Periodontology 2000, Vol.

40, 2006, 144163

Printed in the UK. All rights reserved

2006 The Authors.

Journal compilation
2006 Blackwell Munksgaard

PERIODONTOLOGY 2000

Host-mediated resolution of
inflammation in periodontal
diseases
A L P D O G A N K A N T A R C I , H A T I C E H A S T U R K & T H O M A S E. V A N D Y K E

According to the Merriam-Webster dictionary, the

noun host has several meanings. Its etymologic
origin is from the Latin hostis, which was used to
describe a host or guest. In modern English, the word
refers to one that receives or entertains guests socially, commercially, or officially (91). In biology, host
is defined as a living animal or plant affording
subsistence or lodgment to a parasite; the larger,
stronger, or dominant member of a commensal or
symbiotic pair; an individual into which a tissue, part,
or embryo is transplanted from another (32). Thus,
host response represents the reaction (or response)
of the body of living animal or plant against invading
or threatening factors. Within the context of immunology, this term specifically refers to the response
against parasites. Therefore, host response in the
periodontium is the defense mechanisms in periodontal tissues against bacterial infections.
Edward Jenner, who in 1796 discovered that cowpox (or vaccinia) induced protection against human
smallpox, is recognized as the founder of modern
immunology (76, 141). The term vaccination coined
by Jenner to describe his procedure, is still used to
explain an important aspect of host response, that is,
inoculation of healthy individuals with weakened or
attenuated strains of disease-causing agents to protect against disease (63). Later in the 19th century,
Robert Koch recognized these agents as infectious
microorganisms. Through his work and the studies of
Louis Pasteur and Emil von Behring, the host
response and the importance of the adaptive
immune response have been accepted as the protective arm of immunity against reinfection with
the same pathogen (63). The hallmark of adaptive
immunity is specificity, or recognition of specific
antigens. Elie Metchnikoff later determined that not

144

all host response modes are specific; some cells and

processes immediately respond to the invader nonspecifically. He described these immediate-response
cells as phagocytes as they engulf and digest the
microorganisms upon the initial challenge and
recognition of invaders was not dependent on the
adaptive immune response (62).
Both the innate and the adaptive processes of the
host immune response depend on the activity of
leukocytes. Phagocytes, namely, macrophages and
polymorphonuclear granulocytes (neutrophils), are a
group of leukocytes that are immediately available
to combat a wide range of pathogens without prior
exposure, being the key components of the innate
immune response (62, 66). Conversely, lymphocytes
are the key element in the adaptive immune
response. From an evolutionary perspective the
innate immune response precedes the adaptive
mechanisms, which are observed only in higher
animals. The innate and adaptive immune systems
provide a remarkably effective defense system
ensuring that the host becomes rarely ill although
being exposed continuously to potentially pathogenic
microorganisms. Many infections are handled successfully by the innate immune response and cause
no disease. Infections that cannot be resolved by innate immunity trigger adaptive immunity, which can
overcome the infection successfully followed by
memory. However, as in all other systems in nature,
immune defense is not perfect or free of failures.
Furthermore, malfunction of the immune system to
respond properly to infections can also cause disease
by itself, as demonstrated in allergy and autoimmunity (81). As demonstrated by Jenner, the immune
system can be bolstered using several methods.
Vaccination is an established method used to boost

Host-mediated resolution of inflammation

the hosts defense against infectious agents. Nutrition, genetics, and environment are all major contributors to a healthy immune response.

Modulation of the host as a

treatment method, and resolution
Manipulation of the immune response to suppress
unwanted reactions is desirable in conditions such as
autoimmunity, allergy, or graft rejection. It is also
required in the case of infectious disease to stimulate
the protective processes. Strategies to achieve these
goals are collectively referred to as modulation of
host response and provide a novel concept in treatment (48, 135). The rationale behind this approach is
to aid the host in its fight against infectious agents by
supplementing the natural inherent defense mechanisms or to modify its response by changing the
course of inflammatory systems. Compared to other
weapons against infection, host response modulation
potentially has fewer side-effects, is not invasive, and
does not require complicated application methods
(84, 133).

Resolution
Once the inflammatory response is initiated, a continuous cascade of events takes place. During this
series of events, the body attempts to eliminate
invaders through proinflammatory actions of cells
and their products. A basic tenet of modern medicine
is that upon neutralization of the invader, inflammation resolves due to catabolism of proinflammatory
mediators; in reality, the resolution of inflammation
is a highly coordinated and active process. The process of resolution of inflammation, similar to proinflammatory mechanisms, utilizes cells and various
messenger molecules generated by cells to provide
stop signals that lead to shut-down and clearance
of inflammatory cells (135). Thus, inflammation
includes both proinflammatory and resolving mechanisms inherent to the body where the host attempts
to confine and or eliminate the invaders and, when
accomplished, actively resolves the response to limit
damage to self (154). Hence, the body has the capacity
to actively control inflammation.
Pro-resolving mediators are readily generated in
tissues. These factors limit leukocyte trafficking
directed into the inflamed site, reverse the cardinal
signs of inflammation such as vasodilation and vascular permeability, and coordinate the clearance of
exhausted leukocytes, exudates, and fibrin; eventually

leading to the restoration of function (106). All of

these inflammation-resolving processes limit and
prevent tissue injury and the further progression of
acute inflammation into chronic inflammation. If
there is a failure of the host in its ability to eliminate
the injury, however, acute inflammation proceeds to
a chronic phase and results in varying degrees of
tissue injury (48). When tissue injury is mild and
confined, necrotic cells will be replaced by new cells
by regeneration. If tissue damage is extensive, the
process of healing is repair (scarring). When repair
takes place, fibrin is not cleared rapidly and efficiently after the acute phase of inflammation and
granulation tissue is formed from surrounding tissue
compartments. Later phases of repair involve fibroblast-mediated collagen deposition, disappearance of
vascular tissues and replacement of these areas by
avascular and fibrotic scar tissue (81). Thus, in the
context of resolution of inflammation, acute resolution leads to regeneration, whereas chronic resolution results in repair; these terms are applicable to
periodontal tissue healing. In periodontal disease
pathogenesis, similar to other forms of host-mediated tissue injury, such as rheumatoid arthritis and
asthma, chronic resolution also leads to ongoing
tissue damage through continuous and recurring
episodes of acute inflammation (79). Therefore, the
induction and resolution of inflammation processes
are concurrent phases in chronic inflammation and
such pathologies should be defined as continuous
inflammatory diseases rather than independent
stages.
Based on these findings, the next question is how
can resolution of inflammation be modified? Current
therapeutic approaches based on this strategy do not
exist for the treatment of periodontal disease or, for
that matter, any other inflammation-based pathology
such as asthma, rheumatoid arthritis, osteoarthritis
or other more subtle inflammatory diseases like cardiovascular disease. In fact, quite the opposite
approach is taken, that of blocking the activity of
proinflammatory molecules. The classic pharmacologic agents in this category are enzyme inhibitors
such as cyclooxygenase inhibitors.
Although infectious in nature, the pathogenesis of
periodontitis is similar in nature to other inflammatory diseases in its progression pathways. Attempts at
elimination of infectious agents often do not represent a definitive therapy in periodontitis, necessitating the administration of more sophisticated
biological treatment modalities. It was established in
the 1980s that modulation of the host response with
cyclooxygenase inhibitors (64, 65, 101, 104, 160163)

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Kantarci et al.

was effective in halting the progression of periodontitis. However, the side-effects of chronic long-term
use of cyclooxygenase inhibitors were significant,
creating poor risk benefit ration, and the use of
these drugs for the routine treatment of periodontitis
was abandoned.

Proinflammatory cytokine
inhibition
Immune modulation therapy
The immune system is a dynamic equilibrium, with
inflammatory responses (mediated by T-helper type
1 cells, interleukin (IL)-1b, interferon-Ic (IFN-c), and
tumor necrosis factor-a (TNF-a)) being counterbalanced by endogenous anti-inflammatory responses
(mediated by T regulatory type 1 cell, T-helper type 3
cells, IL-4, IL-10, and transforming growth factor-b
(TGF-b)). These pathways regulate homeostatic stability of immune system. The inflammatory disease
process is characterized by domination of proinflammatory cytokine mediators. Therefore, external
neutralization of inappropriate inflammatory cytokines is a therapeutic strategy that has been
attempted in many chronic inflammatory conditions,
mostly targeting tumor necrosis factor-a, using either
monoclonal antibodies or modified receptor proteins
(35, 36, 40, 85). Within these parameters, blocking
production of proinflammatory cytokines through
soluble antagonists of IL-1 and tumor necrosis factor-a
is a potentially therapeutic approach to modulate
the hosts immune response. Increased understanding of the pathophysiology of a number of human
autoimmune diseases, and the realization that
cytokines play a major role, has provided the pharmaceutical industry as well as the researchers with a
wide array of new targets for therapeutic interventions. This has resulted in a heightened interest in the
development of ways of blocking cytokines and their
actions in a specific and safe manner. Currently,
anticytokine therapy using anti-IL-1 or anti-tumor
necrosis factor-a monoclonal antibodies and soluble
tumor necrosis factor receptors have been approved
for the treatment of rheumatoid arthritis, Crohns
disease, juvenile arthritis and psoriatic arthritis (5, 6,
35) with research continuing on periodontal disease
(9, 28, 54, 165).
Therapy for rheumatoid arthritis aims at interfering
with the disease process, namely inflammation and
destruction of the joints, and thus preventing longterm disability. Proinflammatory cytokines play a

146

decisive role in the generation of the inflammatory

and destructive responses in rheumatoid arthritis
(23). Aside from traditional disease-modifying antirheumatic drugs and tumor necrosis factor-blocking
agents, a number of targeted therapies are currently
being evaluation, such as abatacept (interfering with
costimulation), rituximab (an anti-B-cell agent) and
tocilizumab (an anti-IL-6 receptor antibody). In
phase II trials, all these agents have resulted in significant, albeit modest, clinical improvement, and
phase III trials have been partly completed with
similar results (1). Because the clinical responses in
patients have been somewhat disappointing and
many patients had only relatively low responses, it
will still be a challenge to find the best therapeutic
paths to combat the inflammatory house of cards of
rheumatoid arthritis (143). Also, post marketing
monitoring of these agents has revealed concerns
about potentially serious complications including
tuberculosis, lymphoma, and cardiac failure due both
to the underlying inflammatory disease activity and
to the immunosuppressive effects of many conventional disease-modifying antirheumatic drugs (60).
Another medication, the aldosterone-inhibitor, spironolactone, possesses anti-tumor necrosis factor-a
activity. Endotoxic shock models showed a significant
reduction in tumor necrosis factor-a levels in
response to spironolactone treatment, suggesting
that spironolactone acts as a tumor necrosis factor
inhibitor (52). However, spironolactone-treated rats
did not demonstrate significantly less alveolar bone
destruction compared to nontreated rats in a periodontitis model. The lack of efficiency of spironolactone treatment may be explained by the fast
metabolism of spironolactone and by its incomplete
inhibition of tumor necrosis factor production in rats.
Moreover, many other cytokines and mediators
involved in alveolar bone destruction may account
for the lack of response to spironolactone.
Crohns disease also presents an interesting field
for immune modulation therapy. Several recent trials
of intravenously administered anti-tumor necrosis
factor-a monoclonal antibody have shown dramatic
responses among patients with this disease (121, 145,
153). The results indicate a primary role for tumor
necrosis factor-a in the mediation of altered mucosal
immune function. Clinical responses in patients
treated with a single infusion of anti-tumor necrosis
factor-a persisted for as long as 1 year. The prolonged
period of clinical benefit shows that the effect of
short-term tumor necrosis factor-a elimination
remained long after the monoclonal antibody had
been cleared. Corresponding in vitro investigations

Host-mediated resolution of inflammation

also showed that T-helper 1-mediated cytokine production of interferon-c was down-regulated in the
involved mucosa to a level consistent with that seen
in uninflamed mucosa (151). These results suggest
that removal of tumor necrosis factor-a alters the
tumor necrosis factor-a-specific augmentation of
mucosal Th1 function, producing the prolonged
response.
Understanding how tumor necrosis factor-a
modulates mucosal Th1 function may lead to the
definition of a key feature of Crohns disease pathogenesis.
There are, however, concerns over baseline risk
factors for malignancy in inflammatory diseases and
the incidence of malignancies observed in clinical
trials of anti-tumor necrosis factor-a therapy (24).
Although the preclinical data and early clinical
experience do not provide evidence for a causal
relationship between tumor necrosis factor-a antagonism and the development of lymphoid or
nonlymphoid cancers, more detailed studies are
required. Indeed, clinical studies indicate that tumor
necrosis factor-a-neutralizing therapy should not be
given to patients with cardiac failure or a history of
demyelinating disease. Increased rates of infection
such as latent tuberculosis or opportunistic infections like pneumonia were also reported, but the
effect of tumor necrosis factor inhibition on the
frequency of infection with more common bacterial
pathogens is less clear (34, 46). All these side-effects
stem from the inhibition of essential endogenous
factors that play a role in normal physiology. Antitumor necrosis factor-a dampens the hosts ability to
adequately deal with infection. Detailed characterization of the biochemical pathways leading to resolution through neutralization of tumor necrosis
factor-a or other immune system pathways requires
proper and more extensive studies.
In periodontology, it has been known that the hostresponse in some individuals may lead to an overreaction to invading oral pathogens, resulting in the
destruction of periodontal tissues. Similar to other
host-mediated diseases, several host-derived factors
are believed to contribute to this response and
studies have shown that proinflammatory cytokines
may play different functional roles in early vs. late
phases of periodontal wound healing (44, 74, 75).
Two agents considered to be essential in periodontal
destruction are IL-1 and tumor necrosis factor-a (53).
Therefore, it has been proposed that short-term
blockade of IL-1b and tumor necrosis factor-a may
facilitate periodontal wound healing, whereas prolonged blockade may have adverse effects. The effects

of local IL-1 and tumor necrosis factor soluble

receptors on a periodontal wound-healing model and
in the loss of connective tissue attachment were
tested in a Macaca fascicularis primate model of
experimental periodontitis (28). IL-1 and tumor
necrosis factor antagonists significantly reduced the
loss of connective tissue attachment and the loss of
alveolar bone height, demonstrating that the loss
of connective tissue attachment and progression of
periodontal disease can be retarded by antagonists to
specific host mediators such as IL-1 and tumor necrosis factor and may provide a potential treatment
modality to combat the disease process (9, 28, 54, 97).
The clinical, radiographic, and biochemical findings
of these experiments showed that IL-1b and tumor
necrosis factor-a antagonists blocked the progression
of the inflammatory cell infiltrate towards the alveolar crest and inhibited the recruitment of osteoclasts.
Under natural conditions, an uncontrolled inflammatory response with rapid tissue destruction due to
the activities of IL-1b and tumor necrosis factor-a are
reversed by the production of anti-inflammatory
cytokines such as IL-4, IL-10, and IL-11 (29, 39). The
potential to down-regulate mediators of inflammation associated with periodontal tissue destruction
was investigated during experimental periodontitis in
beagle dogs over an 8-week period. The findings
indicated that subcutaneous injection of recombinant human IL-11 was able to alter periodontal disease
progression measured by changes in attachment level
and radiographic bone height (89). These studies
suggest that the conversion from gingivitis to periodontitis is directly associated with the movement of
an inflammatory infiltrate toward alveolar bone, and
that this activity is at least partially dependent upon
IL-1 and or tumor necrosis factor (124). We have
recently shown that a possible cross-talk between
neutrophils and monocytes could account for this
effect and delayed apoptosis of neutrophils in periodontitis would be, at least in part, responsible for the
reduced IL-10 and elevated IL-1b production from
monocytes (11). This aspect of periodontitis warrants
more detailed studies and could clarify why inflammatory cytokine release blockage might be an
important target in treatment.
In conclusion, despite expanding use of drugs
blocking proinflammatory cytokine production, their
precise mechanisms of action remain unclear. Early
assumptions that they act by direct neutralization of
the toxic inflammatory effects of tumor necrosis
factor-a might be too simplistic, because they cannot
explain the range of effects observed or the varying
properties of different tumor necrosis factor-blocking

147

Kantarci et al.

agents. There is functional redundancy among the

inflammatory cytokines. For example, in addition to
tumor necrosis factor-a, both IL-1b and IL-6 are
elevated in patients with chronic heart failure; thus
neutralizing the activity of tumor necrosis factor-a
alone may be an inadequate approach in this patient
group (14, 25). Immune modulation therapy results
in down-regulation of proinflammatory cytokine
levels and up-regulation of anti-inflammatory
cytokines. This alteration in the balance between
proinflammatory and anti-inflammatory cytokines
may be more appropriate than neutralizing the
activity of a single cytokine (14). Recent studies have
also demonstrated a key role for mast cell-derived
tumor necrosis factor in the increase in lymph node
size and the organizational complexity that accompanies a developing immune response. Regulation of
this phenomenon might constitute a novel mode of
action for tumor necrosis factor-directed therapy: by
preventing this lymph node hyperplasia, tumor necrosis factor blockade could modulate immune
responses, ameliorating pathology in autoimmune
diseases such as rheumatoid arthritis (22). In addition, the development of novel approaches of cytokine blockade that are based on the characterization
of intracellular signaling pathways regulating cytokine expression (e.g. nuclear factor kappa B (NF-jB)
and p38 mitogen activated protein kinase (MAPK))
and the use of small molecule inhibitors are being
studied (3, 130, 149). Whether these approaches will
live up to their early promise and become a major
and widespread treatment for several devastating
autoimmune diseases will depend on specificity,
safety, durability of the benefit, and pharmacoeconomic issues.

Antiproteinase-blocking of matrix
metalloproteinases
Another therapeutic approach to modulate host
response is based on the inhibition of matrix metalloproteinases (MMPs) with antiproteinases (92, 120).
Matrix metalloproteinases are a family of zincdependent and calcium-requiring endopeptidase
enzymes that are responsible for the degradation of
most extracellular matrix proteins during organogenesis, growth, and normal tissue turnover (13, 112).
Biochemical and clonal studies indicate that there are
three major groups: the specific collagenases cleave
interstitial collagens; the gelatinases degrade types IV,
V, VII and XI collagens and act synergistically
with collagenases by degrading denatured collagens

148

(gelatins); and the stromelysins have broader specificity and can degrade basement membrane collagens
as well as proteoglycans and matrix glycoproteins.
Other matrix metalloproteinases not in these groups
are matrilysin, metalloelastase, and a recently cloned
membrane-bound metalloproteinase. These enzymes
can be produced by several different types of cells
such as fibroblasts, keratinocytes, macrophages,
endothelial cells, mast cells, and eosinophils and their
activity can be specifically inhibited by tissue inhibitors of metalloproteinases (TIMPs), which bind to
active matrix metalloproteinases with 1 : 1 stoichiometry (95). Tissue inhibitors of metalloproteinases are
important controlling factors in the actions of matrix
metalloproteinases, and tissue destruction in disease
processes often correlates with an imbalance of
matrix metalloproteinases over tissue inhibitors of
metalloproteinases. The major inhibitor is tissue
inhibitors of metalloproteinase-1, a 30-kDa glycoprotein that is synthesized by most cells. A second
unglycosylated inhibitor, tissue inhibitor of metalloproteinase-2, which is less abundant, has the interesting property of binding to the proform of gelatinase
A and is involved in controlling its activation (144).
In general, matrix metalloproteinases are not constitutively expressed in most tissues but are induced
temporarily in response to exogenous signals such as
various cytokines, growth factors, cell matrix interactions, and altered cellcell contacts. Matrix metalloproteinases play an important role in proteolytic
remodeling of extracellular matrix in various physiologic situations, including developmental tissue
morphogenesis, tissue repair, and angiogenesis. The
expression and activity of matrix metalloproteinases
in adult tissues is normally quite low, but increases
significantly in various pathologic conditions that
may lead to unwanted tissue destruction, such as
inflammatory diseases, tumor growth, and metastasis
(10, 16, 88, 94, 142). It has been shown that matrix
metalloproteinases are detected at sites of excessive
breakdown of connective tissue in rheumatoid arthritis, osteoarthritis, chronic ulcers, dermal photoageing, and periodontitis, as well as in tumor cell
invasion and metastasis. The expression of matrix
metalloproteinases and tissue inhibitors of metalloproteinases by cells is specific to cell type and many
of them are products of monocytes macrophages.
Their production in inflammatory situations is
therefore part of the chain of events leading to tissue
degradation.
One way in which pathogenic organisms might
mediate tissue degradation in periodontal diseases is
through the ability of cell wall antigens to stimulate

Host-mediated resolution of inflammation

cytokine production by circulating mononuclear cells

(71). These would then induce matrix metalloproteinase synthesis by resident gingival cells (or by the
mononuclear cells themselves), thereby initiating
degradative events (59, 131). Matrix metalloproteinases in human gingival biopsy specimens show
extremely variable distribution both in connective
tissue and in the epithelium, but the results indicate
that host cell production of matrix metalloproteinases may contribute to tissue degradation in periodontal disease. Tissue inhibitors of metalloproteinase
could also be found in some situations and could be a
limiting factor. The role of collagenases, especially
matrix metalloproteinase-8, in periodontitis and periimplantitis is the best-known example of the
unwanted tissue destruction related to increased
presence and activity of matrix metalloproteinases at
the site of disease (19, 77). The activity and release of
matrix metalloproteinase-8, a mainly polymorphonuclear neutrophil leukocyte (PMN)-specific matrix
metalloproteinase stored in specific granules of
neutrophils, are regulated by factors such as cytokines (tumor necrosis factor-a or IL-1b) and various
bacterial virulence factors. These factors induce
de novo synthesis of matrix metalloproteinase-8 by
certain other non-neutrophil lineage cells in the oral
cavity such as gingival and periodontal ligament
fibroblasts. It has been found that matrix metalloproteinase-8 activity of human cell origin in gingival
tissues and gingival crevicular fluid in periodontitis
patients and in peri-implant sulcular fluid of periimplantitis patients is higher than in healthy subjects,
and that this activity was correlated with disease
activity (77). During progression of periodontitis,
marked elevations in levels of active matrix metalloproteinase-8 were noted in gingival crevicular fluid at
the time of detection of connective tissue attachment
loss. Matrix metalloproteinase-8 released from neutrophils in a latent, inactive proform becomes activated by the independent and or combined actions
of host- and microbial-derived proteases and reactive
oxygen species produced by triggered neutrophils
(30, 31, 61, 83). During active phases of periodontitis,
matrix metalloproteinase-8 levels in gingival crevicular fluid are significantly elevated, and the matrix
metalloproteinase-8 is almost completely converted
to the active form. Direct extracts of untreated
inflamed gingival tissue specimens taken from
periodontitis patients in comparison with healthy
noninflamed gingival tissue specimens have been
shown to contain pathologically elevated levels of
matrix metalloproteinase-8 in catalytically competent active form.

Conventional periodontal treatment, involving

scaling and root planing, and adjunctive drug-treatment to inhibit and down-regulate gingival and gingival crevicular fluid matrix metalloproteinase-8 have
been shown to reduce the pathologically excessive
collagenase activities in gingival crevicular fluid in
periodontitis to values close to those of periodontally
healthy gingival crevicular fluid (73). Treatment of
adult periodontitis with medications and down-regulators (such as doxycycline, chemically modified
nonantimicrobial tetracycline-derivates, bisphosphonates, and their combinations) and therapeutic
applications of anticollagenase drugs (such as synthetic matrix metalloproteinase inhibitors) in endotoxin-induced tissue-destructive periodontitis model
in rats have been shown to result in reduced levels of
matrix metalloproteinase-8 and other matrix metalloproteinase and in activity that is associated with
clinically beneficial outcomes (18, 38).
The major antiproteinase used in periodontal
treatment is tetracycline. In addition to its antimicrobial activity, this group of compounds has the
capability of inhibiting the activities of neutrophils,
osteoclasts, and matrix metalloproteinases (specifically matrix metalloproteinase-8), thereby working as
an anti-inflammatory agent that inhibits bone
destruction (111, 115). A germ-free rat model of
connective tissue breakdown and a series of in vitro
studies identified an unexpected nonantimicrobial
property of tetracyclines (110). This ability of tetracyclines to inhibit matrix metalloproteinases was
found to reflect multiple direct and indirect mechanisms of action, and to be therapeutically useful in
adult periodontitis as well as medical diseases such
as arthritis, osteoporosis, and cancer. Identification
of the site on the tetracycline molecule responsible
for its matrix metalloproteinase-inhibitory activity
led to the development of a series of chemically
modified nonantimicrobial analogs, called chemically modified tetracyclines, which also have therapeutic potential but which do not appear to induce
antibiotic side-effects (110). Longitudinal doubleblind studies on humans with adult periodontitis
have demonstrated that a subantimicrobial dose of
doxycycline (previously reported to suppress collagenase activity in the periodontal pocket) is safe and
effective as an adjunct to scaling and root planing
without resulting in the emergence of doxycyclineresistant microorganisms or typical adverse events
(4951, 55). The clinical, biochemical, and microbiological effects of subantimicrobial doses of doxycycline on the modulation of wound healing have
also been reported in a pilot study in patients with

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Kantarci et al.

advanced chronic periodontitis with results showing

that postsurgical wound healing was significantly
enhanced compared with placebo and that adjunctive
subantimicrobial doses of doxycycline administration
did not induce significant shifts in the periodontal
microbiota beyond those attributed to surgery alone
(43). Systemic subantimicrobial dosing of doxycycline
(Periostat) is approved and prescribed in conjunction with mechanical periodontal therapy.
Thus, tetracyclines have nonantimicrobial properties that appear to modulate host response. The
mechanisms by which tetracyclines affect and,
possibly, diminish bone resorption (a key event in the
pathogenesis of periodontal and other diseases) are
not yet fully understood. However, a number of
possibilities concerning the effects of tetracyclines
remain open for investigation:
direct inhibition of the activity of extracellular
collagenase and other matrix metalloproteinases
such as gelatinase;
prevention of the activation of its proenzyme by
scavenging reactive oxygen species generated by
other cell types (e.g. neutrophils, osteoclasts);
inhibition of the secretion of other collagenolytic
enzymes (i.e. lysosomal cathepsins);
a direct effect on other aspects of osteoclast
structure and function.
Matrix metalloproteinase activity and its potential
as a target to suppress the heightened host response
in therapy have also gained attention in other fields
of the medical sciences (10, 16, 88, 94, 142). One of
the major applications of such an approach would be
in cancer therapy where matrix metalloproteinases
are also elevated, and a number of different synthetic
and natural matrix metalloproteinase inhibitors have
been identified as cytostatic and antiangiogenic
agents. Preclinical studies were encouraging and
prompted clinical trials. However, there have been
consistent disappointments, with limited success due
to the cellular source, substrates and mode of action
of matrix metalloproteinases, focusing the attention
of future research on the identification of specific
matrix metalloproteinase targets in tumors at different stages of tumor progression, both to improve
efficacy and to reduce the side-effect profile (88).
Anti-matrix metalloproteinase treatment has also
been validated in other disease models such as
multiple sclerosis and bacterial meningitis. These two
neuro-inflammatory diseases, where current therapeutic approaches are insufficient to prevent severe
disability in the majority of patients, demonstrated
that inhibition of enzymatic activity may prevent
matrix metalloproteinase-mediated neuronal dam-

150

age due to an overactive or deviated immune

response in both diseases (164). Down-regulation of
matrix metalloproteinase release may be the
molecular basis for the beneficial effect of interferonb and steroids in multiple sclerosis, and synthetic
matrix metalloproteinase inhibitors offer the possibility to shut off enzymatic activity of already activated matrix metalloproteinases. In animal models of
multiple sclerosis and bacterial meningitis, matrix
metalloproteinase inhibitors efficiently attenuated
clinical disease symptoms and prevented brain
damage due to excessive matrix metalloproteinase
activity. The effect of endogenously produced interferon-b or parenterally administered interferon-b
may further be increased by gelatinase B inhibitors.
Blockage of chemotaxis or cell adhesion molecule
engagement, and inhibition of hydroxymethyl-glutaryl-coenzyme-A reductase to lower the expression of
gelatinase B may thus become effective treatments of
multiple sclerosis, alone or in combination with
interferon-b (47). This may allow interferon-b to be
used at lower doses and prevent side-effects. However, the required target profile for the therapeutic
use of this novel group of compounds in human
disease is not yet sufficiently defined and may differ
depending on the type and stage of disease. Currently available matrix metalloproteinase inhibitors
show little target-specificity within the matrix metalloproteinase family and may lead to side-effects
due to interference with physiologic functions of
matrix metalloproteinases. Results from human
multiple sclerosis and bacterial meningitis trials
indicate that only a restricted number of matrix
metalloproteinases specific for each disease are
up-regulated. Matrix metalloproteinase inhibitors
with selective target profiles offer the possibility of a
more efficient therapy and may enter clinical trials in
the near future.
A very recent and interesting study showed that the
effect of tranilast, which suppresses collagen synthesis and cell proliferation, on matrix metalloproteinase-1 secretion from human gingival fibroblasts,
did not interfere with cell proliferation at low concentrations (86). However, higher doses of tranilast
significantly decreased the activity of matrix metalloproteinase by 130% and 20%, respectively.
Although these data suggest that tranilast up-regulates the expression of type 1 collagenase suppressed
by gingival overgrowth-inducing drugs, and inhibits
transforming growth factor-b secretion from gingival
fibroblasts at lower doses, higher doses of the drug
lead to increased matrix metalloproteinase-1 activity
(86). Other recent work showed that a novel synthetic

Host-mediated resolution of inflammation

retinoid, seletinoid G, designed by using computeraided molecular modeling, has potential anti-matrix
metalloproteinase activity (72). The topical application of seletinoid G under occlusion induced no skin
irritation and increased the expressions of type I
procollagen, tropoelastin, and fibrillin-1, as well as
reducing matrix metalloproteinase-1 in old skin
in vivo. Seletinoid G was also found to inhibit not
only the decrease of type I procollagen but the
increase of matrix metalloproteinase-1 and c-Jun
protein in young skin in vivo. Novel medications such
as seletinoid G, which has no side-effects such as skin
irritation after topical application, can be used to
repair altered connective tissue in old skin and inhibit collagen deficiency in young skin (72).
In conclusion, these findings suggest that the
clinical efficacy and side-effects of antiproteinase
treatment should be carefully studied. Indeed, recent
work on these agents has focused on safety issues.
For example, a novel sulfonamide derivative, S-3304,
was discovered to be a potent matrix metalloproteinase inhibitor (155). This derivative is a more specific inhibitor of matrix metalloproteinase-2 and
matrix metalloproteinase-9 than matrix metalloproteinase-1, and may therefore lack the musculoskeletal
side-effects seen with nonspecific inhibitors. Adverse
events reported after single dose administration of
S-3304 or placebo were all of mild severity. The most
commonly reported adverse events in the multiple
treatments with S-3304 were headache and somnolence. No clinically significant changes were observed
in the clinical laboratory tests, except for reversible
elevation of alanine aminotransferase of one subject
at 800 mg S-3304. S-3304 demonstrated a good
safety profile and good systemic exposure when
administered orally up to 800 mg twice a day for
1017 days. At the highest dose level of 800 mg twice
daily, S-3304 caused no rheumatoid arthritis-like
symptoms (155). Thus, anti-matrix metalloproteinase
treatment through tetracyclines or their derivatives or
numerous novel medications presents an exciting
and promising field of research in the context of
modulation of host response.

Bisphosphonates
Bisphosphonates are bone-sparing agents used in
the management of various diseases with bone
resorption. These compounds inhibit osteoclastic
activity by blocking acidification by local release and
represent a class of chemical structures related to
pyrophosphate (118, 119). The metabolism of bis-

phosphonates stems from the complicated mechanism of pyrophosphate generation. Pyrophosphate is

an unstable molecule under in vivo conditions and
hydrolyzes rapidly due to pyrophosphatase activity
(139), leading to the formation of a chemically stable
bisphosphonate molecule. On the basis of their
effects on macrophages, bisphosphonates could be
subgrouped into two distinct categories: aminobisphosphonates, which sensitize macrophages to an
inflammatory stimulus, inducing an acute-phase
response, and nonaminobisphosphonates, which
can be metabolized by macrophages and which may
inhibit the inflammatory response of macrophages
(15, 127). Several in vivo studies have demonstrated
an acute-phase reaction after the first administration
of aminobisphosphonates, with a significant increase
in the main proinflammatory cytokines (20, 102, 146,
147). However, nonaminobisphosphonates seem to
have anti-inflammatory activity caused by the inhibition of the release of inflammatory mediators from
activated macrophages, such as IL-6, tumor necrosis
factor-a and IL-1b (146, 147). This activity suggests
the use of nonaminobisphosphonates in several
inflammatory diseases characterized by phagocytemediated production of acute-phase cytokines, such
as rheumatoid arthritis, osteoarthritis, ankylosing
spondylitis, myelofibrosis, and hypertrophic pulmonary osteoarthropathy.
The pathogenesis and clinical manifestations of
bone disease in inflammatory diseases such as cystic
fibrosis suggest that bisphosphonates could be used
in their treatment (7, 58).
The effect of bisphosphonates on bone metabolism is mediated through the suppression of the
interactions between the receptor activator of nuclear factor kappa B (RANK) and its ligand (RANKL) as
well as osteoprotegerin. These are the final effector
molecules of bone resorption and their activation is
responsible for inflammatory arthritis and metabolic
bone disorders (116). Bisphosphonates are widely
used in the management of systemic metabolic bone
disorders such as osteoporosis and Pagets disease
(42). They are also indicated in cancer-related diseases such as neoplastic hypercalcemia, multiple
myeloma, and bone metastases secondary to breast
and prostate cancer (127), suggesting a direct antitumor effect of bisphosphonates at different levels of
action. Some new in vitro and in vivo studies support the cytostatic effects of bisphosphonates on
tumor cells, and the effects on the regulation of cell
growth, apoptosis, angiogenesis, cell adhesion, and
invasion, with particular attention to biological
properties.

151

Kantarci et al.

Given their known affinity to bone and their ability

to decrease osteoblastic differentiation and inhibit
osteoclast recruitment and activity, there exists a
possible use for bisphosphonates in the management
of periodontal diseases. Bisphosphonates downregulate levels of several matrix metalloproteinases
including matrix metalloproteinase-3, matrix metalloproteinase-8, and matrix metalloproteinase-13
from human periodontal ligament cells (87, 96, 152).
These bone-specific properties also provide an
interesting management strategy to stimulate osteogenesis in conjunction with regenerative materials
around osseous defects and may result in the promotion of bone formation around endosseous
implants. Early trials showed that alendronate, an
aminobisphosphonate, may inhibit bone loss in
osteolytic diseases by altering osteoclast activity. In a
double-blind study, alendronate inhibition of alveolar bone loss was studied in the naturally occurring
beagle dog model of periodontitis and a statistically
significant difference in bone mass was observed
between the alendronate and placebo groups. The
bisphosphonate had no effect on the clinical
parameters of gingival inflammation or plaque. A
trend toward decreased attachment loss and mobility
was also observed in favor of the alendronate group
(114). Several other animal studies have examined
the effects of bisphosphonate on alveolar bone
resorption by using the experimental periodontitis
model or after mucoperiosteal flap elevation (4, 17,
18, 33, 45, 69, 70, 82, 93, 112, 113, 128, 140, 148, 150,
159). Collectively, the findings of these experiments
showed that, although bone loss was reduced by
systemic delivery of alendronate, clinical signs of
inflammation and pocket depth were not affected.
One proposed explanation for this result may be that
high-dose release of alendronate from hydroxyapatite
in inflamed periodontal pockets up-regulated the
inflammatory host response by stimulating the
secretion of cytokines (2, 129). Apparent disagreement between the anticipated results and the data
from the studies could also stem from the dual
role attributed to bisphosphonates outlined above.
Indeed, bisphosphonate activity, which could prime
phagocyte-mediated acute inflammation while also
possessing the capability of inhibition of the phagocyte-driven inflammatory response, could lead to
different effects in the short- and long-term. In
human studies, conflicting data on the effects of
systemic bisphosphonate administration have also
been reported (37, 65, 148). A very recent clinical trial
evaluated the effect of bisphosphonate therapy as an
adjunct to nonsurgical periodontal treatment in

152

patients with moderate to severe chronic periodontitis (82). Bisphosphonate therapy significantly
improved clinical measures of periodontal therapy
during the 6- to 12-month period but there was no
difference in periodontal bone mass change between
the bisphosphonate and placebo groups. These data
suggest that bisphosphonate treatment improves the
clinical outcome of nonsurgical periodontal therapy
and may be an appropriate adjunctive treatment to
preserve periodontal bone mass. However, there were
no effects on clinical parameters of periodontal
inflammation, necessitating further and more extensive analyses.

Nonsteroidal anti-inflammatory
drugs
One of the earliest pharmacological strategies described to block the inflammatory processes in periodontal tissues as well as elsewhere in the body are
nonsteroidal anti-inflammatory drugs (NSAIDs). The
basic rationale behind the use of nonsteroidal antiinflammatory drugs is to block the arachidonic acid
metabolites that are proinflammatory mediators
implicated in a variety of bone resorptive and tissuedegrading processes. Nonsteroidal anti-inflammatory
drugs include analgesics such as ibuprofen and
aspirin with multiple levels of anti-inflammatory
effects (123). These compounds block platelet activity
through thromboxane inhibition, inhibit cyclooxygenase, and prevent the production of arachidonic acid
metabolites. Arachidonic acid was initially isolated
from peanut oil together with linoleic acid. It is an
important component of phospholipid metabolism
in animals through which biosynthesis of most
eicosanoids such as prostanoids (further grouped as
prostaglandins and thromboxanes) and leukotrienes
starts (158). Prostanoids are structurally similar; they
contain a cyclic ring and are produced via the action
of the enzyme cyclooxygenase. Virtually all tissues of
mammalian origin contain these important molecules and they play a major role in host defense (125).
Leukotrienes, on the other hand, are generated
through the lipoxygenase pathway (125, 126).
Arachidonic acid derivatives and lipid mediators of
inflammation play critical roles in health and disease.
They can initiate and take part in the progression of
inflammation and thus are named proinflammatory
mediators (122). Interactions between cells and at
the transcellular level amplify and generate lipidderived mediators, particularly those produced by
lipoxygenase. In addition to the proinflammatory

Host-mediated resolution of inflammation

mediators, pro-resolving mediators are also produced during these interactions (137).
Data on the levels of prostaglandin E2 (PGE2) in
periodontal diseases and the association of periodontal diseases with low birth weight infants in
mothers with periodontitis suggest that periodontal
infections alter prostaglandin metabolism and might
lead to systemic problems (99). The link between
increased cardiovascular diseases and periodontitis
severity further suggest that these two diseases share
common inflammatory pathways where lipid mediators play a role (57, 108, 109, 132). Thus, lipid
mediators are important regulators in many diseases
involving inflammatory reactions. Since many molecules in eicosanoid metabolism are associated with
proinflammatory roles, blocking the actions of the
arachidonic acid cascade has been realized to be an
effective means of blocking the inflammation. Based
on this principle, several drugs have been developed
to arrest or modify inflammation by blocking the
enzymatic pathways that lead to the generation of
lipid mediators. Part of the activity of corticosteroids
is thought to be through blocking the release of
arachidonic acid from the membrane phospholipids
(105). This nonspecific inhibition of eicosanoid generation, although highly effective, leads to multiple
side-effects, including suppression of the acquired
immune system. As an alternative, nonsteroidal
anti-inflammatory drugs or specific cyclooxygenase inhibitors have been used to block prostaglandin production. Nonsteroidal anti-inflammatory
drugs specifically suppress cyclooxygenase-mediated
inflammation without blocking acquired immunity
and are effective and used widely. However, these
agents also lead to significant side-effects due to their
lack of selectivity, blocking both the constitutive
(cyclooxygenase (COX)-1) and the inducible (cyclooxygenase (COX)-2) isoforms.
Aspirin has been widely used for a long time to
decrease inflammation, pain, and fever. It was discovered that aspirin inhibits the synthesis of prostaglandin by inhibiting the cyclooxygenase-2 pathway
(156, 157). The specific action of aspirin has long
been thought to be attributable to its irreversible
blockage of cyclooxygenase activity by acetylation of
a specific serine hydroxyl group. Since aspirin suppresses the synthesis of prostaglandin at this initial
step, for many years the activity of aspirin was
attributed to this mechanism. However, recent new
data has demonstrated that aspirin acetylated cyclooxygenase-2 is not inactive; it in fact acquires a new
activity, that of a 15-lipoxygenase. This new, novel
form of 15-lipoxygenase is also unusual in its activity

since aspirin-triggered 15-lipoxygenase yields a product with a unique stereochemistry: 15R-hydroxyeicosatetraenoic acid. This increase in 15-lipoxygenase activity associated with aspirin therapy is
translated into increased production of 15- hydroxyeicosatetraenoic acid metabolites including lipoxin
A4 (LXA4). Lipoxin A4 is a well appreciated resolving
molecule whose actions lead to reduced neutrophil
actions and neutrophil apoptosis and accumulation
of mononuclear phagocytes that display only nonphlogistic activity, e.g. they phagocytose apoptotic
polymorphonuclear neutrophil leukocytes, but do
not secrete proinflammatory cytokines. Hence, the
cardiovascular-friendly actions of aspirin are mediated by the pro-resolving actions of lipoxins in
addition to the prevention of blood clot formation
through inhibition of thromboxane A2 formation
(157).
Nonsteroidal anti-inflammatory drugs block the
activity of both cyclooxygenase isozymes (cyclooxygenase-1 and -2), which mediate the enzymatic
conversion of arachidonate to prostaglandin H2 and
other prostaglandin metabolites. Cyclooxygenase-2
selective inhibitors were developed with the prime
object of minimizing gastrointestinal adverse effects,
which are seen with the use of traditional nonsteroidal anti-inflammatory drugs. However, recently,
there has been considerable controversy in the clinical literature about the unwanted side-effects of
cyclooxygenase-2 inhibitors in the gastrointestinal
and cardiovascular systems (80). Specifically, the longterm use of cyclooxygenase-2 inhibitors has been
linked to the development of hypertension, edema,
and congestive heart failure in a significant proportion
of patients. There can be multiple mechanisms
through which these effects can occur. For example, it
has been shown that some cyclooxygenase-2 inhibitors (i.e. celecoxib, valdecoxib, and rofecoxib) present
cyclooxygenase-independent effects such as carbonic
anhydrase inhibition. Carbonic anhydrases are zinc
metalloenzymes expressed in various cell types,
including those of the kidney, where they act as general
acid-base catalysts. Celecoxib and valdecoxib, but not
the other cyclooxygenase-2 inhibitors, exhibit the
characteristics of a potent carbonic anhydrase inhibitor, showing a selective inhibitory human carbonic
anhydrase II activity in the nanomolar range (78).
Another potential mechanism is linked to the very
basic route through which cyclooxygenase-2 inhibitors exert their effects, limiting their long-term use. The
cardiovascular profile of cyclooxygenase-2 inhibitors
can be accounted for by inhibition of cyclooxygenasedependent prostaglandin synthesis. Following the

153

Kantarci et al.

cyclooxygenase-mediated synthesis of prostaglandin

H2 from arachidonate, prostaglandin H2 is metabolized to one of at least five bioactive prostaglandins,
including prostaglandin E2, prostaglandin I2 (PGI2),
prostaglandin F2 (PGF2), prostaglandin D2 (PGD2), or
thromboxane A2. These prostanoids have pleiotropic
cardiovascular effects, altering platelet function
and renal function, and they act as either vasodilators
or vasoconstrictors. Although cyclooxygenase-1 and
cyclooxygenase-2 exhibit similar biochemical
activity in converting arachidonate to prostaglandin
H2 (PGH2) in vitro, the ultimate prostanoids they
produce in vivo may be different due to differential
regulation of cyclooxygenase-1 and cyclooxygenase-2,
tissue distribution, and availability of the prostanoid synthases. Prostaglandins have been established
as being critically involved in mitigating hypertension, helping to maintain medullary blood flow,
promoting urinary salt excretion, and preserving
the normal homeostasis of thrombosis, and it has
been found that the use of cyclooxygenase-2 inhibitors caused many serious complications by altering
normal body homeostasis (80, 138). Collectively,
these findings may have important implications for
the elucidation of the mechanisms of action as well as
the side-effects associated with cyclooxygenase-2
inhibitors.

Lipoxins and resolvins: localized

aggressive periodontitis as a model
Localized aggressive periodontitis (LAP) is an
important example of unwanted, excessive immune
response becoming harmful to host tissues through
neutrophil-mediated tissue injury (66). Unlike other
forms of periodontal disease, localized aggressive
periodontitis presents with various abnormalities of
host cell function. Our laboratory, as well as results
from other centers over the last decade, has shown
that neutrophil play a pivotal role in localized
aggressive periodontitis. Recently, we have shown
that the neutrophil abnormalities in localized
aggressive periodontitis are the result of a chronic
hyperactivated or primed state of localized aggressive
periodontitis neutrophil (66). In fact, the neutrophil is
not deficient but hyperfunctional, and the excess
activity of neutrophil as well as the release of toxic
products from the cell are responsible for the tissue
destruction in chronic periodontal inflammation. As
a result of hyperactivity of neutrophil, the protective
functions targeting invading microorganism might
lead to the injury of the host tissue, eventually

154

contributing the clinical signs of disease or neutrophil-mediated tissue injury. Localized aggressive
periodontitis is an example of neutrophil-mediated
tissue injury in which neutrophils exhibit elevated
basal levels of superoxide generation that lead to
further increase in response to secondary stimulus.
Hence, excessive recruitment of neutrophils followed
by excessive release of inflammatory mediators contributes to the onset of periodontal disease and appears to be associated with rapid and widespread
tissue destruction. This tissue-damaging activity can
also be further amplified by the release of an array of
inflammatory mediators by neutrophils within the
periodontium. Excessive accumulation of neutrophils
in periodontal disease therefore suggests that the
neutrophils are unable to remove the noxious stimuli
(bacteria), perpetuating inflammation and tissue
damage.
The pathogenesis of periodontitis is mediated
by cytokines, chemokines, and metalloproteinases
(prostaglandin E2, IL-1, IL-6, IL-8, tumor necrosis
factor-a, and matrix metalloproteinase-1) (98, 103).
The neutrophil is also a rich source of prostaglandin
E2, which probably accounts for the majority of
prostaglandin E2 detected in the gingival crevicular
fluid of periodontitis patients (12, 41). Thus, the
longstanding notion that the source of inflammatory
mediators in periodontitis is mononuclear phagocytes and stromal cells in the periodontal lesion must
be updated. Using an in vivo model of leukocyte
infiltration, we recently demonstrated that Porphyromonas gingivalis stimulated a massive influx of
neutrophils that was accompanied by activation of
neutrophil cyclooxygenase-2, followed by an increase
in prostaglandin E2 levels (107). Prominent inflammatory mediators associated with periodontal disease include the arachidonic acid-derived products
leukotriene-B4 and prostaglandin E2. Indeed, many of
the pathophysiologic events that occur in periodontal
diseases can be explained to a large extent by the
activities of lipid mediators. Along these lines, prostaglandin E2 is a potent stimulator of bone loss,
which is the hallmark of periodontal disease (100).
Levels of prostaglandin E2 are significantly elevated
in crevicular fluid of patients with periodontal
infections compared to healthy controls. These levels
correlate with disease severity and aggressiveness,
and constitute a reliable indicator of ongoing clinical
periodontal tissue destruction. Prostaglandin endoperoxide synthase (cyclooxygenase) catalyzes two
reactions by which arachidonic acid is converted
to prostaglandin H2, the common precursor of all
prostanoids including prostaglandin E2. The early

Host-mediated resolution of inflammation

findings that homogenates of inflamed periodontal

tissues display an increased prostaglandin E2 synthetic capacity when compared to homogenates from
healthy tissues suggested that an increased cyclooxygenase activity is associated with periodontal tissues. Moreover, given the potentially deleterious
actions of prostaglandin E2 on the integrity of tissues
of the periodontium, both the potential involvement
of the cyclooxygenase-2 in periodontal disease and
the potential role of novel lipid mediators are of
interest in the pathogenesis of periodontal disease.
The role of lipid mediators in the neutrophil
response to P. gingivalis was characterized in an
animal model. When P. gingivalis was introduced
into murine dorsal air pouches, leukocyte infiltration
was initiated. Elevated prostaglandin E2 levels in the
cellular exudate and up-regulated cyclooxygenase-2
expression in the leukocyte infiltrate accompanied
neutrophil accumulation. In addition, human neutrophils exposed to P. gingivalis also demonstrated
up-regulation of cyclooxygenase-2 mRNA expression.
Interestingly, P. gingivalis introduced into the epithelial lined air pouch caused significant increases in
the murine tissue levels of cyclooxygenase-2 mRNA
associated with both heart and lung, supporting a
potential role for this oral pathogen in the evolution
of systemic events. Significantly, the administration
of metabolically stable analogs of lipoxin and of
aspirin-triggered lipoxins blocked neutrophil trafficking into the dorsal pouch cavity and lowered
prostaglandin E2 levels within exudates without
allowing spread of infection. These results show that
neutrophils can provide an important source of
prostaglandin E2 in periodontal tissues. The results
also provide strong support for a protective role of
lipoxin in periodontitis, limiting further neutrophil
recruitment and neutrophil-mediated tissue injury
that can lead to loss of inflammatory barriers preventing tissue invasion by oral microbial pathogens
(107). It has been further proposed that lipoxin generation and its relationship to prostaglandin E2 and
leukotriene-B4 can be an important marker for the
pathogenesis of periodontal disease. Indeed, activated neutrophils from localized aggressive periodontitis patients produced lipoxins, whereas healthy
neutrophils did not.
In dermal inflammation, lipoxin stable analogs,
when applied topically to mouse ears, inhibit both
neutrophil infiltration and vascular permeability
changes (21). Inhibition was by either local intra-air
pouch delivery or via systemic delivery by intravenous injection and proved more potent than local
delivery of aspirin. Using a casein-induced perito-

nitis model in rats, lipoxin receptor agonists were

shown to significantly inhibit neutrophil infiltration
( 43%) and protein extravasation ( 42%) when
given intravenously with two consecutive doses at
approximately 60 mg kg per injection. Transgenic
overexpression of human lipoxin receptor (the
human receptor expressed in the mouse model) gives
markedly decreased neutrophil infiltration to the
peritoneum in zymosan-initiated peritonitis and
displayed increased sensitivity to suboptimal doses of
lipoxin stable analogs (21). Lipoxin analogs were also
shown to rapidly promote macrophage phagocytosis
of apoptotic neutrophil in a thioglycolate-induced
peritonitis, supporting a role for lipoxins as proresolution signals in inflammation (8).
Recently, we have demonstrated that transgenic
rabbits overexpressing 15-lipoxygenase generate
enhanced levels of lipoxin, have a hypo-inflammatory phenotype, and are protected from the inflammatory bone loss of periodontal disease (136). In
the first of these series of studies, leukocytes
from 15-lipoxygenase transgenic rabbits exhibited
enhanced lipoxin production, underscoring differences in lipid mediator profiles compared with
nontransgenic rabbits. P. gingivalis-associated inflammation and leukocyte-mediated bone destruction
were assessed by initiating acute periodontitis.
15-Lipoxygenase transgenic rabbits exhibited markedly reduced bone loss and local inflammation.
Because enhanced lipoxin production was associated
with a hypo-inflammatory phenotype in 15-lipoxygenase transgenic rabbits, a stable analog of lipoxin A4
was applied topically in ligature induced periodontitis. Topical application of 15-epi-16-phenoxy-parafluoro-lipoxin A4, stable analog, dramatically reduced
leukocyte infiltration, ensuing bone loss, and inflammation. These results indicate that overexpression of
15-lipoxygenase and lipoxin A4 is associated with
dampened neutrophil-mediated tissue degradation
and bone loss, confirming that resolution of inflammation is an active process and that inflammation is
responsible for tissue destruction in periodontitis
(136). Moreover, the findings also suggested that
lipoxin has potential for novel approaches to therapy
in diseases, e.g. periodontitis and arthritis, where
inflammation and bone destruction are features (67,
90). Following these findings on stable analogs of
lipoxins, we have also analyzed the local resolvin E1
(RvE1) application on experimental periodontitis in
rabbits. The results showed that both compounds
had comparable efficacy on preventing P. gingivalisinduced periodontal disease and bone resorption
(Fig. 1).

155

Kantarci et al.

100
RvE1

OH

ATLa

OH

HO

COOCH3

OH

80
OH

Percent Bone Loss

COOH
OH

60

40

20

*
0

Ligature

Ligature +

Ligature +

Ligature +

Alone

P. gingivalis

P. gingivalis +

P. gingivalis +

RvE1

ATLa

Fig. 1. Topical application of pro-resolving lipid mediators prevents periodontal bone loss. Experimental periodontitis was induced in New Zealand White rabbits by
ligature placement around mandibular second molars
followed by P. gingivalis administration. Topical application of aspirin-triggered lipoxin stable analog (ATLa) or
resolvin E (RvE1) was performed for 6 weeks where the
compounds were delivered in ethanol. Ethanol also served
as placebo in the vehicle group. After sacrificing the ani-

mals, the mandible was dissected free of muscle and soft

tissue, defleshed, and stained with Methylene blue for
visual distinction between tooth and bone. The bone level
around the second premolar was measured directly using
a 0.5 mm calibrated periodontal probe. Bone values are
expressed as the percentage of bone loss. Both ATLa and
RvE1 led to significant prevention of P. gingivalis-induced
bone loss (*P < 0.05) compared to the vehicle group.

Animals do not have the capacity to desaturate

fatty acids fully compared to plants. Therefore, for
many animals, it is necessary to acquire certain polyunsaturated essential fatty acids derived from a
plant source as a part of their diet. In humans, skin
lesions, for example, occur when the diet lacks
essential fatty acids (117). Linoleic acid-rich diets or
essential fatty acid intake that consists of 12% of the
total caloric requirement can reverse such pathological symptoms. In addition to the lack of dietary
intake of essential fatty acids, abnormal metabolism
of these molecules can also be associated with
diseases such as cystic fibrosis, Crohns disease, cirrhosis, and alcoholism. A diet with high polyunsaturated fatty acid content is beneficial in decreasing
serum cholesterol levels and low-density lipopro-

teins, while balanced consumption of essential fatty

acids is essential to prevent the risk of cardiovascular
diseases associated with high cholesterol levels (26,
27). Within these lines, novel lipid mediator pathways
are very attractive targets for new therapeutic interventions because they are
small molecules (< 500 molecular weight);
amenable to total organic synthesis;
can be manufactured with currently available
pharmaceutical facilities.
A pro-resolution pathway involves novel lipid
mediators that possess endogenous anti-inflammatory and pro-resolving properties. Novel oxygenated
products generated from omega-3 fatty acid precursors eicosapentanoic acid and docosahexanoic acid
generated in the presence of aspirin that possess

156

Host-mediated resolution of inflammation

P r o - R e s o l ut i on

Proi nflammation

A n ti- In fl a m m at i o n
Tissue Inhibitor of
Metalloproteinases

M M P- 8

Lipox ins
(e.g. LXA4)

Resolvins
(e.g. RvE1)

Neutrophil

Tetracyclines
(e.g. chemically
modified
tetracyclines,
low dose
doxycycline)

Proinflammatory
Cytokines and
Lipid Mediators
(e.g. IL-1, IL-6,
PGE2,GM-CSF)
Reactive Oxygen
Sp e c i e s

Bisphosphonates

TNF-

Anti-TNF-

Monocyte/ Macrophage

Tissue Destruction
Fig. 2. Pathways of inflammation and mechanism of control. Neutrophils and macrophages monocytes initiate the
proinflammatory series of events by generating cytokines,
lipid mediators, matrix metalloproteinases, or reactive
oxygen species. These molecules, in turn, lead to tissue
destruction. Traditionally, anti-inflammatory pathways
could be used against specific targets of inflammation with
considerable side-effects. Pro-resolution of inflammatory

cascade can be accomplished through recently described

endogenous lipid mediators (lipoxins and resolvins) that
turn off the inflammatory events. Straight arrows demonstrate activation and block arrows represent inhibition.
IL-1, interleukin 1; IL-6, interleukin 6; PGE2, prostaglandin
E2; GM-CSF, granulocyte macrophage colony stimulating
factor; TNF-a, tumor necrosis factor alpha, MMP-8, matrix
metalloproteinase 8; LXA4, lipoxin A4; RvE1, resolvin E1.

potent bioactions were identified in resolving

inflammatory exudates, and similar structures were
elucidated in tissues rich in docosahexanoic acid.
These newly described molecules, termed resolvins
(resolution phase interaction products) and docosatrienes, display potent anti-inflammatory and
immunoregulatory properties (134). Unlike other
products identified earlier from omega-3 fatty acids
that are similar in structure to eicosanoids but less
potent or devoid of bioactions, the resolvins, docosatrienes, and neuroprotectins evoke potent biological actions in vitro and in vivo. Specific receptors for
these novel omega-3 bioactive products are abbreviated Reso (E or D) receptors to designate the precursor origin and a numerical index (i.e. ResoER1)
in recognition of their respective cognate ligands.
These novel bioactive epimers are denoted as aspirintriggered resolvin Ds and docosatrienes (134, 135).

Lipoxins, resolvins, and docosatrienes are novel

families comprising separate chemical series of
lipid-derived mediators, each with unique structures
and apparent complementary anti-inflammatory
properties and actions. The resolvins and docosatrienes dampen from within both inflammation and
neutrophil-mediated injury, key culprits in many
human diseases. It is likely that these compounds
and their aspirin-triggered related forms may play
roles in other tissues and organs, since they are involved in physiologic and pathologic processes. In
view of the important roles of their precursors,
eicosapentanoic acid and docosahexanoic acid in
human biology and medicine, it is likely that these
novel pathways and compounds are responsible in
part for the beneficial impact of omega-3 essential
fatty acids in complex systems and could be of use
in periodontal treatment.

157

Kantarci et al.

Conclusion
Inflammation comprises a series of events that leads
to a host response against trauma and microbial
invasion, results in liquefaction of surrounding tissues to prevent microbial metastasis, and eventually
to healing of injured tissue compartments. Thus, by
definition, the host response involves not only the
mechanisms of defense but also processes of repair
of damage that occur by the direct effect of invaders
or trauma or host systems. Periodontal diseases are
inflammatory processes in which microbial etiologic
factors induce a series of host responses that mediate
an inflammatory cascade of events in an attempt to
protect and heal the periodontal tissues. However,
the progression of periodontal disease and its commonality with other systemic disorders such as cardiovascular disease and diabetes is based on the
inflammatory events underlying the pathogenesis.
Recent work has shown that in addition to the on
signals that initiate the inflammatory events, periodontal tissues are capable of generating off or stop
signals as checkpoint controls in inflammation.
These control mechanisms are specific resolving
cellular and biochemical circuits that have evolved to
activate resolution, thus limiting uncontrolled dissemination of inflammation. We have already identified several common inflammatory pathways of
pathogenesis in chronic periodontitis and diabetes
(68) where neutrophils play an important role as an
inducer in conveying the inflammatory processes.
These neutrophil-mediated pathways, which could
very well be shared by the other phagocytes (such as
monocytes) and cells of the adaptive immune system,
could be used to control and manage inflammatory
processes. Likewise, findings from localized aggressive periodontitis as a disease model where neutrophil responses are genetically altered show that this
form of periodontitis represents a valuable model in
which neutrophil-mediated tissue destruction follows
similar routes (56). Thus, here we propose a model
for regulation of phagocyte-mediated inflammation,
in which, in addition to the traditional pro- and antiinflammatory mechanisms, novel endogenous lipid
mediators (lipoxins and resolvins) could represent a
pro-resolution phase (Fig. 2). In this model, blockage of proinflammatory pathways could be accomplished not only by immune modulation therapy (e.g.
anti-tumor necrosis factor-a), bisphosphonates,
tetracyclines (e.g. chemically modified tetracyclines,
low-dose doxycycline), or activation of tissue inhibitors of metalloproteinases, all of which have sideeffects or shortcomings, but also through shutting

158

down the cellular and molecular circuits endogenously by lipoxins (e.g. lipoxin A4) or resolvins (e.g.
resolvin E1). Pro-resolution has a net advantage over
the traditional methods in that it suppresses excessive cellular activity. Available data and the results of
ongoing studies demonstrate a new treatment concept where natural pathways of resolution of
inflammation can be used to limit inflammation and
promote healing and regeneration with minor risk of
side-effects.

Acknowledgments
This manuscript is supported partially by USPHS
DE13499 and DE16191.

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