Endod Dent Traumatol 2000; 16: 1–8
C Munksgaard 2000
Printed in Denmark . All rights reserved
Macrophages in periapical lesions
Metzger Z. Macrophages in periapical lesions. Endod Dent
Traumatol 2000; 16: 1–8. C Munksgaard, 2000.
Department of Oral Biology, Goldschleger Schoolof Dental Medicine, Tel Aviv University, Tel Aviv,Israel and Department of Endodontics, University
Abstract – Macrophages are major constituents of periapical granu-
of North Carolina at Chapel Hill, Chapel Hill, North
lomas. They have a central protective role in both innate immunity
and adoptive, antigen-specific immune response. Macrophage acti-vation may occur in periapical granulomas by cytokines producedby antigen-activated T-lymphocytes; by bacterial endotoxin, as partof the innate immunity; or by both these processes. Recent studiesin athymic animals have shown that periapical granulomas maydevelop independently of T-lymphocytes. This observation revealsthe major role that the activated macrophage may have in the
Key words: apical periodontitis; macrophages;
formation of periapical lesions. Only a few of the macrophages in
the periapical granuloma are activated. Current studies indicate
Zvi Metzger, The Goldschleger School of Dental
that these activated cells are the source of the bone-resorbing
Medicine, Tel Aviv University, Ramat Aviv,
cytokines in the periapical granuloma. Understanding the central
Tel Aviv 96978, Israel
role of the activated macrophage in the formation as well as the
Fax: π972 3 6409250e-mail: metzger/post.tau.ac.il
perpetuation of periapical lesions may lead to the development ofnew diagnostic and therapeutic tools in endodontics.
Accepted August 30, 1999
Periapical lesions are an expression of the host re-
specifically identify plasma cells in periapical lesions
sponse which actively prevents dissemination of bac-
by their immunoglobulin content were reported. In
teria from the infected root canal into the surround-
the last decade, intensive use of monoclonal anti-
ing bone. The cells involved in this process include
bodies against subsets of T-lymphocytes, B-lympho-
B- and T-lymphocytes, plasma cells and the ‘‘pro-
cytes, macrophages, dendritic cells, as well as plasma
fessional'' phagocytes: macrophages and PMNs. The
cells and PMNs, resulted in a major breakthrough in
engagement, phagocytosis and killing of bacteria are
the understanding of the immunobiology of periapical
the main tasks of the periapical host response; never-
host response, in both naturally occurring human
theless, formation of these lesions is associated with
periapical lesions and those experimentally induced
bone loss in the area surrounding the root apex. The
resulting radiolucent periapical lesion is one of the
Cells with a distinct morphology such as PMNs,
main clinical manifestations of this inflammatory re-
mast cells and osteoclasts have always been identifi-
sponse, and its progress or healing is commonly
able. This was also the case with lymphocytes as a
evaluated by the size and morphology of the lesion as
group, but not with macrophages. In earlier studies
shown on a radiographic image.
only cells with a classic macrophage morphology
Qualitative and quantitative studies of the cellular
could be identified as such. Currently available mono-
composition of periapical granulomas have been pro-
clonal antibodies make it possible to identify macro-
foundly influenced by the methodology available at
phages of diverse morphology and recognize subsets
the time. Initial attempts to characterize the cells par-
of these cells.
ticipating in these lesions were based on the classic
The purpose of the present review is to examine
morphology of the cells. Electron microscopy and
the role of macrophages in the formation and main-
histochemistry followed later. With the introduction
tenance of these lesions, as it gradually emerges from
of immunohistological methods, the first attempts to
the vast literature on this subject.
inate the invading microorganisms. Macrophages
Presence of macrophages in periapical lesions
present in the periapical granuloma contribute by
The presence of macrophages in human periapical
their function as phagocytes to effectively preventing
inflammatory lesions has been a common and fre-
the dissemination of bacteria from the infected root
quently reported finding. Macrophages constitute up
to 46% of the periapical inflammatory cells found in
Macrophages may also serve as ‘‘antigen-present-
tissue sections of human periapical granulomas (1).
ing cells'' in the essential initial steps of the induction
When Stern et al. (2) dispersed periapical granulomas
of acquired immunity. They process the antigen and
to cell suspensions, 30% of the resulting cells were
present it to the antigen-specific clones of T-helper
macrophages. Macrophages were also found to be the
lymphocytes by a process involving the recognition
predominant inflammatory cell when Kopp &
by the lymphocytes of an MHC II molecule on the
Schwarting (3) used monoclonal antibodies to identify
macrophages. Additionally, they produce the cytokine
them in human periapical lesions. Piattelli et al. (4)
IL-1, which is an essential complementary signal for
have similarly reported that macrophages outnumber
the activation of these lymphocytes. Macrophages
T-lymphocytes in human periapical granulomas.
that carry MHC II molecules, and thus may serve as
In the rat model, Kawashima et al. (5) recently
antigen-presenting cells, have been identified in peri-
demonstrated that macrophages are the predominant
apical granulomas in both humans and the rat model
immunocompetent cells throughout the development
(termed also HLA-DR or Ia antigen-positive cells) (3,
of the lesion. The kinetics of their presence in these
experimental periapical lesions were studied by Aka-
Macrophages are considered a main source of the
mine et al. (6) who followed the periapical lesions for
cytokines IL-1a IL-1b and TNFa, which contribute
as long as 150 days. Macrophages increased in num-
to the initiation and regulation of the inflammatory
bers during the first 10 days, maintained this level
process. Additionally, they produce a plethora of
through day 60, and declined gradually thereafter.
other active molecules, including metallo-proteases(collagenase, elastase), and prostaglandins, which mayalso contribute to the destructive outcome of the peri-
Potential role of macrophages in the periapical
apical inflammatory process. Some of these products
directly damage connective tissue constituents, while
Macrophages have central roles in (a) innate, nonspe-
others, including the cytokines produced by the
cific immunity; (b) the onset, regulation and outcome
macrophages, activate other cells to either (a) destruc-
of antigen-specific, acquired, immunity; and (c) the
tive action such as osteoclast activation and bone re-
regulation of connective tissue destruction and repair.
sorption or (b) the constructive process of repair by
Macrophages are professional phagocytic cells that
activating fibroblast proliferation and collagen pro-
can internalize and kill bacteria by several mechan-
duction by these cells.
isms, some of which are part of the innate immunity
Though it is commonly assumed that all
while others require the presence of specific anti-
above long list of potential activities of the macro-
bodies against the bacterium and should be con-
phage take place in the periapical granuloma, it is not
sidered part of the effector arm of specific, acquired
essentially true. Certain processes may be active while
immunity. Bacteria that are new to the host may acti-
others may rarely occur in this lesion. Similarly, it is
vate the complement system by the alternative path-
commonly implied that all
macrophages perform all
way, resulting in their opsonization by the C3b com-
the above tasks, which similarly is erroneous: subsets
ponent. This in turn will result in their phagocytosis
of these cells, which may exist in relatively small num-
by the macrophages via a C3b-receptor-mediated
bers, may be responsible for a specific activity. Emerg-
process. Other bacteria may attach to the macro-
ing evidence indicates that some of these functions,
phages through lectin-mediated mechanisms, leading
such as active production of IL-1, involve only a few
to lectinophagocytosis, which is independent of the
activated macrophages, which in chronic human peri-
common receptor-ligand binding (7). Once specific
apical granulomas do not exceed 2%–3% of the
antibodies to a bacterium are present, either develop-
macrophages present in these lesions (9).
ing through the course of the current infection or asresult of a former encounter with this bacterium, a
Evolvement of the immunobiological concept of
most efficient form of phagocytosis will occur, involv-
ing dual opsonization by IgG and C3b and the en-gagement of both the Fc and C3b macrophage recep-
Studies that aim to elucidate the immunobiology of
periapical lesions may roughly be divided into three
It is the innate immunity that enables the host to
eras. Early studies concentrated on the production
survive the initial steps of infection, while the ac-
and function of immunoglobulins in these lesions.
quired, specific, immunity allows it to efficiently elim-
Next, the specific T-lymphocyte function was empha-
Macrophages in periapical lesions
sized and their subsets meticulously studied in relation
ripheral blood. These findings were interpreted as an
to periapical inflammation. The third and current era
initial active function of T-lymphocytes, which is later
has been initiated by the use of immunodeficient ani-
down-regulated and controlled by T-suppressor cells.
mal models such as athymic and ‘‘knock-out'' ani-
The balance of their action is expressed in chronic
mals, which reveal the central role that macrophages
periapical lesions, such as those encountered in
have in this complex local host response.
In the long-term perspective the inevitable con-
clusion is that the availability of new methodologies
Protective function of T-lymphocytes in periapical
influenced the type of studies performed and eventu-
ally affected the evolvement of the immunobiologicalunderstanding of the complex nature of periapical
A protective role of T-helper lymphocyte function
should eventually be expressed as a better ability of
Initially, the commercial availability of specific anti-
the host to prevent bacteria from spreading from the
bodies directed against human IgG, IgM, IgA and
infected root canal. This may be accomplished by (a)
IgE allowed immunofluorescent or immunohisto-
producing antibodies locally and (b) increasing the lo-
chemical detection of these molecules in periapical
cal availability of phagocytes and enhancing their
lesions, either in a free form or as a marker of subsets
function (Fig. 1). Local activation of antigen-specific
of B-lymphocytes and plasma cells. Later, the combi-
T- helper lymphocytes is a prerequisite for a local
nation of these antibodies with those directed against
production of antibodies specific to the bacteria that
human complement allowed the demonstration of ac-
periodically emerge from the root canal (16, 17). This
rather than the simple presence
in turn will enable the effective opsonization of the
ulins in periapical lesions: Johannessen et al. (10) have
bacteria, followed by phagocytosis and killing.
demonstrated intracellular colocalization of IgG and
Local macrophage activation is accomplished
C3b in macrophages in periapical inflammatory
mainly by g-interferon produced by the activated T-
lesions, suggesting phagocytosis of bacteria by dual
helper cells (Fig. 1). Even though the activation of the
opsonization by both opsonins.
lymphocytes is antigen-specific, once macrophages
At a later stage, the availability of monoclonal anti-
are activated, the effector result will be nonspecific,
bodies against T-lymphocyte subsets made it possible
and their phagocytic and killing abilities will be
to explore the presence of these cells in both human
greatly enhanced. IL-1 production by activated
periapical lesions as well as in those experimentally
macrophages will locally elevate CAM-1 molecule ex-
induced in rats. T-cells in human periapical granu-lomas were studied by Cymerman et al. and others(11–13). It became apparent that both T-helper andT-suppressor lymphocytes are present in these lesions(11). In delayed hypersensitivity in humans, a typicalT-helper to T-suppressor relation is about 2:1 (14). Itwas therefore of interest to define whether T-lympho-cytes in periapical lesions follow this trend. Babal etal. (12) have found a T-helper to T-suppressor ratiowhich was ∞1.0 in periapical granulomas, while Bar-khordar & Desouza (13) report a ratio of ∂1.0.
Therefore, it seems that the predominance of T-helper lymphocytes, which is typical of delayed hyper-sensitivity, does not exist in the chronic periapicalgranuloma. Nevertheless, this is not a uniform find-ing, as Kopp & Schwarting (3) found a T-helper toT-suppressor ratio of 3:2 in periapical granulomas,which diminished to ∂1.0 in periapical scars.
The rat model allows a further insight into the kin-
etics of T-lymphocyte subsets in the developing peri-apical lesion. Stashenko & Yu (15) demonstrated that
Protective role of activated macrophages and T-lymphocytesin periapical granulomas. T-lymphocyte activation leads to antigen-
during the early, active, phase of lesion development
specific B-lymphocyte activation and local production of specific
T-helper cells predominate while at the later chronic
antibodies. It also leads to macrophage activation, which will result
stage T-suppressor cells outnumber the T-helper cell
in enhanced phagocytosis by these cells, as well as in cytokine-
population. The initial T-helper to T-supressor ratio
mediated enhanced PMN margination, chemotaxis and their acti-
of 1.7 turned at the later stage into ∞1.0, as com-
vation. Macrophage activation may also be achieved independently
pared to a T-helper to T-supressor ratio of 2.0 in pe-
of T-lymphocytes by bacterial endotoxin (LPS).
pression by endothelial cells in the capillaries, thus
glandins (21), bacterial endotoxin (22), complement
enhancing the local attachment of PMNs and mono-
activation products, as well as the inflammatory cyto-
cytes and enhancing their migration into the area.
kines IL-1a, IL-1b, TNFa, TNFb, IL-6 and IL-11
IL-8 produced by these macrophages will chemo-
which, as a group, were previously referred to as ‘‘os-
tactically attract the PMNs and activate them, making
teoclast activating factor'' (OAF) (23). Among these
them more available and more competent to engage
IL-1b is the most active cytokine and its bone-re-
and kill the bacteria (Fig. 1). Activation of the macro-
sorbing capacity is 13 times that of IL-1a and 1000
phages has a major role in maintaining the two lines
times that of TNFa or TNFb (24).
of phagocitic cell defence, typically described in the
All of these have been mentioned in relation to the
periapical lesion: an inner area, closer to the apex, in
periapical bone resorption associated with infected
which PMNs predominate; and around it the area in
root canals. The question is which of these potential
which the phagocytic macrophages are seen (5).
bone-resorbing stimuli is actually involved
Therefore, the defensive function of T-helper
the osteoclasts in these lesions?
lymphocytes is achieved indirectly through allowing
Two recent studies by Wang & Stashenko (25, 26)
the activation of (a) specific B-lymphocytes to become
provided convincing evidence that among the long
plasma cells and produce antibodies and (b) nonspec-
list of potential
mediators that may activate osteoclasts
ific effector cells: the macrophages. In order to avoid
and cause periapical bone resorption, the main and
an endless loop of mutual activation of macrophages
most important in human chronic periapical lesions
and T-lymphocytes, the process is actively controlled
are IL-1b and TNFb. In the rat model of active peri-
and down-regulated by T-suppressor lymphocytes.
apical bone resorption, IL-1a and, to a lesser extent
The essential role of the T-lymphocytes in the pro-
IL-1b and TNFb, are the major bone-resorbing cyto-
cess is generally acknowledged. The first studies that
kines. Both studies indicate that osteoclast activation
used athymic mice and rats to study the formation
by these cytokines is mediated by the formation of
of periapical inflammatory lesions were accordingly
cyclooxygenase pathway products such as prosta-
designed to finally ‘‘nail down'' the critical role of T-
glandins, as the effect could be significantly blocked
lymphocytes in the formation of these lesions (18, 28).
by nonsteroid anti-inflammatory drugs (NSAID) (25,
As it transpired, these studies are the turning point in
proving otherwise. Both demonstrated that periapical
The formation of periapical lesions was studied in
lesions can develop independently
of T-lymphocyte ac-
the rat model by Kakehashi, Stashenko and others (5,
tivity, thus leaving the stage to the other key actor:
15, 27–30). Following the exposure and contami-
the macrophage (as will be detailed below).
nation of the pulp and root canal, an inflammatoryresponse is activated in the periapical region. This isassociated with a rapid growth of a periapical lesion
Bone resorption in periapical lesions
whose size can be monitored using either radiographs
Bone resorption in the periapical region is one of the
or histologic sections. This rapid growth persists for
clinical hallmarks of periapical pathosis. Host defense
15 days and is associated with ‘‘bone-resorbing activ-
against the spread of bacteria from the infected root
ity'' that can be detected in homogenates of the
canal does not depend directly on bone resorption in
lesions and measured using an in vitro
the area. The resorption may be viewed as either an
assay (29). Following the active resorptive phase, the
undesirable byproduct of the host response, as is the
size of the lesions remains stable for up to 30 days
case with periodontal disease, or alternatively as a
(29). During this stationary phase the bone-resorbing
process by which the bone is removed from a risky
activity declines to 10%–30% of that in the active
area, thus allowing a ‘‘buffer zone'' to be formed, in
growing stage. This stationary phase is considered an
which host-response constituents engage the bacteria
equivalent of an existing, chronic, periapical granu-
(20). In either case, it is bone resorption in the peri-
loma in humans which also contains bone-resorptive
apical area which serves the clinician as a major indi-
cator for either progress of disease or repair of the
The cytokines defined in the above studies are
periapical lesion. As such it has been thoroughly
found in human periapical lesions in measurable
studied in both humans and animal models.
amounts. Lim et al. (31) found significant amounts ofIL-1b in homogenates of human periapical lesions,even though none of the patients had detectable
Potential vs actual bone-resorbing agents
serum levels of this cytokine. Noninflamed pulp tissue
Bone resorption occurs through the activation of the
that served as control was also free of the cytokine.
bone-resorbing cells: the osteoclasts. A wide range of
Periapical exudates were studied by Matsuo et al. (32)
biologically active molecules have been demonstrated
for their IL1-a and IL-1b content. Exudates, ob-
to have the capacity to activate osteoclastic bone re-
tained through the root canal, contained an average
sorption in in vitro
models. These include prosta-
level of 6.57(∫0.73) ng/ml of IL-1-b and 3.23
Macrophages in periapical lesions
(∫0.66) ng/ml of IL-1a. The cytokine profile
tissue responses of conventional and athymic rats (18).
changed following root canal treatment with a ten-
A similar result is reported by Tani-Ishii et al. (28)
dency of IL-1a to increase and of IL-1b to decrease.
who used athymic mice. They also found that peri-apical lesions develop in animals lacking T-cells at arate that precludes the possibility that T-lymphocytes
Cellular sources of bone-resorbing cytokines
are an essential prerequisite for the development of
Although IL-1 and TNF may be produced by many
these lesions. Even though T-lymphocytes may, and
cell kinds, the activated macrophage is considered the
most probably do, usually contribute to the process,
main source of IL-1a, IL-1b and TNFa (33). On the
alternative routes exist that enable the formation of
other hand, TNFb is commonly considered an acti-
the lesions in their absence.
vated T-lymphocyte product (34).
The activated macrophage may serve as such a route
In view of the above, two cell types should be con-
in the formation of periapical lesions. Macrophage ac-
sidered responsible for bone-resorbing activity in peri-
tivation may occur by a variety of pathways. Cytokines
apical lesions: activated T-cells and activated macro-
such as g-interferon, which are produced by antigen-
phages. Not all T-lymphocytes or macrophages in the
specific activated T-lymphocytes, are the main im-
periapical lesion are in a state of activation. Kopp &
mune-response-related activators of the macrophage
Schwarting (3) found that only 20% of the T-lympho-
(33, 38). Nevertheless, in their absence, bacterial endo-
cytes in human periapical granulomas are activated.
toxin (LPS) may successfully accomplish this task (35,
Artese et al. (9), who also used human periapical
39, 40). This activation of the macrophage may be
granulomas, demonstrated that while 41% of the
viewed as part of the innate immunity, which is inde-
mononuclear inflammatory cells are macrophages,
pendent of specific response to antigens. This may be a
only 2%–3% of these cells are activated and produce
mechanism by which the lesions developed in the
IL-1b and TNFa, which were used in this study as
athymic animals. The bacterial content of the infected
markers of their activation (9). Therefore, it seems
root canals in these animals gradually developed to a
that a rather small part of the cells in the periapical
46% gram-negative flora (41). LPS derived from these
granuloma are of potential importance as the source
gram-negative bacteria could activate macrophages in
of bone-resorbing activity in these lesions. It may not
the periapical area. These cells, in turn, produce their
be the total number of T-lymphocytes or macro-
cytokines IL-1a, IL-1b and TNFa, which activate os-
phages in the lesion that is important but rather the
teoclastic bone resorption. This does not preclude par-
number of activated cells of each kind.
ticipation of the T-cell in the process in normal ani-
The states of activation of these cells are closely
mals, but rather turns the spotlight on the main effector
related to each other: T-helper lymphocytes may be
: the macrophage. This is also in agreement with the
activated in an antigen-specific manner by antigen-
finding that in the rat model IL-1a is the major bone-
presenting macrophages which also produce the IL-1
resorbing cytokine while TNFb, the T-cell product,
required for this process. Macrophage activation, as
could not be detected in these lesions, neither in anti-
part of the acquired, specific, immune response, may
body-blocking nor in immunohistochemical studies
be achieved by cytokines such as interferon-g, pro-
duced by the activated T-lymphocytes (Fig. 1). Never-theless, macrophages may also be activated by otherroutes, such as exposure to bacterial endotoxin (LPS),
Kinetics of macrophage infiltration in periapical lesions
as part of the innate, nonspecific immunity (35).
The unique study by Akamine et al. (6) followed ratperiapical lesions for as long as 150 days. Analysis
Studies in athymic animals
of their data reveals that the active growing stage of
Athymic rats and mice are powerful tools to study
periapical lesions in the rat, which lasted for the first
and demonstrate the essential role of T-lymphocytes,
60 days, coincides with a peak of macrophage pres-
in immunobiologic processes (36, 37). These animals
ence in the lesion. When active growth stops and a
lack T-cells, and consequently T-cell function is miss-
stationary stage is reached, the presence of macro-
ing in a variety of immune responses which are thus
phages in the lesion gradually declines. This may be a
inactive. Such animals were recently used in two
coincidence; nevertheless, it may express a significant
studies, and it was assumed that periapical bone re-
correlation. Further support for this notion may be
sorption and development of periapical lesions will be
found in a recent study by Kawashima et al. (5) who
defective. The results of these studies should be view-
showed that macrophage infiltration in the periapical
ed as a turning point in understanding the immunobi-
lesions is associated with bone resorption in the area.
ology of the host response and bone resorption in
In their study, macrophage infiltration preceded that
periapical lesions. Wallstrom et al. (18) demonstrated
of lymphocytes and gradually increased throughout
that no significant difference exists between periapical
the 56 days of the experiment.
IL-1 and macrophages in the periapical granuloma
The presence of IL-1b in association with a subpopu-lation of the macrophages in periapical lesions hasbeen reported by several investigators (9, 30, 42). Ar-tese et al. (9) reported that in established human peri-apical granulomas, there are very few cells with im-munoreactivity of IL-1b and TNFa and that thesecells have a macrophage morphology. Tani-Ishii et al.
(42) demonstrated in the rat model that IL-1a andTNFa are associated with macrophages in the peri-apical lesion as soon as 2 days after exposure of thepulp. They persisted through the 30 days of the ex-periment. In contrast, TNFb and IL-1b could not bedetected in the sections.
Nevertheless, the presence of cytokines in association
with these cells does not essentially prove that theyare the source of these molecules. For example, IgE
Elimination of macrophage-derived destructive mediators.
is found in specific association with basophils and
(A) Traditional method: by root canal treatment, eliminating acti-vation stimuli such as bacterial antigens and LPS. (B) Proposed
mast cells, even though it is a plasma cell product
method: by pharmacological agents such as steroids, tetracyclines,
that attaches itself to a receptor on the former cells.
receptor antagonists or NSAIDs, which interfere with mediators'
Similarly, the cytokine may potentially have been at-
production or action.
tached to, or taken into, these cells, rather than pro-duced by them. Recently, direct proof was providedwhich clearly demonstrates that the activated macro-phages in fact produce IL-1b in periapical lesions. In
tissue repair and bone repair from taking place (19,
an in situ
hybridization study, Hamachi et al. (30)
demonstrated the presence of messenger RNA for IL-
If this is true, it might be important and possible
1b in the macrophages. This proves not only that
to monitor their state of activation by sampling the
these cells are capable of producing cytokines in gen-
interstitial fluid of the lesion through the root canal
eral and that the cytokines are associated with them
(32, 43). Recently Kuo et al. (43) were able to measure
in the periapical lesion, but also that subpopulations
the IL-1b content of apical exudates and correlate it
of macrophages are actively engaged in producing
with clinical and radiological features of the lesions.
cytokine in periapical granulomas.
A longitudinal study to establish a correlation be-tween the diminishing IL-1b content of the lesionsand their gradual radiographic repair will be required
to prove this point.
Endodontic treatment aims to eliminate bacteria from
Assuming that such inhibitory mechanisms are in-
the infected root canals, which will later be sealed, to
volved in the prolonged and delayed repair of peri-
prevent recontamination. With the bacterial stimuli
apical lesions, pharmacological modulation of the
that evoked the periapical inflammation gone, the
process may be considered (Fig. 2). Stashenko et al.
periapical lesion should resolve, and repair should
(23) demonstrated that IL-1 receptor-antagonist may
take place. Nevertheless, healing of the lesion may
be used in animals to reduce bone-resorbing activity
take many months. It may be argued that if the lesion
and the formation of periapical lesions. Similarly,
eventually heals in 12 months, there is no benefit in
NSAIDs were successfully used for a similar purpose
rushing the process. Nevertheless, this may have clin-
in experimental and human periodontal diseases, as
ical importance, as it may allow earlier decisions to
well as in the cat model for periapical lesion (44, 45).
be made in regard to the restorative treatment plan
These two approaches are directed at either blocking
for the treated teeth.
of the already produced cytokine to its tar-
This prolonged healing process raises the possibility
get cells or interfering with its action
on osteoclasts and
that the activated cells in the lesion may maintain
osteoblasts, which involves prostaglandin production
their state of activation long after the initial cause of
their activation has been eliminated.
Tetracyclines may be used to inhibit cytokine secre-
Macrophages are known to persist in the tissues for
by activated macrophages (46). Shapira et al. (46)
many months and if their state of activation persists,
studied tetracycline inhibition of TNF and IL-1 pro-
they may inhibit the fibroblasts and maintain osteo-
duction by LPS-activated macrophages and found its
clast activity, thus preventing both soft connective
effect to be at a post-transcriptional level: both m-
Macrophages in periapical lesions
RNA and the cytokines themselves are produced but
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the activated macrophages, thus lowering the local
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pression of fibroblast proliferation by LPS-activated
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ported by others and are attributed to inhibitory ef-
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TABLE OF CONTENTS *Perspectives from Biogen leadership For the fourth consecutive year, our global colleagues participated in ON THE COVER Biogen's Care Deeply Volunteer Day, which shattered last year's record Inspired by the new Biogen turnout with a 54-percent increase in employee participation. This worldwide logo, the front cover graphic
NeuroImage 17, 1384 –1393 (2002)doi:10.1006/nimg.2002.1241 Human Vestibular Cortex as Identified with Caloric Stimulation in Functional Magnetic Resonance Imaging Oliver Fasold, Michael von Brevern, Marc Kuhberg, Christoph J. Ploner, Arno Villringer, Thomas Lempert, and Ru Department of Neurology, Charite´, Humboldt-University, D-10098 Berlin, Germany