Acta Odontologica Scandinavica

ISSN: 0001-6357 (Print) 1502-3850 (Online) Journal homepage: https://www.tandfonline.com/loi/iode20

Inflammatory profile of chronic apical

periodontitis: a literature review

Paulo Henrique Braz-Silva, Mariana Lobo Bergamini, Andressa Pinto

Mardegan, Catharina Simioni De Rosa, Bengt Hasseus & Peter Jonasson

To cite this article: Paulo Henrique Braz-Silva, Mariana Lobo Bergamini, Andressa Pinto
Mardegan, Catharina Simioni De Rosa, Bengt Hasseus & Peter Jonasson (2019) Inflammatory
profile of chronic apical periodontitis: a literature review, Acta Odontologica Scandinavica, 77:3,
173-180, DOI: 10.1080/00016357.2018.1521005

To link to this article: https://doi.org/10.1080/00016357.2018.1521005

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Published online: 26 Dec 2018.

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ACTA ODONTOLOGICA SCANDINAVICA
2019, VOL. 77, NO. 3, 173–180
https://doi.org/10.1080/00016357.2018.1521005

REVIEW ARTICLE

Inflammatory profile of chronic apical periodontitis: a literature review

Paulo Henrique Braz-Silvaa,b , Mariana Lobo Bergaminia, Andressa Pinto Mardegana,
Catharina Simioni De Rosaa, Bengt Hasseusc and Peter Jonassond
a
Division of General Pathology, Department of Stomatology, School of Dentistry, University of Sao Paulo, Sao Paulo, Brazil; bLaboratory of
Virology, Institute of Tropical Medicine of Sao Paulo, University of Sao Paulo, Sao Paulo, Brazil; cDepartment of Oral Medicine and
Pathology, Institute of Odontology, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; dDepartment of
Endodontology, Institute of Odontology The Sahlgrenska Academy University of Gothenburg, Gothenburg, Sweden

ABSTRACT ARTICLE HISTORY

Apical periodontitis caused by root canal infection is the most frequent pathological lesion in the Received 20 April 2018
jaws, mainly manifested as periapical granulomas and cysts. Understanding of the formation and pro- Revised 5 August 2018
gression of apical periodontitis as well as the identification of inflammatory biomarkers can help Accepted 4 September 2018
increase the knowledge of pathogenic mechanisms, improve the diagnosis and provide support for
KEYWORDS
different therapeutic strategies. The objective of the present article is to review inflammatory bio- Apical periodontitis;
markers such as cytokines, chemokines, inflammatory cells, neuropeptides, RANK/RANKL/OPG system endodontic inflammation;
and other inflammatory markers and to relate these systems to the development and progression of inflammation mediators;
pathological conditions related to apical periodontitis. osteoprotegerin;
RANK ligand

Introduction It is known that microbial antigens from the root

canal infection are capable to stimulate both specific and
Apical periodontitis (AP) is a prevalent infectious disease
non-specific immune responses in periapical tissue [14,15].
worldwide and is characterised by an inflammatory response
The inflammatory cell infiltrate in granulomas and radicular
and bone destruction in the periapical tissues caused by
cysts is primarily mononuclear cells. The interaction between
microbial infection in the dental pulp [1–3]. AP is the most
cells, cytokines and other inflammatory elements present in
frequent inflammatory lesion related to teeth in the jaws.
AP, including their specific functions, is not completely eluci-
The jaws are unique in comparison with other bones in the
dated [16–19].
body as the presence of teeth creates a direct pathway
Studies have demonstrated that macrophages, mastcells,
towards the bone marrow, with no epithelial barriers against
T cells and neutrophils participate in the formation of AP,
infectious and inflammatory agents if the dental pulp
also including cytokines, chemokines and RANK/RANKL/OPG
becomes necrotic and infected. Hence, tissue- and immuno-
(Receptor Activator of Nuclear Factor kappa B ligand/osteo-
logical responses are fundamental for protecting from the
protegerin) system [6,19,20]. The great amount and interac-
spread of infectious agents to other locations. Due to the
tions of various inflammatory stimuli can influence and alter
state of the infection in the root canal, acute or chronic
the state and progression of the disease [21–23].
inflammatory reaction can develop. In AP, bone destruction
The objective of this article is to review inflammatory bio-
is caused by both microbial infection and immune response
markers related to the development and progression of
as part of the defence reaction [1–3].
chronic AP, which can help increase the knowledge of patho-
Histologically, AP is classified as abscess, granuloma or
genic mechanisms. A computerized literature search was
radicular cyst [4–6]. Periapical abscess reflects a formation of
conducted on the PubMed database for studies evaluating
pus as a consequence of a shift in cellular dynamics in
the human and animal inflammatory response in the periapi-
response to an acute infection, whereas periapical granulomas
cal tissue published from 1965 to 2018. This resulted in 87
consist of granulation tissue with inflammatory cells, fibro-
included articles that were read in full text.
blasts and well-developed fibrous capsule. The granuloma
may eventually evolve into radicular cysts when epithelial
rests of Malassez, located in the periodontal tissue, are stimu-
lated by the immunological response to proliferate [7–13].

CONTACT Peter Jonasson Peter.Jonasson@odontologi.gu.se Department of Endodontology, Institute of Odontology, The Sahlgrenska Academy, University
of Gothenburg, Medicinaregatan 12, Gothenburg, 41390, Sweden
ß 2018 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.
This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License (http://creativecommons.org/licenses/by-nc-nd/4.
0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited, and is not altered, transformed, or built upon in
any way.
174 P. H. BRAZ-SILVA ET AL.
Review
Infection and inflammatory response
AP is essentially an inflammatory disease of microbial aeti-
ology. Knowledge of microbial location, organisation and
virulence factors within the root canal system is important
for understanding the disease process. Although fungi,
archaea and viruses have been found in association with AP,
bacteria are the main microbial aetiological agents.
Microbiota are found in highly organised and complex enti-
ties, known as multi-species biofilms mainly located inside
the root canal. In specific circumstances, microorganisms can
overcome the defence barrier and even establish an extra-
radicular infection [24,25].
There is a clear evidence that microbial interaction
plays an important role for the pathogenesis of AP [25,26].
Microorganisms may cause direct tissue damage and modu-
late the immunological response by secretion of products,
including enzymes, exotoxins and metabolic end-products
[27–29]. Based on the variation in root-canal infection with
different virulence factors, the immunological response caus-
ing AP will vary over time.
Inflammatory cells
Distinct sub-populations of inflammatory cells have been
described in AP. Neutrophils and their interaction with micro-
organisms are of particular importance in the acute phase as
first line of defence and for progression of AP, causing tissue
damage and chemotaxis. Mast cells and macrophages are
related to important components of the inflammatory infil-
trate of chronic AP, although one cannot know exactly how
these cells are associated with the production of Interleukin-
6 (IL-6) and other inflammatory mediators. A study on the
distribution of these cells in periapical cysts showed that
mast cells have the capacity to degranulate and produce sev-
eral inflammatogenic substances, such as vasoactive media-
tors [19]. The release of these substances is directly related
to inflammatory events and bone resorption, also influencing
other cells of the immune system [19].
Studies have compared the presence of mast cells in peri-
apical granulomas and cysts, confirming that these cells are
found in great amount in the latter. In addition, it was
observed that mast cells are widely found in sub-epithelial
regions rather than in the deep regions of the cystic capsule.
These results would explain the growth trend of the cysts as
these cells account for the release of inflammatory media-
tors, such as tumour necrosis factor a (TNF-a), interleukin-1b
(IL-1b), macrophage inflammatory protein-1a (MIP-1a) and
monocyte chemoattractant protein-1 (MCP-1). Mast cell
degranulation may cause inflammatory and vascular changes,
thus contributing to the development and expansion of the
cysts [30–32].
Macrophages, in turn, are capable to produce pro- and
anti-inflammatory substances which act on the development
and repair of these lesions by secreting soluble IL-1a, TNF-a,
IL-6, TGF-b (Transforming growth factor beta) and prosta-
glandins. These cytokines play a role in the initiation and
regulation of inflammatory processes through activation and
differentiation of osteoclasts, activation and proliferation of
fibroblasts, production of collagen and neo-vascularisa-
tion [12,19,33].
T cells are abundant in AP, but the activation and func-
tion of these cells are yet not well understood. Several regu-
latory circuits are activated by T cells, influencing not only
the immune system, but also the interaction with other cells,
oral epithelium and oral bacteria. T helper 1 (Th1) and
T helper 2 (Th2) cell responses modulate the expression of
IL-1, which according to IhanHren and Ihan [34], might be
the main mediators of bone resorption and activator of mac-
rophages in the context of AP. A larger population of acti-
vated T cells was found in granulomas compared to cysts,
with a Th1/Th2 ratio being similar between cysts and granu-
lomas [34,35].
According to some studies, Th1 and Th2 response pat-
terns occur concomitantly [6,34]. It is believed that the Th1
immune response is involved in both lesion progression and
bone destruction, whereas Th2 involves immunosuppressive
mechanisms which are important in the repair process,
occurring in the more advanced stages of lesion develop-
ment [35]. This is demonstrated in experimental models in
which absence of Th1 cytokines does not alter significantly
the lesion development, whereas the lack of Th2 cytokines
results in an increase in lesion size [14,36]. This concept,
however, needs to be reviewed as recent findings indicate a
pattern characterised by the presence of IL-17, a cytokine dif-
ferent from the traditional Th1 and Th2 lines [34].
The predominance of Th1 response in granulomas and
Th2 in cysts is demonstrated by authors who suggest
that both immune responses can be suppressed by regula-
tory T cells (Tregs) through mechanisms depending on cell
contact and/or production of IL-10 and TGF-b [36,37]. An
increase in the expression of IL-10 and FoxP3 can be
observed in granulomas compared to cysts, which suggests
that Treg cell population is present to a higher extent in the
former [36]. Francisconi et al. [37] suggest that the use of
Treg chemoattractants could be a promising strategy for clin-
ical management of AP, since the migration of these cells
switches active lesion into inactivity phenotypes [37].
There are still studies reporting a predominance of Th1
response in lesions mainly mediated by T cells, whereas
lesions mediated by B cells and/or plasma cells exhibit a Th2
response [15]. Some authors suggest that T cells would be
involved in the beginning and development of the lesion,
whereas B cells would in turn be involved in the process of
repair [38].
New subsets of T-helper cells (e.g. Th9, Th17 and Th22)
have been recently discovered, including their prototypic
cytokines IL-9 and IL-22. It was found that the expression of
IL-9 and IL-22 is predominant in inactive lesions, suggesting
the existence of a possible protective role of these cytokines
in the pathogenesis of AP [39]. Aranha et al. [39] demon-
strated the over-expression of IL-9 in inactive granulomas
and a negative correlation with TNF-a, IFN-c and IL-17 in the
lesions [39]. Studies with experimental models of AP in mice
also showed that IL-9 expression seems to help in the

control of the lesion as no differences were observed in its
extension. However, further studies are needed to determine
the immunosuppressive role of IL-9 and IL-22 in AP
[23,39,40]. Oseko et al. [41] showed that IL-17 knockout mice
are resistant to the development of experimental AP, indicat-
ing a role for Th17 cells and their cytokine production in the
inflammatory process [41].
Langerhans cells, a subset of dendritic cells, are found in
AP and seem to be strongly related to the chemotaxis of T
cells with an epithelial proliferative potential. An increase in
the density of Langerhans cells may be one of the factors
associated with the development of lesions with more
intense inflammatory infiltrates. Discrepant results were
found in studies aimed at detecting these cells in periapical
cysts and granulomas. This fact may be attributed to the
apoptosis process the dendritic cells undergo after presenta-
tion of an antigen, tissue repair process characterised by
lower number of these cells, maturation profile of these cells
and difference in the methods used by authors [42–44].
Cytokines
Cytokines are proteins secreted by cells into injured tissues
in response to microbial agents and other injuries through
recruitment of leucocytes [21]. Together with prostaglandins,
cytokines participate in the initiation and regulation of
inflammatory processes through activation and differenti-
ation of osteoblasts, activation and proliferation of fibro-
blasts, production of collagen and neo-vascularisation [21].
IL-17 and TGF-b are two important cytokines found in
apical periodontitis, being secreted mainly by Th17 cells and
Tregs, respectively. They seem to interact with each other,
thus characterising the action of pro-inflammatory and
immunoregulatory cytokines. These cytokines have opposite
effects, but with no mutual inhibition. While TGF-b is a
potent immune-modulating cytokine, IL-17 is capable to
reactivate the inflammatory process by stimulating the pro-
duction of IL-8 [38,43], meaning that re-acutisation of chronic
apical periodontitis is closely related to higher levels of IL-17
and increased infiltration of leukocytes [12,13].
Higher levels of IL-17 were observed in patients with fistu-
lae and exhibiting mixed inflammatory infiltrate, which in
turn promotes exacerbation of the inflammatory response
and increases the number of neutrophils and bone resorp-
tion [13,14]. IL-17 seems to attract neutrophils and might
also induce the production of RANK-L by activating osteo-
clasts, involved in the bone resorption present in AP [19].
Nevertheless, there are studies attributing a protective role
to IL-17 in the bone resorption process as a result of the
control this cytokine exerts in the expression of chemokines
and recruitment of neutrophils. Therefore, the oppositional
influence of IL-17 on the regulation of neutrophils would
outweigh its potential of causing bone destruction [34].
High levels of TGF-b may be important for the resolution
of AP, since this factor not only inhibits bone resorption and
promotes tissue remodelling and repair by stimulating syn-
thesis of collagen, neo-vascularisation and proliferation of
fibroblasts, but it also seems to be involved in the
ACTA ODONTOLOGICA SCANDINAVICA 175
differentiation of Treg and Th17. Therefore, TGF-b drives the
immune response into a suppressive mode by inducing and
recruiting Tregs in order to restrain the inflammatory reac-
tion, whereas low numbers of Tregs drive the immune
response into Th17 in order to stimulate the inflammatory
process [12].
IL-6 is an important cytokine in bone re-modelling and
activation and differentiation of immune cells and osteo-
clasts, with macrophages being the main sources in periapi-
cal cysts [19,20,45,46]. High levels of IL-6 in AP seem to be
correlated with symptomatic and active lesions [45]. IL-6 is
an important pro-inflammatory biomarker and some recent
studies aimed to correlate the expression in AP (as a reser-
voir of inflammatory cytokines) with blood levels in order to
verify the relationship of these lesions with systemic inflam-
matory conditions, showing very conflicting results [3,47–49].
Analysis of the number of macrophages and TNF-a levels
in cyst capsules showed a positive correlation with capsule
thickness. In fact, the expression of TNF-a was correlated
with the amount of macrophages in cystic walls, since they
are the main source of TNF-a. A relationship between
amount of macrophages in tissues surrounding the cyst and
high expression of TNF-a was also determined, thus indicat-
ing a correlation between production of this cytokine and
tissue vascularisation in cysts as well as between angiogen-
esis and inflammation [50].
Chemokines
Chemokines represent a family of small proteins (8-10kD)
which are associated with migration and activation of leuko-
cytes and selectins, with the latter accounting for the adhe-
sion of inflammatory cells to the vessel walls in different
inflammatory cells [13]. Silva et al. [6] demonstrated the
expression of chemokines receptors (i.e. CCR1, CCR2, CCR3,
CCR5, CXCR1, CXCR3) in both periapical granulomas and
cysts. These receptors are found in Th1 and Th2 cells as well
as in monocytes and neutrophils [1,3–5], with Th1 cells
expressing predominantly chemokine receptors CCR5 and
CXCR3, Th2 cells expressing mainly CCR4 and CCR3, and
monocytes/macrophages expressing CCR2 and CCR5 [34].
High levels of chemokine CXCL12/SDF-1 are found in peri-
apical inflammatory lesions, with CD117þ mast cells being
the main source expressing this chemokine in this type of
lesion. It is suggested that CXCL12/SDF-1 plays an important
role in the destruction of the periapical tissue, probably
inducing infiltration by immune cells, especially mast
cells [51].
High levels of chemokines RANTES, IP-10 and MCP-1,
including chemokine receptors CCR3, CCR5, CXCR1, CXCR3 in
periapical cysts, may be related to a possible evolution of
granulomas and cysts. However, the mechanisms involved
are poorly understood, suggesting a possible involvement of
cytokines in the proliferation of epithelial rests of
Malassez [6].
176 P. H. BRAZ-SILVA ET AL.
RANK/RANKL/OPG system
Odontogenic cysts are lesions characterised by local
bone destruction, in both development and inflammatory
groups. The RANK/RANKL/OPG system is an important
bone metabolism regulator which acts on differentiation and
activity of osteoclasts. RANK is a transmembrane protein – a
member of the tumour necrosis factor receptor family – and
expressed mainly by macrophages, pre-osteoclastic mono-
nuclear cells, T- and B cells, dendritic cells and fibroblasts.
RANKL (Receptor Activator of Nuclear Factor kappa B ligand)
is a cytokine similar to TNF-a and acts as a ligand of RANK
and osteoprotegerin (OPG) [52,53]. Activation of RANK by
RANKL results in its interaction with TNF-associated recep-
tors, activation of nuclear factor kB (NF-kB) and protein c-Fos,
all being related to the maturation of osteoclasts through
the increased expression of specific genes [52,54]. On the
other hand, the OPG soluble receptor, also produced by
osteoclasts, is capable to block the interaction RANK/RANKL
by binding to RANKL and preventing osteoclastic differenti-
ation and activation, thus reducing the bone resorp-
tion [53,55,56].
Imbalance in this system is found in some diseases, such
as rheumatoid arthritis and osteoporosis [56]. High levels of
RANKL have been associated with an increase in osteoclastic
activity, thus favouring bone resorption, whereas higher lev-
els of OPG exert an inhibitory effect on the survival of osteo-
clasts, thus reducing the bone resorption capacity [36,57].
This fact is already well established in the literature as sam-
ples of AP were shown to have higher levels of RANKL and
OPG than the levels found in healthy tissues [23,58,59].
The comparison between expressions of RANKL and OPG
in odontogenic lesions with biologically different behaviours
(e.g. radicular cysts, dentigerous cysts, solid ameloblastomas
and keratocysts) shows a higher immune-detection of RANKL
as well as a lower immune-detection of OPG in the latter
two lesions compared to the former two, which is compat-
ible to the more aggressive behaviour of ameloblastomas
and keratocysts [60]. Despite these expected findings, there
are studies reporting a higher number of OPG þ than
RANKL þ cells in keratocystic capsules [61] and lining epithe-
lium of dentigerous and radicular cysts [57]. This demon-
strates that discrepant results may be found by different
authors, probably due to differences in their methods and
also to the developmental stage of the lesion [6,57].
In addition, it was observed that the expression of
RANKL/OPG is not significantly different between symptom-
atic and asymptomatic AP, but a positive correlation was
found between number of bacteria and levels of OPG in
symptomatic AP [62,63]. Santos et al. [64] investigated the
participation of RANKL, OPG, IL-33, cathepsin K and TNF-a
in radicular cysts and periapical granulomas, demonstrating
that there was a higher immune-expression of these mole-
cules in connective tissue cells (capsule of radicular cysts),
which indicates that RANKL, OPG, IL-33, cathepsin K and
TNF-a stimulate the osteolytic activity. Differently from
radicular cysts, however, levels of OPG were found to be
rather lower compared to RANKL and cathepsin K in peri-
apical granulomas, suggesting that these lesions are more
stable as OPG competes with RANKL by preventing its
binding to RANK, thus impeding the osteolytic activ-
ity [64].
The complex process of bone resorption involves other
bone metabolism-related factors rather than RANKL and OPG
mediators, such as TNF-a and macrophage colony-stimulat-
ing factor, showing that bone metabolism can be directly
associated with the inflammatory conditions [46,60]. An
immune-regulatory role of RANKL has been recently
described, mediated by the induction of Treg development
and resulting in an antigen-specific immunologic hypo-
responsiveness, with arrest of the periapical lesion progres-
sion in animal model [65].
Armada et al. [66] analysed the expression and distribu-
tion of RANK, RANKL and OPG in periradicular cysts and
found higher expressions of RANK and RANKL in the con-
nective tissue during presence of chronic inflammatory
infiltrate compared to mixed inflammatory infiltrate.
Another study investigated the possible association
between expressions of RANKL and OPG and inflammatory
infiltrate in the chronic AP, demonstrating that RANKL
expression was increased in chronic inflammatory infiltrate
containing lymphocytes (T and B cells) and macrophages
[67]. These findings are corroborated by the fact that other
cells rather than osteoblasts, such as fibroblasts and lym-
phocytes T and B, express a greater amount of
RANKL [66,67].
Neuropeptides
Neuropeptides are conceptualised as neurotransmitters of
peptides or neuromodulators [68] as they determine their
synthesis and release from neurons and have biological
actions mediated by extracellular receptors on target cells
[69]. The involvement of afferent neuron fibres in peripheral
inflammatory processes has been studied for more than a
century, and the excitation of these fibres is known to lead
to vasodilatation and subsequent oedema [68,69].
The term ‘neurogenic inflammation’ describes the compo-
nent of the inflammatory process triggered by an appropri-
ate stimulus applied to peripheral neurons, resulting in the
release of neuropeptides that alter multiple processes,
including vascular permeability, hypersensitivity and vasodila-
tation at the injury site [68]. From these findings, studies
have focussed on the role of neuropeptides, including sub-
stance P (SP), vasoactive intestinal polypeptide (VIP), neuro-
peptide Y (NPY), calcitonin gene-related peptide (CGRP) and
neurokinin A (NKA) [68,69].
Neuropeptides have been associated with the develop-
ment of AP due to their abundant innervation. Studies dem-
onstrate that VIP is related to growth and maturation
processes of the lesion, since it was associated with bone
resorption and regulation of osteoclast functions [68,70]. SP
array in immune cells located in periradicular granulomas
has also been reported, with SP being expressed cytoplas-
matically in macrophages in acute and chronic inflammatory
lesions [68,71].

Experimental studies support the involvement of CGRP in
bone remodelling. Reduction of active osteoclasts in induced
periapical lesions was observed when the density of the
nerve fibres of the immune-reactive CGRP reached its peak,
suggesting a possible role for CGRP in inhibiting reabsorp-
tion [68,72,73]. CGRP receptors have been found in osteo-
blasts, providing evidence of the nervous system
s influence
on bone metabolism [68].
Other inflammatory markers
The cell protection mechanism involves the expression of a
polypeptide family called ‘heat-shock’ proteins (HSPs) [74],
which play a protective role against harmful environmental
conditions and pathogens. HSPs are characteristically
induced by stress signals, such as inflammatory mediators,
high temperature, reduced oxygen supply, and infectious
agents, playing important roles in the doubling and trans-
location of polypeptides through the cell’s membrane [75].
According to their molecular weight, HSPs are sub-divided
into the following groups: HSPH (HSP110), HSPC (HSP90),
HSPA (HSP70), DNAJ (HSP40), HSPD (HSP60) and HSPB
(HSP27) [74,75].
Goodman et al. [74] compared the expression of 44 HSP
genes in human periapical granulomas and cell culture with
healthy periodontal ligament tissue (control) in macrophages
with and without LPS treatment, revealing that members of
the families of genes HSP27 (HSPB1), HSP40 (HSPA6), HSP70
(DNAJC3) and HSP110 (HSPA4) were significantly over-
expressed in periapical granulomas, especially in active ones
compared to controls, as well as in LPS-treated cells. HSPA-4,
a member of the HSP70 family, showed higher expression in
inactive granulomas. These findings suggest that HSPs can
have modulatory functions during the development of peri-
apical lesion and that different heat-shock genes/proteins
may play different roles in this process [74].
Nitric oxide (NO) is also an important inflammatory medi-
ator involved in the AP. NO is an omnipresent free radical
produced by several cells through a family of enzymes col-
lectively known as NO synthases (NOSs) [76]. Although the
role of NO in AP is unknown, studies have shown that NO
modulates the levels of pro-inflammatory cytokine, such as
IFN-c and TNF-a during the pathogenesis of AP [77].
Cintra et al. [77] assessed the serum levels of TNF-a, IFN-c,
IL-6, IL-17, IL-23 and NO in rats with AP regarding one tooth
or multiple teeth. The findings showed an increase in the
serum levels of IL-6, IL-17, IL-23 and TNF-a in rats with AP
involving multiple teeth. On the other hand, the serum levels
of NO were decreased in rats with AP involving either one
tooth or multiple teeth. The increase in the serum levels of
pro-inflammatory cytokines in rats with AP corroborates the
hypothesis that endodontic infections affect negatively the
systemic health.
Micro-RNAs (miRNAs) are small non-coding RNAs account-
ing for the regulation of gene expression at the post-tran-
scriptional level [78–80]. They act as controllers of several
biological activities, including differentiation, proliferation
and apoptosis [78]. Changes in the miRNA expression affect
ACTA ODONTOLOGICA SCANDINAVICA 177
the expression of its target-genes, thus influencing various
cell signalling pathways [79]. The profile of miRNA expression
can be considered as a diagnostic and prognostic marker in
a number of conditions, including odontogenic tumours [81].
Yue et al. [79] assessed the expression of miRNAs (miR-
29b, 106b, 125b, 143, 155 and 198) associated with inflam-
mation involving AP lesions and human periodontal ligament
fibroblasts (HPDLFs), showing that all of them were signifi-
cantly up-regulated in tissues of asymptomatic AP. On the
other hand, miR-29b, 106b, 125b and 198 were significantly
reduced in acute inflammation involving HPDLFs, whereas
miR-143 and 155 suffered no change, thus suggesting that
miRNA expressions associated with inflammation were differ-
ent between AP lesions and HPDLFs.
Reactive oxygen species (ROS) are unstable, extremely-
reactive molecules capable to transform other molecules
they collide with. ROS are generated in great amount during
oxidative stress (i.e. an imbalance between oxidant anti-oxi-
dant agents), a condition in which proteins, carbohydrates,
lipids and nucleic acids are affected [82]. The production of
ROS is an important defence mechanism against pathogen
invasion, with close involvement of bone resorption in the
case of endodontic lesions [82–87].
During the process of endodontic infection, the binding
of bacterial motifs to Toll-like receptors (TLRs) on the surface
of phagocytes leads to the beginning of phagocytosis,
inducement of humoral and cellular responses (mediated by
lymphocytes B and T, respectively), ROS synthesis and conse-
quent production of inflammatory mediators with cytocines
and metalloproteinases (MMPs) [82,83]. The increased expres-
sion of ROS-related markers has been associated with the
pathogenesis of periapical periodontitis [82–86] at both local
and systemic levels [83,85–87].
Dezerega et al. [83] demonstrated that lesions of asymp-
tomatic AP are characterised by a pro-oxidative profile, with
consequent increase in the expressions of MMP-2 and MMP-
9 compared to healthy tissue. This same difference in profile
was demonstrated in the gingival crevicular fluid, thus show-
ing the potential use of these biomarkers as a possible diag-
nostic tool.
The bone metabolism regulation is also altered in the oxi-
dative stress environment [84]. In a recent study, Jakovljevic
et al. [84] suggested that periapical periodontitis is character-
ised by increased levels of oxidative stress markers, such as
8-hydroxydeoxy guanosine (8-OHdG), oxidised glutathione
(GSSG) and bone resorption regulators (RANKL and OPG),
compared to healthy tissue – a factor which might explain
the process of extensive bone resorption in these lesions.
Conclusion
Understanding the formation process of apical periodontitis,
as well as the inflammatory biomarkers associated with its
development, is important for evaluation of pathogenesis,
diagnosis and development of therapeutic strategies for AP.
Although the inflammatory profile of these lesions is still
poorly understood, it can be concluded that this formation
process is dynamic and that different inflammatory cells and
178 P. H. BRAZ-SILVA ET AL.
their by-products are involved in the process. Nevertheless,
further studies are needed to understand how cellular and
molecular events contribute to the development of AP.
Disclosure statement
The authors have stated explicitly that there are no conflicts of interest
regarding this article.
Funding
This study was supported by grants from Sao Paulo Research
Foundation – FAPESP, Sao Paulo, Brazil [grant no. 2015/07727-9] and
from Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior -
Brasil (CAPES) - Finance Code 001.
ORCID
Paulo Henrique Braz-Silva http://orcid.org/0000-0002-1842-9521
Peter Jonasson http://orcid.org/0000-0002-7541-983X
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