as muscle contraction ofairwaysand gastrointestinal tracts.Numerous

mast cells

havebeen detected in human

periradicular lesions

.

23,24

Physical or chemical irritation ofperiradicular tissuesduring root canal therapy can cause mast cell de-granulation.The discharged vasoactive amines can ini-tiate an in

ﬂ

ammatory response or aggravate an existingin

ﬂ

ammatory process in the periradicular tissues.

Lysosomal Enzymes.

Lysosomal enzymes are storedpreformed in membrane-bound bodies within in

ﬂ

am-matory cell cytoplasm.Lysosomal bodies are found inPMNs,macrophages,and platelets and contain acid aswell as alkaline phosphatases,lysozyme,peroxidase,cathepsins,and collagenase.They can be released viaexocytotic type events during cell lysis or secreted dur-ing phagocytosis.Release ofthese enzymes into the tis-sues causes increased vascular permeability,leukocytechemotaxis,generation ofC5a from C5,and

bradykinin

formation.

15

Aqrabawi and associatesexamined human periradicular lesions for the presenceoflysosomal hydrolytic arylsulfatase A and B andfound higher levels ofthese substances in lesions of endodontic origin compared to the control tissues.

25

Cytokines.

The major cytokines that have beenimplicated in bone resorption are various

interleukins(ILs)

and

tumor necrosis factors (TNFs)

.

15

Interleukin-1 is produced primarily by monocytesand macrophages.

26,27

Human monocytes produce atleast two IL-1 species,IL-1

α

and IL-1

β

.

28

Interleukin-1

β

is the major form secreted by human

monocytes

.The chiefcomponent ofosteoclast activating factor waspuri

ﬁ

ed and found to be identical to IL-1

β

.

29

Interleukin-1

β

is the most active ofthe cytokines in

stimulating bone resorption

in vitro,15-fold morepotent than IL-1

α

and 1,000-fold more potent thanTNFs.

30

Interleukin-1 has been associated withincreased bone resorption in vivo in several diseases.

Interleukin-1

has been implicated in the

bone resorp-

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