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ABSTRACT
Periodontitis is a polymicrobial infectious disease of multifactorial origin. Plaque bioûlm and associated host responses
are involved in the pathogenesis of periodontitis. Organisms strongly implicated as etiologic agents include Gram-
negative, anaerobic or microaerophilic bacteria within the bioûlm . The microbial challenge consisting of antigens,
lipopolysaccharide (LPS), and other virulence factors stimulates host responses which result in disease limited to the
gingiva (i.e., gingivitis) or initiation of periodontitis. Protective aspects of the host response include recruitment of
neutrophils, production of protective antibodies, and possibly the release of antiinûammatory cytokines including
transforming growth factor-β (TGF-β), interleukin-4 (IL-4), IL-10, and IL-12.Perpetuation of the host response due to a
persistent bacterial challenge disrupts homeostatic mechanisms and results in release of mediators including
proinflammatory cytokines (e.g., IL-1, IL-6, tumor necrosis factor-α [TNF-α]), proteases (e.g., matrix metalloproteinases),
and prostanoids (e.g., prostaglandin E2[PGE2]) which can promote extracellular matrix destruction in the gingiva and
stimulate bone resorption. The determination that periodontal tissue destruction is primarily due to the host response
has created areas of research directed at altering an individual’s reaction to the bacterial challenge the present paper
aims at reviewing various host modulatory therapies (HMT) have been developed or proposed to block pathways
responsible for periodontal tissue breakdown.
Keywords : Polymicrobial disease, host response, proanti-inflammatory cytokines, host modulation therapy.
Antimicrobial therapies both local and systemic “Perioceutics” or the use of the pharmacological
administration along with mechanical debridement is one agents specifically developed to manage periodontitis is
of the mainstay in periodontal treatment strategies, which an interesting and emerging aid in the management of
answered microbial etiology of periodontal diseases, albeit periodontal diseases along with mechanical debridement39.
critical step in a complex chain of events leading to Host modulation therapies are being proposed and
periodontal tissue destruction. These treatment strategies developed to bring down excessive levels of enzymes,
however, failed to block (or) inhibit the host response cytokines, prostanoids, as well modulate osteoclast
mediated tissue destruction to continued bacterial functions.Over the last two decades periodontal scientists
challenge46. have produced and investigated various host modulating
agents in both animal and early human clinical studies.
In 1985, research began to focus very closely on These agents include non-steroidal anti-inflammatory drugs
bacterial-host interaction, leading to “host-bacterial inter- (NSAIDS), sub antimicrobial dose doxycycline (periostat),
relationship era 14. During this era it was recognized that systemic biphosphonates. The non-steroidal anti-
although there is evidence that specific bacterial pathogens inflammatory drugs (NSAIDS) like systemic flurbiprofen
initiate pathogenesis of disease, the host response to these and topical ketoprofen act by inhibiting prostanoids (PGE2).
pathogens is equally important in mediating connective Systemic biphosphonates (alendronate) modulates the
tissue breakdown and bone loss. It has become clear that it osteoclast function and subantimicrobial dose doxycycline
is the host derived enzymes and mediators like matrix (Periostat) utilizes the anticollagenase properties of
metalloproteases (MMPS), cytokines, and other tetracycline. This is the only drug, which is approved by
FDA for clinical use. Future bodes for anticytokine drugs, This present review highlights various host
bone resorption uncouplers, chemically modified modulation therapeutic agents and ongoing development
tetracyclines (CMT’S), anti metabolites and lipoxins. These of safe and effective pharmaco therapies that specially target
provide operators with additional armamentarium to host response mechanism. Introduction of such
mechanical debridement, which could enhance and make pharmocotherapies as an adjunct to the traditional
clinical therapeutic response more predictable, in more periodontal therapies represent a new integrated approach
susceptible host for the better management of periodontal in long-term treatment and management of periodontitis.
disease14.
Plaque bacteria such as porphyromonas gingivalis, If the bacterial challenge is not controlled by these
bacteriodes forsythus and actinobacillus mechanisms and if pathogens and their products penetrate
actinomycetemcomitans remain as primary causative host tissues, the inflammation worsens and progress to
agents. Their introduction as an exogenous infection and periodontitis. However, if these mechanisms fail and if
predominance in the pathogenic flora trigger a cascade of pathogens and their products penetrate host tissues, the
immune responses in the host. Once these bacteria disease becomes periodontitis.
colonizes, the tooth surface near the gingival margins,
bacteria and their metabolic products and the The host monocyte-lymphocytic axis is
lipopolysaccharide (LPS) initiate the host response. The stimulated, leading to the local release of inflammatory
bacteria and their byproducts directly challenge the cells mediators such as arachidonic acid metabolites and
of junctional epithelium. In response, the junctional cytokines. These inflammatory mediators inturn directly
epithelial cells release various inflammatory mediators cause the local tissue destruction, clinically perceived as
including cytokines, PGE 2, MMPs and TNF. These periodontal pocketing and alveolar bone loss in patients.
mediators stimulate the immune response, recruiting In addition, local environmental conditions secondary to
neutrophils to the site of periodontal infection. If these these inflammatory and destructive events (such as low
inflammatory cells are able to contain bacterial challenge oxygen tension and iron availability) continue to support a
and their products (such as LPS endotoxins) by intercellular pathogenic flora and perpetuate the cycle of events
killing mechanisms, the disease limits itself to the gingiva. proposed in the model. (fig.2)
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Host Modulation In Periodontics www.ejournalofdentistry.com
Neutrophil clearance
The Microbial challenge consisting of antigens, Various host modulation therapies (HMT) have been
lipopolysaccharide (LPS) and other virulence factors developed and proposed to block pathways responsible
stimulates host responses, which result in disease limited for periodontal tissue breakdown14 .
to gingiva (that gingivitis) or initiation of periodontitis
One of the tremendous benefits of fundamental research
(Offenbacher, 1996).
which seeks to elucidate key mechanism of host tissue
Protective aspects of the host response include recruitment destruction is the simultaneous identification of critical
of neutrophils, production of protective antibodies and intervention with host modulating agents. So here we have
possibly release of anti-inflammatory cytokines including given an overview of Specific aspects of disease
transforming growth factor– (TGF-), IL-4, IL-10 and IL- pathogenesis for modulation:
12.
Specific aspects of disease pathogenesis for modulation
Perpetuation of the host response due to persistant bacterial
a) Regulation of immune and inflammatory responses.
challenge disrupts homeostatic mechanisms and results in
( Table 1)
release of pro inflammatory cytokines (e.g.: IL-6, IL-1, TNF-
) proteases (e.g.: matrix metalloproteinases) and b) Regulation of excessive production of matrix
prostanoids (PGE2) which can promote extracellular matrix metalloproteinase’s29,45 . (Table 2)
destruction in the gingiva and stimulate bone resorption. c) Regulation of arachidonic acid metabolites32,33,37
The determination that periodontal tissue destruction is (Table 3)
primarily due to the host response, has directed areas of d) Regulation of bone metabolism7,24,42. ( Table 4)
research at altering an individual’s reaction to the bacterial
challenge.
TGF- is an anti-inflammatory
agent which induces synthesis and
secretion of IL-1 is potent
regulator of bone resorption invitro
and it may promote osteoblast
growth and matrix synthesis.
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Host Modulation In Periodontics www.ejournalofdentistry.com
Precursor The activator proteinase first attacks Nagase Organomercuria Insufficient data
activation. the susceptible 1997 l,chaotropic available.
'bait' region (located in the middle of agent CKI,
the propeptide) NaSCN &
detergents
Changes in the propeptide CSDC.
Proteolytic
Rendering the final activation site enzymes:
readily cleaved by a second trypsin,
proteolysis plasmin,
chymotrypsin,
neutrophil
elastase,
cathepsin B and
plasma
kalikrein.
Substrate A certain level of regulation of MMP Insufficient data
specificity activity is encoded at the level of the available.
substrate, although enzymes have
somewhat overlapping substrate
specificities.
MMP inhibition -macroglobulins, particularly 2-M play Rayan and Tetracycline, Tetracycline apart
( TIMP’s)45,18,27. an important role in the regulation of MMP Golub 2000, CMT from its antimicrobial
activity by bond cleavage region. Brew 2000, Minocycline, property has
The inhibition probably occurs as a result Kinane Doxycycline ( capability of
of binding the TIMP’s at the MMP active 2000, Lee sub inhibiting the
site. However, the amino acid residues in 1995. antimicrobial activities of
TIMP’s that are responsible for binding at dose of neutrophil,osteoclast,
the active site of MMP’s are still unknown. doxicycline), MMP 8, thereby
lipoxins, working as anti-
Lipoxins regulate local acute inflammatory resolvins. inflammatory agent
responses in periodontal disease by limiting that inhibits bone
neutrophil recruitment and neutrophil destruction.
mediated tissue injury.
proliferation and cytokine production, and increase osteoclasts following pulp exposure (Indahyani et al., 2002),
endogenous host anti-oxidant capacity, e.g., SOD and significantly reduced the gingival tissue levels of lipid
catalase (Alam et al., 1991; Blok et al., 1992; Fernandes and inflammatory mediators in LPS-induced experimental
Venkataraman, 1993). These effects have been proposed to periodontitis (Vardar et al., 2004), and reduced osteoclastic
account for the potent anti-inflammatory properties of activity and alveolar bone resorption although Rosenstein
omega ()-3 fatty acids (FA) in human, non-human primate, et al. (2003) suggested that dietary fatty acid
and rodent disease models. While much of the attention supplementation in adult periodontitis correlated with an
over the last decades has focused on the beneficial effects improvement in gingival inflammation. Treatment of rats
of fish oil, particularly the -3 FA components, on a v a r i e with fish oil significantly reduced osteoclasts and pre-
t y of ch r on i c in fl a m m a t or y di sea ses (c osteoclasts following pulp exposure (Indahyani et al., 2002),
a r d i o v a s c u l a r d i s e a s e , rheumatoid arthritis), few significantly reduced the gingival tissue levels of lipid
studies have examined its effects on the chronic immuno- inflammatory mediators in LPS-induced experimental
inflammatory lesions of periodontal disease. In a recent periodontitis (Vardar et al., 2004),ion, suggesting that this
study, eicosapentaenoic acid (EPA) and docosahexaenoic model may be useful in exploring host bacterial interactions
acid (DHA), principal - 3 polyunsaturated fatty acids (PUFA) leading to periodontitis (Iwami-Morimoto et al., 1999). The
present in fish oil, were shown to decrease osteoclast hypothesis tested in this investigation was that a fish-oil-
activation in vitro (Sun et al., 2003). Campan et al. (1996, supplemented diet would modulate the host response to
1997) reported that human experimental gingivitis appeared oral P.gingivalis determined by decreased alveolar bone
to be modified by -3 FA, although no definitive conclusions resorption in rats.
were provided. It has also been reported that the n-6 PUFA
levels in the serum are higher in periodontitis patients, After reviewing the work of various researchers in the field
suggesting that an imbalance between n-6 and n-3 fatty of perioceutics the following articles were selected to be
acids may contribute to susceptibility to oral bone loss reviewed on the basis of various criteria such as size of the
(Requirand et al., 2000). Topical application of n-3 or n-6 study sample, validity of the material and methods and
fatty acids failed to inhibit the development of experimental follow up period in the study.
gingivitis (Eberhard et al., 2002), osteoclasts and pre-
Howell th, To study the effects of piroxicam in Piroxicam Gingival Beagle dogs Significantly inhibit
fiorellini i, preventing gingival inflammation inflammation, the development of
weber hp et and plaque formation plaque index gingival inflammation
al (1991)14
Nip lh, vitto To know the effects of tetracycline Oxytetracycline, Radioactive
vj et al on periodontal epithelial cells were doxycycline and gelatin Results showed that
(1993)26 investigated by culture in cells from de- degradation and periodontal epithelial
porcine rests of malassez dimethylamino gelatin cells produce MMP’s
tetracycline enzymography whose activities are
inhibited by
tetracycline and their
non-antimicrobial
analogues at
concentration present
in gingival crevicular
fluid following
tetracycline therapy.
Roy S, To evaluate the effect on bone Aspirin (asp) or Radiographs Humans Percentage bone loss
Feldman, resorption: A retrospective study aspirin plus for the entire
Szeto B et al indomethcin dentition was lower in
(1983)38 asa group
Weaks– To determine if prostaglandins Indomethacin Alveolar bone Squirrel monkeys Indomethacin
Dybvig M, play a role in loss of bone in 5mg / kg /day height treatment abolished
Farshid ligature model of periodontitis the significant loss of
Sanavi et al alveolar bone height
(1982)47
Offenbacher To examine four principal Flurbiprofen Crevicular fluid Rhesus monkey It prevented rise in
S, Odle BM metabolites of cyclooxygenase levels of PGE2 TXB2, but did not
et al (1989)30 (co) during the progression of and TXB2 affect the increase in
experimental periodontitis PGE2.
Meikle MC, To investigate the effect of TNF- Exogenous TNF- (or) IL-1 in
Atkinson SJ (or) il-1 on human gingival human timp collagen degradation
et al (1989)21 fibroblasts (hgf’s), stimulated on human gingival
collagenolysis. fibroblast.
Heasman PA Long-term efficacy of non- NSAID’s Plaque index, Humans Highly significant
and Seymour steroidal anti-inflammatory drug gingival index differences were seen
RA (1990)11 (nsaid) therapy. pocket probing between GCF flow in
depth, loss of study (16.74b±28.63)
attachment, groups.
gingival
recession, and
gingival fluid
flow
Taiyeb ali To investigate the influence of Ibuprofen Gingival Humans Significantly greater reduction
TB and short-term ibuprofen therapy on the bleeding, color for all parameters.
Waite IM early phase of the treatment of and pocket
(1993)43 adult chronic periodontitis. depth
Heasman To evaluate the efficacy of Flurbiprofen GCF Human
PA, flurbiprofen (50mg) on both concentration Flurbiprofen control gingival
Offenbac developing and established of PGE2, TXB2 inflammation with both
her S et al gingivitis and LTB4, preventive and therapeutic
(1993)10 Bleeding index properties.
Shoji K, Efficacy of risendronate to prevent Risendronate Bone mineral Rats. In preventing bone resorption
Horiuchi alveolar bone resorption density in periodontitis.
H and
Shinoda
H
(1995)42
Mathur To evaluate the concentration of Gingival Humans
a, IL-1 IL-8) and interferon- in crevicular fluid. IL-8 and interferon- were
Michalow periodontitis patients. significantly correlated in
icz b, et al diseased sites, suggesting that
(1996)20 levels of these two cytokines
rise (or) fall in tandem.
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Host Modulation In Periodontics www.ejournalofdentistry.com
M y oung H , T o ev alu a te th e clin ic al av ailab ility B is p h o sp h o n ates C lin ica l R a ts C lin ical ap p lica tio n o f
P a rk J Y et a l o f b is p h o sp h o n a te in au to g en o u s m e asu re m en ts, b isp h o sp h o n ates fo r
(2 0 0 1 ) 2 5 fre e b o n e g rafts h isto m o rp h o lo g i d ecreas in g res o rp tio n o f
cal rev ie w g ra fte d b o n e .
R a m a m u r-th y T o ev alu a te th e effic ac y o f to p ica l C lo d ro n a te B o n e m in eral R a ts . T o p ic a l a d m in istra tio n o f
N S , B a in s e t ad m in istratio n o f a b ip h o sp h o n a te d en sity c lo d ro n a te m a y b e
34 in p rev en tio n o f a lv e o lar b o n e lo ss
a l (2 0 0 1 ) e ffe c tiv e in p re v e n tin g
in rats w ith e x p erim en ta l o ste o c la stic b o n e
p erio d o n titis.
re so rp tio n in
p e rio d o n titis.
Z ha n g D , In v estig ate th e ro le o f il- 1 an d TNF α R eces sio n H u m an s T h e am o u n ts o f ro o t
G o e tz W e t tu m o r n ecro sis fa cto r alp h a h eig h t, w id th . reso rp tio n w as sig n ifica n tly
a l (2 0 0 3 ) 48 (T N F ) in th e co u rs e o f red u ce d , esp ecially
m e ch a n ically in d u ced ro o t fo llo w in g s y ste m ic
res o rp tio n . a p p licatio n o f T N F α , ro o t
reso rp tio n w as co m p letely
p re v en ted .
A u th o r P u rp o se H o st P a ram e ters S u b je c ts R e s u lt s
m o d u la ti n g
a g en t
H is - M i n g L e e , T o e v a lu a t e e f f ic a c y o f t h e D o x y c y c li n e , H o s t- d e r iv e d H um ans
S e b a stia n G e t a l a d m in is t r a ti o n o f s u b f lu r b ip r o f e n n e u tra l C o m b i n a ti o n t h e r a p y
(2 0 0 4 ) 12 a n t im ic r o b ia l d o s e d o x y c y c l in e p r o t e in a s e s p r o d u c e d a s t a ti s ti c a l ly
t o c h r o n ic p e r i o d o n ti ti s p a ti e n ts le v e ls s ig n if i c a n t s y n e r g is t ic
a n d N S A ID ’s. r e d u c ti o n o f c o l la g e n a s e .
C h ia r a S , T a t a k is T o d e t e r m in e th e a s s o c i a t io n o f I L - 1 le v e ls H um ans
D N e t a l (2 0 0 5 )4 i n te r l e u k in - 1 ( I L - 1 ) g e n e A s s o c i a ti o n b e t w e e n I L - 1
p o l y m o r p h i s m s w ith c l in i c a l p o ly m o r p h is m a n d
p a r a m e t e r s o f g i n g i v i ti s i n l a r g e s u b je c t b a s e d c l in ic a l
e x p e r i m e n ta l g in g i v iti s b e h a v i o u r o f g in g i v a in
r e s p o n s e to p la q u e
a c c u m u la t io n , a s w e l l a s
a p o s s ib l e a s s o c i a tio n
b e tw e e n I L - 1
p o ly m o r p h is m a n d
g i n g iv it is s u s c e p t ib i li ty .
D u r a te P M , T o e v a lu a t e w h e th e r A le n d r o n a t e E s tr o g e n O v a r ie c t o
G u r g el B C D e t al a le n d r o n a te ( a ld ) in fl u e n c e le v e ls m i z e d r a ts . A l e n d r o n a te m a y p r e v e n t
(2 0 0 5 ) 7 b o n e h e a li n g a r o u n d tit a n iu m n e g a t iv e i n f lu e n c e o f
i m p l a n ts i n s e r t e d i n e s tr o g e n d e f ic i e n c y o n
o v a r i e c t o m i z e d r a ts . b o n e h e a l in g a r o u n d
ti ta n i u m i m p l a n ts .
S ek in os, T o s tu d y t h e e f f e c t o f s y s t e m i c Ib u p r o fen , P l a q u e in d e x H um ans T h e s u b je c t s r in s e d w i th
R am b erg P et al a d m in is t r a ti o n o f i b u p r o f e n o n c h lo r h e x id in e a n d g i n g iv a l s a li n e a c c u m u la t e d l a r g e
(2 0 0 5 ) 40 g in g i v i ti s a n d p l a q u e b u i ld . d i g l u c o n a te in d e x a m o u n t s o f p la q u e a n d
d evelo p ed m arked sign o f
g i n g iv it is .
T h e p a ti e n ts p r e s e n t e d
w i th s i g n if ic a n t l y f e w e r
s it e s t h a t s c o r e d G in g i v a l
in d e x 2
H o lz h a u s e n M , T o e v a lu a t e t h e e f f e c t o f E to r ic o x ib W B C coun t W i s te r r a t s G r o u p s tr e a te d w it h b o t h
S p o li d o r i D M P e t s e l e c t iv e c y c l o o x y g e n a s e - 2 a n d se ru m d o s e s o f e t o r ic o x i b h a d
a l (2 0 0 5 )1 3 ( c o x - 2 ) i n h ib it o r , e t o r ic o x ib i n le v e ls , d ig it a l s ig n if i c a n tl y l e s s a l v e o la r
t h e p r e v e n t io n o f a lv e o l a r b o n e ra d io g ra p h s b o n e lo ss co m p ared to
l o s s i n e x p e r im e n ta l c o n tr o l s .
p e r i o d o n ti ti s .
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Host Modulation In Periodontics www.ejournalofdentistry.com
Recent research has examined the inflammatory and 5. Crout RJ, Lee HM, Schroeder K, Crout H, Golub LM, et al. The ‘cyclic’ regimen
of low dose doxycycline for adult periodontitis: A preliminary study. J
resolution cascade in greater detail while looking at Periodontol 1996; 67: 506-514.
endogenous and exogenous mediators that can be utilized 6. Delima AJ, Oates T, Assuma R, Schwartz Z, Cochran D, Amar S. Soluble
to achieve therapeutic end-points. The possible antagonists to interleukin-1 (IL-1) and/and Graven DT: tumour necrosis
introduction of “resolution indices” for drug testing factor (TNF) inhibits loss of tissue attachment in experimental periodontitis.
J Clin Periodontol 2001; 28: 233-240.
warrants a new look at pharmacologic agents that might
7. Durate PM, Gurgel BCD, Sallum AW, Filho GN, Enilson and Nociti Jr.
have been overlooked for their beneficial effects in Alendronate therapy may be effective in the prevention of bone loss around
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fragments and specific collagenases in gingival crevicular fluid during adult
Host response modulation has emerged as a valid treatment periodontitis. J Inflamm Res 1997; 46: 310-319.
concept for the management of periodontal disease and
9. Golub LM, McNamara TF, Ryan ME, Kohut B, Blieden T. Adjunctive treatment
represents a significant step forward for clinicians and with substantimicrobial doses of doxycycline: effects on gingival fluid
patients. To date, only sub antimicrobial dose doxycycline collagenase activity and attachment loss in adult periodontitis. J Clin
Periodontol 2001; 28: 146-156.
has been approved specifically as a host response
modulator. Further research is necessary to evaluate the 10. Heasman PA, Offenbacher S, Collins JG, Edwards G and Seymour RA.
Flurbiprofen in the prevention and treatment of experimental gingivitis. J
efficacy of sub antimicrobial dose doxycycline in primary Clin Periodontol 1993; 20: 732-738.
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inhibitor in chronic periodontitis patients is enhanced when combined with
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