| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
Institute of Oral Biology, Section of Oral Structures and Development, Center of Dental and Oral Medicine, University of Zürich, Plattenstrasse 11, CH-8028 Zürich, Switzerland; nair{at}zzmk.unizh.ch
Abstract (I) Introduction (II) Etiology of Apical Periodontitis (A) CHAIN OF EVIDENCE (B) PORTALS OF ROOT CANAL INFECTION (C) ENDODONTIC FLORA OF TEETH WITH PRIMARY APICAL PERIODONTITIS (D) PATHOGENICITY OF ENDODONTIC FLORA (1) Microbial interaction (2) Microbial interference (3) LPS and other microbial modulins (4) Enzymes (III) Host Response (A) CELLULAR ELEMENTS (1) PMN (2) Lymphocytes (a) T-lymphocytes (b) B-lymphocytes (3) Macrophages (Metchinkoff, 1968) (4) Osteoclasts (5) Epithelial cells (B) MOLECULAR MEDIATORS (1) Pro-inflammatory & chemotactic cytokines (2) IFN (3) Colony-stimulating factors (CSF) (4) Growth factors (5) Eicosanoids (a) Prostaglandins (b) Leukotrienes (6) Effector molecules (7) Antibodies (IV) Pathogenesis of Apical Periodontitis Lesions (A) INITIAL APICAL PERIODONTITIS (B) ESTABLISHED CHRONIC APICAL PERIODONTITIS (C) ESTABLISHED CYSTIC APICAL PERIODONTITIS (RADICULAR CYSTS) (1) Periapical true cyst (2) Periapical pocket cyst (V) Causes of Endodontic Failures (A) INTRARADICULAR INFECTION (B) ENDODONTIC FLORA OF ROOT-CANAL-TREATED TEETH (C) EXTRARADICULAR ACTINOMYCOSIS (D) OTHER EXTRARADICULAR INFECTIONS (E) CYSTIC APICAL PERIODONTITIS (F) FOREIGN-BODY REACTIONS (1) Cholesterol crystals (2) Foreign bodies (a) Gutta percha (b) Plant materials (c) Other foreign materials (G) SCAR-TISSUE HEALING (VI) Concluding Remarks Acknowledgments REFERENCES
| Abstract |
|---|
 Top Next |
|---|
Key words. Apical periodontitis, periapical lesions, pathogenesis, endodontic failures
In the long-term conflict between microbes and technology, microbes will win. (adapted from Albert Einstein)
| (I) Introduction |
|---|
|
TopPreviousNext |
|---|
). Initially, the tooth pulp becomes infected and necrotic by an autogenous oral microflora. The endodontic environment provides a selective habitat for the establishment of a mixed, predominantly anaerobic, flora. Collectively, this habitat-adapted polymicrobial community residing in the root canal has several biological and pathogenic properties, such as antigenicity, mitogenic activity, chemotaxis, enzymatic histolysis, and activation of host cells. The microbial invaders in the root canal can advance, or their products can egress, into the periapex. In response, the host mounts an array of defenses consisting of several classes of cells, intercellular messengers, antibodies, and effector molecules. The microbial factors and host defense forces encounter, clash with, and destroy much of the periapical tissue, resulting in the formation of various categories of apical periodontitis lesions. In spite of the formidable defense, the body is unable to destroy the microbes well-entrenched in the sanctuary of the necrotic root canal, which is beyond the reaches of body defenses (Fig. 2). Therefore, apical periodontitis is not self-healing. The treatment of apical periodontitis consists of eliminating infection from the root canal and preventing re-infection by a hydraulic seal of the root canal space. Nevertheless, endodontic treatment can fail for various reasons. The pathogenesis of apical periodontitis has been well-reviewed (Stashenko, 1990; Nair, 1997; Stashenko et al., 1998). However, even recent textbooks of endodontology (Cohen and Burns, 2002; Bergenholtz et al., 2003) do not provide an overview of the causes of endodontic failures. The data on the biological causes of endodontic treatment failures are recent, scattered throughout various journals, and need consolidation. The purpose of this communication is to provide a comprehensive review of the pathogenesis of apical periodontitis and the causes of endodontic failures.
|
|
| (II) Etiology of Apical Periodontitis |
|---|
|
TopPreviousNext |
|---|
, 2)—aggregates of one and co-aggregates of several species of microbes suspended in the fluid phase of infected root canals—was visualized by the application of the precise technique of correlative light and transmission electron microscopy (Nair, 1987). Today, there is a clear consensus on the essential etiological role of intraradicular micro-organisms in apical periodontitis.
(B) PORTALS OF ROOT CANAL INFECTION
Openings in the dental hard tissue wall—resulting from caries, clinical procedures, or trauma-induced fractures and cracks—are the most frequent portals of pulpal infection. But microbes have also been isolated from teeth with necrotic pulps and clinically intact crowns (Brown and Rudolph, 1957; Chirnside, 1957; Macdonald et al., 1957; Engström and Frostell, 1961; Möller, 1966; Bergenholtz, 1974; Wittgow and Sabiston, 1975; Sundqvist, 1976; Baumgartner et al., 1999). Endodontic infections of such teeth are preceded by pulpal necrosis. The teeth may appear to be clinically intact but reveal micro-cracks in hard tissues that provide portals of entry for bacteria. Bacteria from the gingival sulci or periodontal pockets have been suggested to reach the root canals of these teeth through severed periodontal blood vessels (Grossman, 1967). Pulpal infection can also occur through exposed dentinal tubules at the cervical root surface, due to gaps in the cemental coating. Microbes have also been claimed to ‘seed’ in the necrotic pulp via the blood circulation (anachoresis) (Robinson and Boling, 1941; Burke and Knighton, 1960; Gier and Mitchel, 1968; Allard et al., 1979). However, bacteria could not be recovered from the root canals when the blood stream was experimentally infected, unless the root canals were over-instrumented and presumably the apical periodontal blood vessels were injured during the period of bacteremia (Delivanis and Fan, 1984). In another study (Möller et al., 1981), all experimentally devitalized monkey pulps (n = 26) remained sterile for more than six months. Therefore, exposure of the dental pulp to the oral cavity is the most important route of endodontic infection.
(C) ENDODONTIC FLORA OF TEETH WITH PRIMARY APICAL PERIODONTITIS
Contemporary knowledge of the taxonomy of infected root canal flora is based on advanced microbial culture techniques. This might soon change with the judicious application of molecular genetic techniques in endodontic microbiology (Munson et al., 2002). Although a sample of the vast oral microbiota (Moore and Moore, 1994) can infect the exposed tooth pulp, culture studies have long established that only a subset of oral microflora, consisting of a limited number of species, is consistently isolated from such root canals. The root canal flora of teeth with clinically intact crowns, but having necrotic pulps and diseased periapices, is dominated (> 90%) by obligate anaerobes (Sundqvist, 1976; Byström and Sundqvist, 1981; Haapasalo, 1989; Sundqvist et al., 1989), usually belonging to the genera Fusobacterium, Porphyromonas (formerly Bacteroides; Shah and Collins, 1988), Prevotella (formerly Bacteroides; Shah and Collins, 1988), Eubacterium, and Peptostreptococcus. In contrast, the microbial composition—even in the apical third of the root canal of periapically affected teeth with pulp canals exposed to the oral cavity—is not only different from but also less dominated (< 70%) by strict anaerobes (Baumgartner and Falkler, 1991). Using culture techniques (Hampp, 1957; Kantz and Henry, 1974; Dahle et al., 1996), dark-field (Brown and Rudolph, 1957; Thilo et al., 1986; Dahle et al., 1993), and transmission electron microscopy (Nair, 1987), investigators have found spirochetes in necrotic root canals. Culture studies (for review, see Waltimo et al., 2003) and the application of scanning electron microscopy (Sen et al., 1995) have revealed the presence of fungi in canals of teeth with primary apical periodontitis. The presence of intraradicular viruses has so far been shown only in non-inflamed dental pulps of patients infected with immuno-deficiency virus (Glick et al., 1991).
The invention of the polymerase chain-reaction (PCR) (Mullis and Faloona, 1987) technique and its application in microbiology (Pollard et al., 1989; Spratt et al., 1999) has enabled bacteria to be detected by the amplification of their DNA. These molecular methods have largely confirmed the microbial species that have been previously detected and grown by culture methods (Munson et al., 2002). They have also facilitated the identification of as-yet-culture-difficult endodontic organisms, and their precise taxonomic grouping (Munson et al., 2002). Although the application of molecular techniques may widen the taxonomic spectra of potential endodontic microflora, there is currently no evidence that the culture-difficult organisms reported by the highly sensitive molecular methods are viable root canal pathogens. This is because the molecular genetic methods are often applied without the enhanced precautions needed and without consideration of the limitations of the techniques (Siqueira et al., 2000; Siqueira and Rôças, 2003).
(D) PATHOGENICITY OF ENDODONTIC FLORA
Any microbe that infects the root canal has the potential to initiate periapical inflammation. However, the virulence and pathogenicity of individual species vary considerably and can be affected in the presence of other microbes. Although the individual species in the endodontic flora are usually of low virulence, their intraradicular survival and pathogenic properties are influenced by a combination of factors, including: (i) interactions with other micro-organisms in the root canal, to develop synergistically beneficial partners; (ii) the ability to interfere with and evade host defenses; (iii) the release of lipopolysaccharides (LPS) and other bacterial modulins; and (iv) the synthesis of enzymes that damage host tissues,
(1) Microbial interaction
There is clear evidence that microbial interaction plays a significant role in the ecological regulation and eventual development of an endodontic habitat-adapted polymicrobial flora (for reviews, see Sundqvist, 1992a,b; Sundqvist and Figdor, 2003). The importance of the mixed bacterial flora has been well-exemplified in carefully planned animal studies (Sundqvist et al., 1979; Fabricius et al., 1982a,b). Bacteria (Prevotella oralis and 11 other species) isolated from the root canals of periapically involved teeth from experimental monkeys were inoculated in various combinations or as separate species into the root canals of other monkeys (Fabricius et al., 1982b). When individual bacterial species were inoculated, only mild apical periodontitis developed. But in combinations, the same bacterial species induced more severe periapical reactions. Further, Prevotella oralis did not establish in root canals as a mono-infection, whereas it survived and dominated the endodontic flora when introduced with the other bacterial species involved in the study. Microbial interactions that influence the ecology of the endodontic flora may be positive (synergistic) or negative associations, as a result of certain organisms influencing the respiratory and nutritional environments of the entire root canal flora (Lew et al., 1971; Fabricius et al., 1982a; Loesche et al., 1983; Carlsson, 1990).
(2) Microbial interference
The ability of certain microbes to shirk and interfere with the host defenses has been well-elaborated (for review, see Sundqvist, 1994). Bacterial LPS can signal the endothelial cells to express leukocyte adhesion molecules that initiate extravasation of leukocytes into the area of the infection. It has been reported that Porphyromonas gingivalis, an important endodontic and periodontal pathogen, and its LPS do not signal the endothelial cells to express E-selectin. P. gingivalis therefore has the ability to block the initial step of inflammatory response, ‘hide’ from the host, and multiply. The antigenicity of LPS occurs in several forms that include mitogenic stimulation of B-lymphocytes, to produce non-specific antibodies. Gram-negative organisms release membrane particles (blebs) and soluble antigens which may ‘mop up’ effective antibodies, to make them unavailable to act against the organism itself (Mims, 1988). Actinomyces israelii, a recalcitrant periapical pathogen, is easily killed by PMN in vitro (Figdor et al., 1992). In tissues, A. israelii aggregate to form large cohesive colonies that cannot be killed by host phagocytes (Figdor et al., 1992).
(3) LPS and other microbial modulins
LPS, also historically known as endotoxins, form an integral part of Gram-negative cell walls. They are released during disintegration of bacteria after death and also during multiplication and growth. The effects of LPS are due to their interaction with endothelial cells and macrophages. LPS not only signal the endothelial cells to express adhesion molecules but also activate macrophages to produce several molecular mediators, such as the tumor necrosis factor-
(TNF-) and interleukins (IL) (Arden, 1979). Exogenous TNF- administered to experimental animals can induce a lethal shock that is indistinguishable from that induced by LPS. The latter signal the presence of Gram-negative micro-organisms in the area. The impact of LPS in tissues has been aptly stated (Thomas, 1974): "...when we sense LPS, we are likely to turn on every defense at our disposal; we will bomb, defoliate, blockade, seal off and destroy all tissues in the area." The presence of LPS has been reported in samples taken from the root canal (Schein and Schilder, 1975; Dahlén and Bergenholtz, 1980) and the pulpal-dentinal wall of periapically involved teeth (Horiba et al., 1990). The Gram-negative organisms of the endodontic flora multiply and also die in the apical root canal, thereby releasing LPS that egress through the apical foramen into the periapex (Yamasaki et al., 1992), where they initiate and sustain apical periodontitis (Dahlén, 1980; Dahlén et al., 1981).
However, LPS are not the only bacterial degradation product that can induce mammalian cells to produce cytokines. Many proteins, certain carbohydrates, and lipids of bacterial origin are now considered as belonging to a novel class of ‘modulins’ that induce the formation of cytokine networks and host tissue pathology (for review, see Henderson et al., 1996).
(4) Enzymes
Endodontic microbes produce a variety of enzymes that are not directly toxic but may aid the spread of the organisms in host tissues. Microbial collagenase, hyaluronidase, fibrinolysins, and several proteases are examples. Microbes are also known to produce enzymes that degrade various plasma proteins involved in blood coagulation and other body defenses. The ability of some Porphyromonas and Prevotella species to break down plasma proteins—particularly IgG, IgM (Killian, 1981), and the complement factor C3 (Sundqvist et al., 1985)—is of particular significance, since these molecules are opsonins necessary for both humoral and phagocytic host defenses.
| (III) Host Response |
|---|
|
TopPreviousNext |
|---|
). The latter involves cells, intercellular mediators, metabolites, effector molecules, and humoral antibodies.
(A) CELLULAR ELEMENTS
Several classes of body cells participate in periapical defense (Fig. 3). A majority of them are from the defense systems and include polymorphonuclear leukocytes (PMN), lymphocytes, plasma cells, and monocyte/macrophages. Structural cells include fibroblasts, osteoblasts, and epithelial rests (Malassez, 1884) that play significant roles. The importance of PMN and monocyte derivatives in apical periodontitis has been shown experimentally (Stashenko et al., 1995). The intensity of induced murine pulpitis and apical periodontitis can be suppressed if the animals are treated with a biological response-modifying drug, PGG glucan, that enhances the number and ability of circulating neutrophils and monocytes.
|
). Their cytoplasmic granules contain several enzymes that, on release, degrade the structural elements of tissue cells and extracellular matrices (Nagase et al., 1992; Van Dyke and Vaikuntam, 1994). Because they are short-lived cells, PMN die in great numbers (Fig. 3a) at acute inflammatory sites (Ryan and Majno, 1977). Therefore, the accumulation and massive death of neutrophils are a major cause for tissue breakdown in acute phases of apical periodontitis.
(2) Lymphocytes
Among the three major classes of lymphocytes—T-lymphocytes, B-lymphocytes, and the natural killer (NK) cells—the T- and B-lymphocytes are of importance in apical periodontitis. They are morphologically identical (Fig. 3b) and cannot be distinguished by conventional staining or microscopic examination, but are phenotyped on the basis of surface receptors with the use of monoclonal antibodies against the latter. Cells so identified are given a ‘cluster of differentiation’ (CD) number.
(a) T-lymphocytes
Traditionally, the thymus-derived (T) cells have been designated after their effects or functions—for instance, the T-cells working with B-cells have been known as T-helper/inducer (Th/i) cells, and those with direct toxic and suppressive effects on other cells have been named T-cytotoxic/suppressive (Tc/s) cells. The Th/i cells are CD4+, and the Tc/s cells are CD8+. The CD4+ cells differentiate further into two types, known as Th1 and Th2 cells. The former produce IL-2 and interferon-
(IF-) and control the cell-mediated arm of the immune system. The Th2 cells secrete IL-4, -5, -6, and -10, that regulate the production of antibodies by the plasma cells.
(b) B-lymphocytes
The lymphocytes directly responsible for antibody production are the bursa-equivalent (B) cells, named after their discovery in a chicken organ called the ‘bursa of Fabricius’ (Chang et al., 1955). On receiving signals from antigens and the Th2-cells, some of the B-cells transform into plasma cells (Fig. 3c) that manufacture and secrete antibodies.
(3) Macrophages (Metchinkoff, 1968)
Macrophages (Fig. 3d) represent the major differentiated cells of the mononuclear phagocytic system (Van Furth et al., 1972; Papadimitriou and Ashman, 1989), previously known as the ‘reticulo-endothelial system’, that have been extensively characterized (Carr, 1980). Macrophages are activated by micro-organisms, their products (LPS), chemical mediators, or foreign particles. Among the various molecular mediators that are secreted by macrophages, the cytokines IL-1, TNF-, interferons (IFN), and growth factors are of particular importance in apical periodontitis. They also contribute serum components and metabolites, such as prostaglandins and leukotrienes, that are important in inflammation. Antigen-presenting dendritic cells are also reported in induced murine apical periodontitis (Okiji et al., 1994). Whether they ‘seed’ in periapical lesions via general circulation (Jontell et al., 1998) or spread locally from inflamed dental pulp is unknown.
(4) Osteoclasts
A major pathological event of apical periodontitis is the osteoclastic destruction of bone and dental hard tissues. There are extensive reviews on the origin (Nijweide and De Grooth, 1992), structure (Gay, 1992), regulation (Heersche, 1992), and ‘coupling’ (Puzas and Ishibe, 1992) of these cells with osteoblasts. Briefly, the pro-osteoclasts migrate through blood as monocytes to the periradicular tissues and attach themselves to the surface of bone. They remain dormant until signaled by osteoblasts to proliferate. Several daughter cells fuse to form multinucleated osteoclasts that spread over injured and exposed bone surfaces. The cytoplasmic border of the osteoclasts facing the bony surface becomes ruffled as a result of multiple infolding of the plasma membrane. Bone resorption takes place beneath this ruffled border, known as the sub-osteoclastic resorption compartment. At the periphery, the cytoplasmic ‘clear zone’ is a highly specialized area which regulates the biochemical activities involved in breaking down the bone. The bone destruction happens extracellularly at the osteoclast/bone interface and involves: (i) demineralization of the bone by solubilizing the mineral phase in the resorption compartment, as a result of ionic lowering of pH in the micro-environment; and (ii) enzymatic dissolution of the organic matrix. Root cementum and dentin are also resorbed in apical periodontitis by fusion macrophages designated as ‘odontoclasts’. In view of their ultrastructural and histochemical similarities, they belong to the same cell population as osteoclasts (Sahara et al., 1994).
(5) Epithelial cells
About 30 to 52% of all apical periodontitis lesions contain proliferating epithelium (Thoma, 1917; Freeman, 1931; Sonnabend and Oh, 1966; Seltzer et al., 1969; Langeland et al., 1977; Simon, 1980; Yanagisawa, 1980; Nair et al., 1996). During periapical inflammation, the epithelial cell rests (Malassez, 1884) are believed to be stimulated by cytokines and growth factors to undergo division and proliferation, a process commonly described as ‘inflammatory hyperplasia’. These cells participate in the pathogenesis of radicular cysts by serving as the source of epithelium. However, ciliated epithelial cells are also found in periapical lesions (Shear, 1992; Nair et al., 2002), particularly in lesions affecting maxillary molars. The maxillary sinus-epithelium was suggested to be a source of those cells (Nair and Schmid-Meier, 1986; Nair et al., 2002).
(B) MOLECULAR MEDIATORS
Several cytokines (Cohen et al., 1974), eicosanoids, effector-molecules, and antibodies are involved in the pathogenesis and progression of apical periodontitis.
(1) Pro-inflammatory & chemotactic cytokines
They include interleukin (IL)-1, -6, and -8 and tumor necrosis factors (TNF) (Oppenheim, 1994). The systemic effects of IL-1 are identical to those observed in toxic shock. Local effects include enhancement of leukocyte adhesion to endothelial walls, stimulation of lymphocytes, potentiation of neutrophils, activation of the production of prostaglandins and proteolytic enzymes, enhancement of bone resorption, and inhibition of bone formation. IL-1ß is the predominant form found in human periapical lesions and their exudates (Barkhordar et al., 1992; Lim et al., 1994; Matsuo et al., 1994; Ataoglu et al., 2002). IL-1 is primarily involved in apical periodontitis in rats (Wang and Stashenko, 1993; Tani-Ishii et al., 1995). IL-6 (Hirano, 1994) is produced by both lymphoid and non-lymphoid cells under the influence of IL-1, TNF-, and IFN-. It down-regulates the production and counters some of the effects of IL-1. IL-6 has been demonstrated in human periapical lesions (De Sá et al., 2003) and in inflamed marginal periodontal tissues (Yamazaki et al., 1994). IL-8 is a family of chemotactic cytokines (Damme, 1994) produced by monocyte/macrophages and fibroblasts under the influence of IL-1ß and TNF-. Massive infiltration of neutrophils is a characteristic of the acute phases of apical periodontitis, for which IL-8 and other chemo-attractants (such as bacterial-peptides, plasma-derived complement split-factor C5a, and leukotriene B4) are important. TNF has a direct cytotoxic effect and a general debilitating effect in chronic disease. In addition, the macrophage-derived TNF- (Tracey, 1994) and the T-lymphocyte-derived TNF-ß (Ruddle, 1994), formerly lymphotoxin, have numerous systemic and local effects similar to those of IL-1. The presence of TNF- has been reported in human apical periodontitis lesions and root canal exudates of teeth with apical periodontitis (Artese et al., 1991; Safavi and Rossomando, 1991; Ataoglu et al., 2002).
(2) IFN
IFN was originally described as an antiviral agent and is now classified as a cytokine. There are three distinct IFNs, designated as -, -ß, and - molecules. The antiviral protein is the IFN- produced by virus-infected cells and normal T-lymphocytes under various stimuli, whereas the IFN-/ß proteins are produced by a variety of normal cells, particularly macrophages and B-lymphocytes.
(3) Colony-stimulating factors (CSF)
CSFs are cytokines that regulate the proliferation and differentiation of hematopoietic cells. The name originates from the early observation that certain polypeptide molecules promote the formation of granulocyte or monocyte colonies in a semi-solid medium. Three distinct proteins of this category have been isolated, characterized, and designated as cytokines: (i) granulocyte-macrophage colony-stimulating factor (G-MCF), (ii) granulocyte colony-stimulating factor (G-CSF), and (iii) macrophage colony-stimulating factor (M-CSF). In general, CSFs stimulate the proliferation of neutrophil and osteoclast precursors in the bone marrow. They are also produced by osteoblasts (Puzas and Ishibe, 1992), thus providing one of the communication links between osteoblasts and osteoclasts in bone resorption.
(4) Growth factors
Growth factors regulate the growth and differentiation of non-hematopoietic cells. Transforming growth factors (TGFs) are produced by normal and neoplastic cells that were originally identified by their ability to induce non-neoplastic, surface-adherent colonies of fibroblasts in soft agar cultures. This process appears to be similar to the neoplastic transformation of normal to malignant cells, hence the name TGF. Based on their structural relationship to the epidermal growth factor (EGF), they are classified into TGF- and TGF-ß. The former is closely related to EGF in structure and effects but is produced primarily by malignant cells and therefore is not significant in apical periodontitis. But TGF-ß is synthesized by a variety of normal cells and platelets and is involved in the activation of macrophages, proliferation of fibroblasts, synthesis of connectives tissue fibers and matrices, local angiogenesis, healing, and down-regulation of numerous functions of T-lymphocytes. Therefore, TGF-ß is important to counter the adverse effects of inflammatory host responses.
(5) Eicosanoids
When cells are activated or injured by diverse stimuli, their membrane lipids are remodeled to generate compounds that serve as intra- and intercellular signals. Arachidonic acid, a 20-carbon polysaturated fatty acid present in all cell membranes, is released from membrane lipids by a variety of stimuli and is rapidly metabolized to form several C20 compounds, known collectively as eicosanoids (Greek: eicosi = twenty). The eicosanoids are thought of as hormones with physiological effects at very low concentrations. They mediate inflammatory response, pain, and fever, regulate blood pressure, induce blood clotting, and control several reproductive functions such as ovulation and induction of labor. Prostaglandins (PG) and leukotrienes (LT) (Samuelsson, 1983) are two major groups of eicosanoids involved in inflammation.
(a) Prostaglandins
Prostaglandins were first identified in human semen and were thought to have originated from the prostate gland—hence the name. They are formed when arachidonic acid is metabolized via the cyclo-oxygenase pathway (e.g., PGE2, PGD2, PGF2a, PGI2). The PGE2 and PGI2 are potent activators of osteoclasts. Much of the rapid bone loss in marginal and apical periodontitis happens during episodes of acute inflammation, when the lesions are dominated by PMN, which are an important source of PGE2. High levels of PGE2 have been shown to be present in acute apical periodontitis lesions (McNicholas et al., 1991). Apical hard-tissue resorption can be suppressed by parenteral administration of indomethacin, an inhibitor of cyclo-oxygenase (Torabinejad et al., 1979).
(b) Leukotrienes
Leukotrienes (e.g., LTA4, LTB4, LTC4, LTD4, and LTE4) are formed when arachidonic acid is oxidized via the lipoxygenase pathway. LTB4 is a powerful chemotactic agent for neutrophils (Okiji et al., 1991) and causes adhesion of PMN to the endothelial walls. LTB4 (Torabinejad et al., 1992) and LTC4 (Cotti and Torabinejad, 1994) have been detected in apical periodontitis, with a high concentration of the former in symptomatic lesions (Torabinejad et al., 1992).
(6) Effector molecules
One of the earliest histopathological changes that take place in both apical and marginal periodontitis is the degradation of extracellular matrices. The destruction of the matrices is caused by enzymatic effector molecules. Four major degradation pathways have been recognized: (1) osteoclastic, (2) phagocytic, (3) plasminogen-dependent, and (4) metallo-enzyme-regulated (Birkedal-Hansen, 1993). The zinc-dependent proteases that are responsible for the degradation of much of the extracellular matrix components (such as collagen, fibronectin, laminin, gelatin, and proteoglycan core proteins) belong to the superfamily of enzymes called the ‘matrix metalloproteinases’ (MMP). The biology of the MMP has been extensively researched and reviewed (Birkedal-Hansen et al., 1992, 1993). Their presence has also been reported in apical periodontitis lesions (Teronen et al., 1995; Shin et al., 2002).
(7) Antibodies
These are specific weapons of the body that are produced solely by plasma cells. Different classes of immunoglobulins have been found in plasma cells (Kuntz et al., 1977; Morton et al., 1977; Pulver et al., 1978; Jones and Lally, 1980; Stern et al., 1981; Skaug et al., 1982) and extracellularly (Naidorf, 1975; Kuntz et al., 1977; Matsumoto, 1985; Torres et al., 1994) in human apical periodontitis. The concentration of IgG in apical periodontitis was found to be nearly five times that in non-inflamed oral mucosa (Greening and Schonfeld, 1980). Immunoglobulins have also been shown in plasma cells residing in the periapical cyst wall (Toller and Holborow, 1969; Pulver et al., 1978; Stern et al., 1981; Smith et al., 1987) and in the cyst fluid (Toller and Holborow, 1969; Selle, 1974; Skaug, 1974; Ylipaavalniemi, 1977). Their concentration in the cyst fluid was several times higher than that in blood (Selle, 1974; Skaug, 1974). The specificity of the antibodies present in apical periodontitis may be low, since LPS may act as antigens or mitogens. The resulting antibodies may be a mixture of both mono- and polyclonal varieties. The latter are non-specific to their inducer and therefore are ineffective. However, the specific monoclonal component may participate in the antimicrobial response and may even intensify the pathogenic process by forming antigen-antibody complexes (Torabinejad et al., 1979). Intracanal application of an antigen against which the animal had been previously immunized resulted in the induction of a transient apical periodontitis (Torabinejad and Kriger, 1980).
| (IV) Pathogenesis of Apical Periodontitis Lesions |
|---|
|
TopPreviousNext |
|---|
). The equilibrium at the periapex, in favor of or against the host defense, determines the histological picture of the lesions.
|
). But the inflammation can also be induced by accidental trauma, injury from instrumentation, or irritation from chemicals and endodontic materials, each of which can provoke an intense tissue-response of short duration. The process is accompanied by clinical symptoms such as pain, tooth elevation, and tenderness to pressure on the tooth. Such initial, symptomatic lesions are viewed as the acute apical periodontitis (acute periradicular periodontitis [AAE, 2003] [Fig. 4a]). It must be pointed out that, except for the outcome, there is no clear distinction between aseptic and infectious inflammations. The tissue response is generally limited to the apical periodontal ligament and the neighboring spongiosa. It is initiated by the typical neuro-vascular response of inflammation, resulting in hyperemia, vascular congestion, edema of the periodontal ligament, and extravasation of neutrophils. The latter are attracted to the area by chemotaxis, induced initially by tissue injury, bacterial products (LPS), and complement-factor C5a. Since the integrity of bone, cementum, and dentin has not yet been disturbed, the periapical changes at this stage are radiographically undetectable. If non-infectious irritants induced the inflammation, the lesion may resolve, and the structure of the apical periodontium may be restored (Andreasen, 1985).
|
) but also release leukotrienes and prostaglandins. The former (LTB4) attract more neutrophils and macrophages into the area, and the latter activate osteoclasts. In a few days’ time, the bone surrounding the periapex can be resorbed, and a radiolucent area may become detectable at the periapex (Stashenko et al., 1992). This initial rapid bone resorption can be prevented by indomethacin (Torabinejad et al., 1979; Torabinejad and Kriger, 1980) that inhibits cyclo-oxygenase, thus suppressing prostaglandin synthesis. Neutrophils die at the inflammatory site (Fig. 3a) and release enzymes from their cytoplasmic granules that cause destruction of the extracellular matrices and cells. The self-induced destruction of the tissues prevents the spread of infection to other parts of the body and provides space for the infiltration of specialized defense cells. During the acute phase, macrophages also appear at the periapex. Activated macrophages produce a variety of mediators, among which the pro-inflammatory (IL-1, -6, and TNF-) and chemotactic (IL-8) cytokines are of particular importance. These cytokines intensify the local vascular response, osteoclastic bone resorption, and effector-mediated degradation of the extracellular matrices and can place the body on a ‘general alert’ by endocrine action, to raise the output of acute-phase proteins by hepatocytes (Lerner, 1994). They also act in concert with IL-6 to up-regulate the production of hematopoietic colony-stimulating factors, which rapidly mobilize the neutrophils and the pro-macrophages from bone marrow. The acute response can be intensified, particularly in later stages, by the formation of antigen-antibody complexes (Torabinejad et al., 1979; Torabinejad and Kriger, 1980). Acute primary apical periodontitis has several possible outcomes, such as: spontaneous healing, further intensification and spreading into the bone (alveolar abscess), open to the exterior (fistulation or sinus tract formation), or becoming chronic.
(B) ESTABLISHED CHRONIC APICAL PERIODONTITIS
A prolonged presence of microbial irritants leads to a shift in the neutrophil-dominated lesion to a macrophage-, lymphocyte-, and plasma-cell-rich one, encapsulated in collagenous connective tissue. Such asymptomatic, radiolucent lesions can be visualized as a ‘lull phase’ following an intense phase in which PMNs die en masse, the ‘foreign intruders’ having been temporarily beaten and held in the root canal (Fig. 2). The macrophage-derived pro-inflammatory cytokines (IL-1, -6; TNF-) are powerful lymphocyte stimulators. The quantitative data on the various types of cells residing in chronic periapical lesions may not be representative. Nevertheless, investigations based on monoclonal antibodies suggest a predominant role for T-lymphocytes and macrophages. Activated T-cells produce a variety of cytokines that down-regulate the output of pro-inflammatory cytokines (IL-1, -6, and TNF-), leading to the suppression of osteoclastic activity and reduced bone resorption. In contrast, the T-cell-derived cytokines may concomitantly up-regulate the production of connective tissue growth factors (TGF-ß), with stimulatory and proliferative effects on fibroblasts and the microvasculature. Th1 and Th2 cell populations may participate in this process (Stashenko et al., 1998; Gemmell et al., 2002). The option to down-regulate the destructive process explains the absence of or retarded bone resorption and the rebuilding of the collagenous connective tissue during the chronic phase of the disease. Consequently, the chronic lesions can remain ‘dormant’ and symptomless for long periods of time without major changes in radiographic status. But the delicate equilibrium prevailing at the periapex can be disturbed by one or more factors that may favor the micro-organisms ‘stationed’ within the root canal. The microbes may advance into the periapex (Fig. 5), and the lesion spontaneously becomes acute with re-occurrence of symptoms (excerbating apical periodontitis, Phoenix abscess). As a result, micro-organisms can be found extraradicularly during these acute episodes, with rapid enlargement of the radiolucent area. This radiographic feature is due to apical bone resorption occurring rapidly during the acute phases, with relative inactivity during the chronic periods. The progression of the disease, therefore, is not continuous, but happens in discrete leaps after periods of ‘stability’.
Chronic apical periodontitis is commonly referred to as ‘solid dental’ or ‘periapical granuloma’. It consists of a granulomatous tissue with infiltrate cells, fibroblasts, and a well-developed fibrous capsule. Serial sectioning shows that about 45% of all chronic periapical lesions are epithelialized (Nair et al., 1996). When the epithelial cells begin to proliferate, they may do so in all directions at random, forming an irregular epithelial mass in which vascular and infiltrated connective tissue becomes enclosed. In some lesions, the epithelium may grow into the entrance of the root canal, forming a plug-like seal at the apical foramen (Malassez, 1885; Sonnabend and Oh, 1966; Nair and Schroeder, 1985). The epithelial cells generate an ‘epithelial attachment’ to the root surface or canal wall which, in TEM, reveals a basal lamina and hemidesmosomal structures (Nair and Schroeder, 1985). In random histological sections, the epithelium in the lesion appears as arcades and rings. The extra-epithelial tissue predominantly consists of small blood vessels, lymphocytes, plasma cells, and macrophages. Among the lymphocytes, T-cells are likely to be more numerous than B-cells (Cymerman et al., 1984; Nilsen et al., 1984; Torabinejad and Kettering, 1985; Kopp and Schwarting, 1989), and CD4+ cells may outnumber CD8+ cells (Lukic et al., 1990; Piattelli et al., 1991; Barkhordar et al., 1992; Marton and Kiss, 1993) in certain phases of the lesions. The connective tissue capsule of the lesion consists of dense collagenous fibers that are firmly attached to the root surface, so that the lesion may be removed in toto with the extracted tooth.
(C) ESTABLISHED CYSTIC APICAL PERIODONTITIS (RADICULAR CYSTS)
Periapical cysts are a direct sequel to chronic apical periodontitis, but not every chronic lesion develops into a cyst. Although the reported incidence of cysts among apical periodontitis lesions varies from 6 to 55% (for review, see Nair, 1998a), investigations based on meticulous serial-sectioning and strict histopathological criteria (Sonnabend and Oh, 1966; Simon, 1980; Nair et al., 1996) have showed that the actual incidence of the cysts may be well below 20%. There are two distinct categories of radicular cysts, namely, those containing cavities completely enclosed in epithelial lining (Fig. 6), and those containing epithelium-lined cavities that are open to the root canals (Fig. 7; (Simon, 1980; Nair et al., 1996). The latter was originally described as ‘bay cysts’ (Simon, 1980) and has been newly designated as ‘periapical pocket cysts’ (Nair et al., 1996). More than half of the cystic lesions are true apical cysts, and the remainder are apical pocket cysts (Simon, 1980; Nair et al., 1996). In view of the structural difference between the two categories of cysts, the pathogenic pathways leading to their formation may differ in certain respects.
|
|
), with a lumen open to the necrotic root canal, can grow would eliminate osmotic pressure as a potential factor in the development of radicular cysts (Nair et al., 1996; Nair, 1997). Although no direct evidence is yet available, the tissue dynamics and the cellular components of radicular cysts suggest possible molecular pathways for cyst expansion. The neutrophils that die in the cyst lumen provide a continuous source of prostaglandins (Formigli et al., 1995), which can diffuse through the porous epithelial wall (Shear, 1992) into the surrounding tissues. The cell population residing in the extra-epithelial area contains numerous T-lymphocytes (Torabinejad and Kettering, 1985), and macrophages produce a battery of cytokines, particularly the IL-1ß. The prostaglandins and the inflammatory cytokines can activate osteoclasts, culminating in bone resorption. The presence of effector molecules (MMP-1 and -2) has also been reported in human periapical cysts (Teronen et al., 1995).
(2) Periapical pocket cyst
This is probably initiated by the accumulation of neutrophils around the apical foramen in response to the bacterial presence in the apical root canal (Nair et al., 1996; Nair, 1997). The micro-abscess so formed can become enclosed by the proliferating epithelium, which, on coming into contact with the root-tip, forms an epithelial collar with ‘epithelial attachment’ (Nair and Schroeder, 1985). The latter seals off the infected root canal with the micro-abscess from the periapical tissue milieu. When the externalized neutrophils die and disintegrate, the space they occupied becomes a microcystic sac. The presence of microbes in the apical root canal, their products, and the necrotic cells in the cyst-lumen attract more neutrophils by a chemotactic gradient. However, the pouch-like lumen—biologically outside the periapical milieu—acts as a ‘death trap’ for the transmigrating neutrophils. As the necrotic cells accumulate, the sac-like lumen enlarges and may form a voluminous diverticulum of the root canal space, extending into the periapical area (Nair et al., 1996; Nair, 1997). Bone resorption and degradation of the matrices, occurring in association with the enlargement of the pocket cyst, are likely to follow a similar molecular pathway, as in the case of the true periapical cyst (Nair et al., 1996). From the pathogenic, structural, tissue-dynamic, and host-benefit points of view, the pouch-like extension of the root canal space has much in common with a marginal periodontal pocket, justifying the name ‘periapical pocket cyst’ (Nair et al., 1996).
| (V) Causes of Endodontic Failures |
|---|
|
TopPreviousNext |
|---|
(A) INTRARADICULAR INFECTION
Microscopic examination of periapical tissues removed during apical surgery has long been a method for the investigation of causes of failure in root-canal-treated teeth. Early investigations of apical biopsies had several limitations, such as the use of unsuitable specimens and inappropriate methodology and criteria for analysis (Seltzer et al., 1967; Andreasen and Rud, 1972b; Block et al., 1976; Langeland et al., 1977; Lin et al., 1991). Therefore, these studies failed to yield relevant information about the reasons for apical periodontitis persisting as asymptomatic radiolucencies, even after proper conventional endodontic treatment.
In a histological analysis of apical specimens of failed cases (Seltzer et al., 1967), there was not even a mention of persisting microbial infection as a potential cause of the failures. A histo-bacteriological study, with the use of serial-step-sectioning and special bacterial stains, found bacteria in the root canals of 14% of the 66 specimens examined (Andreasen and Rud, 1972a). Two other studies analyzed 230 and 35 endodontic surgical specimens, respectively, by routine paraffin histology (Block et al., 1976; Langeland et al., 1977). Although bacteria were found in 10 and 15% of the respective biopsies, intraradicular infection was detected in only a single specimen in each study. In the remaining biopsies in which bacteria were found, the data also included those specimens in which bacteria were found as ‘contaminants on the surface of the tissue’. In yet another study, ‘bacteria and or debris’ was found in the root canals of 63% of the 86 endodontic surgical specimens (Lin et al., 1991), although it is obvious that ‘bacteria and debris’ cannot be equated as etiological agents in endodontic treatment failures. The low reported incidence of intraradicular infections in these studies is primarily due to a methodological inadequacy, since micro-organisms easily go undetected when the investigations are based on random paraffin sections alone. This has been convincingly demonstrated (Nair, 1987; Nair et al., 1990a). Consequently, persisting intraradicular infection has not been considered as a factor in endodontic failures.
To identify potential etiological agents in asymptomatic endodontic failures by microscopy, one must select the cases from teeth that have had the best possible orthograde root canal treatment, and the radiographic lesions must remain asymptomatic until surgical intervention. The specimens must be anatomically intact block-biopsies that include the apical portions of the roots and the soft tissue of the lesions. Such specimens should undergo meticulous investigation by serial or step-serial sections that are analyzed with the use of correlative light and transmission electron microscopy. A study that met these criteria and also bacterial monitoring before and during treatment revealed intraradicular micro-organisms in 6 of the 9 block biopsies (Fig. 8) (Nair et al., 1990a). The findings showed conclusively that the majority of root-canal-treated teeth evincing asymptomatic apical periodontitis harbor persistent infection in the apical portion of the root canal. However, the proportion of failed cases with intraradicular infection is likely to be much higher in routine endodontic practice than the two-thirds of nine cases reported (Nair et al., 1990a) for several reasons, particularly the absence of routine microbial monitoring of the root canals in ‘field conditions’. At the light microscopic level, it was possible to detect bacteria in only one of the six cases (Nair et al., 1990a). Micro-organisms were found as aggregates located within small canals of apical ramifications (Fig. 8) of the root canal or in the space between the root fillings and the canal wall. This demonstrates the inadequacy of conventional paraffin techniques for detecting infections in apical biopsies.
|
