INDIAN JOURNAL OF DENTAL ADVANCEMENTS
J o u r n a l h o m e p a g e : w w w. n a c d . i n
Harinath Reddy S1, Satyanarayana D2, Vidya Sagar S3, Surykanth M4
Department of Periodontics ABSTRACT: Kamineni Institute of Dental Sciences Chronic inflammatory periodontal disease is caused by host Narketpally, Nalgonda Dist. immune responses to periodontal microorganisms. The past decade has produced remarkable advances in our understanding of host immune responses. New strategies for periodontal disease Professor1&2 management have been emerging as more is learned about the role of the host response. Our increasing understanding of PG Student4 inflammation and its resolution has opened the door to the study of new periodontal treatment strategies. The emerging awareness of inflammation and its control in periodontal disease Article Info management underscores the importance of exploring Received: April 15, 2011 inflammatory pathways and mediators, thus setting the stage for Review Completed:May, 17, 2011 the development of new prevention and treatment strategies of a Accepted: June, 19, 2011 widespread disease. Available Online: October, 2011 NAD, 2011 - All rights reserved Key words: Host response, HMT, Periodontitis, Periodontal Therapy INTRODUCTION
work hard to keep the oral microorganisms on theoutside. For the maintenance of teeth, the
Periodontitis is one of the most common oral
diseases and is characterized by gingival
equilibrium between the microbial attack and the
inflammation and alveolar bone resorption.1 It is
estimated that at least 1014 commensal microbes of
The underlying biological mechanisms of this
various species reside on the surfaces of skin, teeth,
response are characterized by the production of host-
dentures, the mucosal epithelial lining of the
derived inflammatory mediators including cytokines
respiratory, gastrointestinal and urinary tracts, as well
and lipids by neutrophils, monocytes, lymphocytes
as the oral cavity which contains approximately 6
and fibroblasts. Acquired and environmental risk
billion microbes representing 500—700 species. Up
factors, such as diabetes mellitus, cigarette smoking
to 300 oral bacterial species can be cultured from oral
and stress, as well as genetically transmitted traits,
plaque samples.2 Hence, it can be considered among
such as interleukin-1 (IL-1) gene polymorphisms, may
the prevalent and important global health problems
accentuate the host inflammatory response to the
bacterial challenge and, eventually, the susceptibility
The tissue damage and alveolar bone resorption
to the disease.6 Among host proteases degrading
characteristic of the disease are believed to be due
extracellular matrix, matrix metalloproteinases
to destructive innate host response to pathogenic
(MMPs) seem to be highly related to tissue
subgingival biofilm.4 Every tooth forms a perforation
destruction and remodelling events in periodontal
in the patient’s host defence and the body has to
Email for correspondence:[email protected]
response in the periodontium” is the defense
management have been emerging as more is learned
mechanisms in periodontal tissues against bacterial
about the role of the host response. Our increasing
understanding of inflammation and its resolution has
The human body is estimated to be composed
opened the door to the study of new periodontal
of more than 1014 cells, of which only 10% are
mammalian. The majority are the microorganisms
Host modulatory therapy has been proposed as
that colonize the skin, mouth, digestive, and
a treatment for periodontal diseases. The use of
reproductive tracts.12 The resident human microbiota
modulating agents, including inhibition of matrix
does not merely reside passively at a site, but makes
metalloproteinases (MMPs) with antiproteinases,
an active contribution to the maintenance of health
blocking production of proinflammatory cytokines
by promoting the normal development of the
and prostaglandins with anti-inflammatory drugs,
physiology of the host (including the immune
and inhibiting activation of osteoclasts with bone-
system), and by excluding exogenous (and often
sparing agents, has been postulated to be of
therapeutic value as an adjunctive therapy to the
resistance).13 In general, the host lives in a relatively
management of chronic Periodontitis.9 Omega-3 (n-
stable and harmonious relationship with its resident
3) polyunsaturated fatty acids (PUFAs), including
microbes (termed microbial homoeostasis), and both
docosahexaenoic acid (DHA) and eicosapentaenoic
acid (EPA), were shown to have therapeutic anti-
However, if this homoeostasis breaks down, then
inflammatory and protective actions in inflammatory
relationship can result in either exogenous
The present topic highlights various host
microorganisms being able to colonize, or previously
modulation therapeutic agents and ongoing
minor components of the resident microbiota
exploiting new opportunities and increasing in
pharmacotherapies that specially target host
proportion, which in certain circumstances can pre-
pharmocotherapies as an adjunct to the traditional
The Mouth as a Microbial Habitat
periodontal therapies represent a ‘new integrated approach’ in long-term treatment and management
of Periodontitis. The future holds much promise for
environment that suits the growth of many
the host modulation as an important tool not only
microorganisms. The mouth is the only site in the
for the management of Periodontitis, but also for the
human body that normally provides non-shedding
clinical practice of periodontal medicine.
surfaces for microbial colonization; this facilitates thedevelopment of thick biofilms, particularly at
HOST RESPONSE TO PATHOGENESIS OF
stagnant sites whereas desquamation ensures that
the microbial load is lighter elsewhere. Thus, in this
According to the Merriam-Webster dictionary,
way, the host provides unique opportunities for
the noun “host” has several meanings. Its etymologic
biofilm formation in the mouth, and a secure haven
origin is from the Latin hostis, which was used to
describe a host or guest. In modern English, the word
HOST MODULATORY THERAPY
refers to “one that receives or entertains guestssocially, non -commercially, or officially”. Within the
context of immunology, this term specifically refers
suppress unwanted reactions is desirable in
to the response against parasites. Therefore, “host
conditions such as autoimmunity, allergy, or graft
rejection. It is also required in the case of infectious
special modified CMTs that differ in their MMP
disease to stimulate the protective processes.
Strategies to achieve these goals are collectively
MODULATION OF ARACHIDONIC ACID
referred to as “modulation of host response” and MEDIATORS
provide a novel concept in treatment. The rationalebehind this approach is to aid the host in its fight
Historically, there have been three major
against infectious agents by supplementing the
approaches to inhibit PGE synthesis. Steroids inhibit
natural inherent defense mechanisms or to modify
PLA2, stabilize lysosomal membranes, and inhibit
its response by changing the course of inflammatory
cellular degranulation, all serving to reduce the
systems. Compared to other weapons against
availability of free ARA for CO enzymatic activity.
infection, host response modulation potentially has
Steroids also cause degradation of preexisting
fewer side-effects, is not invasive, and does not
mRNAs for IL-1â and TNF-á thereby dampening the
require complicated application methods.11
secondary PGE response.19 The second approach is
by the use of antioxidants which serve to prevent the
DEFINITION AND RATIONALE
oxidation of ARA by molecular oxygen and the
Host modulation therapy (HMT) is a treatment
subsequent hydrolysis to form PGE . The third
concept that aims to reduce tissue destruction and
approach is directed towards inhibiting the
stabilize or even regenerate the periodontium by
cyclooxygenase directly. The fact that NSAIDs can
modifying or down regulating destructive aspects of
suppress alveolar bone resorption suggests that the
the host response and up regulating protective or
synthesis of AA metabolites may represent a critical
regulatory pathway for potentially blockingperiodontal disease progression activity.20
MODULATION OF MATRIX METALLOPROTEINASES
A new family of drugs, the cytokine- suppressing
Matrix metalloproteinases encompass a family
anti-inflammatory drugs, has been described of
of zinc- and calcium-dependent endopeptidases
which SKF 86002 is the prototype. These drugs are
secreted or released by a variety of host cells that
potent and selective inhibitors of one of the mitogen-
function at neutral pH and utilize the various
activated protein kinase family termed alternatively
constituents of extracellular matrix as their substrates.
RK, p38 or cytokine-suppressing anti-inflammatory
MMPs can be self-regulated by their own proteolytic
inactivation. Some cleavages inactivate MMPs orgenerate truncated enzyme species resulting in a
POLYUNSATURATED FATTY ACIDS
concomitant change of action. MMPs are also
inhibited and cleared by endogenous inhibitors like
polyunsaturated fatty acids (n-3 PUFAs) increases
á2-macroglobulin (á2M) and tissue inhibitors of
tissue concentrations of the types of fatty acids (e.g.,
MMPs (TIMPS), the major plasma inhibitor of MMPs.17
eicosapentaenoic acid and docosahexaenoic acid)
TETRACYCLINES IN HOST MODULATION
that downregulate inflammation.22 Improvedoutcomes are attributed to the primary metabolites
The major Antiproteinase used in periodontal
of omega-3 fish oils, eicosapentaenoic acid (EPA) and
treatment is tetracycline (TC). A new approach to
non-antibacterial periodontal therapy is theadministration of specially prepared low-dose
PRORESOLVING LIPID MEDIATORS: POTENTIAL
capsules containing as low as 20 mg of doxycycline. FOR PREVENTION AND TREATMENT OF
Doxycycline is the most potent collagenase inhibitor
of commercially available TCs. The CMTs comprise a
The current therapeutic approach to control
group of at least 10 (CMTs 1-10) analogues plus some
inflammation is to remove aetiology. More recently,
new pathways and processes underlying resolution
resorption. The identification of the interaction
of inflammation have been discovered stimulating
between RANKL and OPG has recently received
increased interest in proresolving lipid mediators of
inflammation. The Proresolving molecules include
lipoxins that are produced from the metabolism ofendogenous arachidonic acid (AA) and resolvins that
Bisphosphonates are ‘bone-sparing’ agents used
are derived from dietary omega-3 polyunsaturated
in the management of various diseases with bone
fatty acids (n-3 PUFA). Resolvins and protectins are
resorption. These compounds inhibit osteoclastic
two new families of compounds identified in the
activity by blocking acidification by local release and
represent a class of chemical structures related topyrophosphate.28 In a recent study by Tipton et al.29
MODULATION OF HOST CELL RECEPTORS:
Human gingival fibroblasts were derived from
explants obtained from healthy individuals with
Inflammatory cytokines are thought to trigger
noninflamed gingiva. The effects of alendronate and
periodontal tissue destruction. In addition to being
pamidronate on the constitutive production, or the
regulated by anti-inflammatory mediators, their
lipopolysaccharide (LPS)- or IL-1â-stimulated
activity is under the control of suppressors of
production, of IL-6, RANKL and OPG by human
cytokine signaling (SOCS), which down-regulate the
gingival fibroblasts was determined and concluded
signal transduction as part of an inhibitory feedback
that LPS and BPs were not cytotoxic, BPs decreased
loop. The increased expression of SOCS-1, -2 and -3
the production of LPS- or IL-1â-stimulated RANKL and
mRNA in diseased periodontal tissues is believed to
decreased constitutive, LPS-stimulated and IL-1â-
be involved in the down-regulation of inflammatory
stimulated RANKL/OPG ratios. In addition, recent
cytokine and Toll-like receptor signaling.25
media reports announced that cases of jawOsteonecrosis occurred in a trial of zoledronic acid
The immunization of non-human primates in
or denosumab (Amgen, Thousand Oaks, CA, USA) for
ligature-induced periodontitis models with P.
bone metastasis. Denosumab is a fully human
gingivalis or a P. gingivalis virulence factor called
monoclonal antibody against receptor activator of
cysteine protease, has demonstrated partial
Chronic periodontitis could benefit from orally
Pentoxifylline (PTX), a methylxanthine derivative,
administered probiotics. The presence of periodontal
specially blocks the synthesis of TNF-á, among other
cytokines, by inhibiting gene transcription, thereby
antagonistic interactions. A decrease in gum
reducing the accumulation of TNF-á mRNA. The
bleeding and reduced gingivitis has been observed
protective effect of PTX could be explained by its
with the application of Lactobacillus reuteri. Probiotic
capacity to inhibit the production of inflammatory
strains included in periodontal dressings at optimal
cytokines or to stimulate anti-inflammatory cytokine
concentration of 108 CFU ml were shown to diminish
the number of most frequently isolated periodontal
MODULATION OF BONE REMODELLING
pathogens: Bacteroides sp., Actinomyces sp. and S.
Factors regulating osteoblast and osteoclast
intermedius, and also C. albicans.31
activity have become important targets for
WHICH SUBJECTS WOULD PARTICULARLY
developing pharmacological and clinical strategies
BENEFIT FROM HOST MODULATION THERAPY
to modulate the rate of bone formation and
Conventional periodontal therapy is effective in
the management of most cases of periodontitis.
Savage, A., Eaton, K. A., Moles, D. R. & Needleman, I. A
However, there are sub-optimally responding
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