LIBRARY DISSERTATION:

HOST

MODULATION

TABLE OF CONTENTS

1. Introduction

2. Host modulation agents

3. MMP inhibition

4. Modulation of Arachidonic acid metabolites

5. Modulation of bony remodelling

6. Cytokines

7. Modulation of cell signalling pathways

8. Locally administered host modulators

INTRODUCTION

Over the last two decades it has become more evident that although oral microorganisms are essential agents of periodontal pathogenesis, interpatient variability in the host response is a major determinant of the expression of periodontal disease extent and severity.

many of the components of the host inflammatory response which serve as critical mediators of clinical inflammation, attachment loss, and bone resorption have now been identified

Until the 1970s, treatment strategies for periodontal disease were based on the understanding that plaque bacteria and their products primarily mediated the tissue destruction in affected patients.

This concept changed when investigators began to document the host’s contribution to disease pathogenesis.

William and colleagues showed that even in presence of excessive bacterial burden, it is possible to block disease progression significantly with a non-steroidal anti-inflammatory agent.

Golub and coworkers showed that collagenase enzymes were an active component of destructive process in Periodontitis.

Horton et.al., (1972) further documented that endotoxin-stimulated lymphocytes secreted a soluble factor (later characterized as the cytokine, interleukin-1) that stimulated osteoclastic activity and bone resorption in organ culture.

Page and Schroeder (1976) chronicled the histopathogenic events in the initial, early, established and advanced lesion in which different host cells such as polymorphonuclear leukocytes, lymphocytes, fibroblasts & macrophages come to occupy periodontal tissues with ensuing destruction.

The microbial challenge consisting of antigens, lipopolysaccharide (LPS), and other virulence factors stimulates host responses which result in disease limited to gingiva (i.e., gingivitis) or initiation of periodontitis (Offenbacher, 1996).

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- (TNF- ), proteases (e.g., matrix metalloproteinases), and prostanoids (e.g., prostaglandin E2) 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.

Various host modulatory therapies have been developed or proposed to block pathways responsible for periodontal tissue breakdown.

HOST MODULATION – “ the alteration of function or status of the host , in response to a stimulus or an altered chemical or physical environment”

Host modulation therapy (HMT) – is a treatment concept that aims to reduce the tissue destruction and stabilize or even regenerate the Periodontium by modifying or down regulating destructive aspects of the host response and up regulating protective or regenerative responses

HMT – simply ,it is treating the host side of the host bacteria interaction

HOST MODULATION AGENTS

CAN BE CLASSIFIED AS:1. Agents that block direct effectors of bone and

connective tissue destruction

Bisphosphonates Matrix metalloproteinases inhibitors like

Subantimicrobial dose doxycycline, Chemically modified Tetracyclines

2. Those that block host mechanisms that regulate direct effectors of inflammation

Non- steroidal anti-inflammatory agents Inhibitors of IL-1 and TNF

3. Block other regulators of host defenses.

ALTERNATE CLASSIFICATION:

1. Systemically administered agents e.g Non steroidal anti-inflammatory agents, Bisphosphonates, Subantimicrobial Dose Doxycycline etc 2. Locally administered agents e.g. Enamel matrix proteins Growth factors Bone morphogenetic proteins etc

1. INHIBITORS OF MATRIX METALLOPROTEINASES

• (MMPs) are a family of zinc and calcium-dependent endopeptidases

• secreted or released by a variety of infiltrating cells (i.e., neutrophils, and macrophages) and

• resident cells (i.e., fibroblast, epithelial, osteoblast and osteoclast) found in periodontium (Ryan & Golub, 2000)

• MMPs function at a neutral pH to degrade constituents of the extracellular matrix (e.g., collagen, gelatin, laminin, fibronectin, and proteoglycan).

• One hypothesis regarding periodontal disease pathogenesis is that host cells stimulated directly or indirectly by components of the plaque biofilm secrete MMPs which are associated with altered connective tissue remodeling and alveolar bone resorption (Golub et al.,1995)

• Although several periodontal pathogens (e.g., P. gingivalis and A. actinomycetemcomitans) produce MMPs, including collagenase, these proteinases are not considered to be the major destructive enzymes associated with disease progression.

•Host cells responsible for the excessive MMPs in periodontitis have not been definitively demonstrated.

•Several studies implicated polymorphonuclear leukocyte-type collagenase (MMP-8) and gelatinase (MMP-9) as the source of excess active enzymes. (Golub et al.,1997)

•It has been demonstrated that MMP-8 may originate from cell types other than neutrophils including fibroblasts and mesenchymal cells.

•Additional studies are required to verify the origin of MMPs and their roles in disease pathogenesis.

•Recognition that the level of activated MMPs and their endogenous inhibitors is related to various pathological conditions including periodontal disease has resulted in treatment strategies that increase endogenous inhibitors or include the administration of exogenous (synthetic) inhibitors.

•Endogenous or natural inhibitors of MMP activity include

1. tissue inhibitors of MMP (TIMP) (in tissues)

2. 2-macroglobulin. (in serum)

3. Glycoprotein 1- antitrypsin (in serum)

TIMP

•While TIMP levels increase during pathologic conditions, this increase may not compensate for elevated concentrations of active MMPs (Bell et al., 2001).

•Most important in periodontal disease is TIMP-1

•Acts on MMPs pericellularly

•Furthermore, cell culture studies have demonstrated that “recombinant TIMP” can reduce stimulated bone resorption.

•Therefore administration of recombinant TIMP might be an effective treatment modality and should be evaluated.

α2 MACROGLOBULIN

functions as a regulator of MMPs in body fluids.

During inflammation however, α2 macroglobulin, which is a high molecular protein, may escape vasculature and also function on the extra cellular matrix.

Exogenous inhibitors

1. Zinc and Calcium chelating agents :

•EDTA & phenanthroline are potent inhibitors of enzyme activity in vitro but are toxic and not used in vivo.

2. Phosphorus containing peptides – are potent inhibitors of metalloproteinases produced by the substitution of a tetrahedral phosphorus atom for the carbonyl carbon atom in a peptide substrate.

•Phosphonamidate and phosphinate analogues of tri-peptide can inhibit human skin fibroblast collagenase in vitro.

3. Sulphur based inhibitors – These were prepared by replacing the scissile C(=O)-NH bond of the peptide with various sulphur containing functional groups.

The mercaptan derivatives are the most potent inhibitors of collagenases, gelatinases and stromelysins of all the sulphur based inhibitors of MMPs in vitro.

4. Peptidyl hydroxamic acid derivative – These are capable of inhibiting MMPs 1,2,3,7,8 and 9 in vitro with very low levels at which collagenase activity declines by 50%. • most widely used synthetic peptides and are receiving the most attention as potential pharmaceutical agents.

Galardin™ designed for topical use in non-healing corneal ulcers

Batimastat™ - in clinical trials for breast cancer (parenterally administered)

Marimastat™- orally administered for four different types of cancer including ovarian, prostatic, pancreatic and gastrointestinal malignancies.

Unfortunately recent reports from these clinical trials imply that these compounds may not have sufficient specificity to prevent unwanted toxicity, with adverse events including joint pain and stiffness indicating unwanted interactions with the wrong MMPs.

TETRACYCLINE ANALOGUES

•The synthetic MMP inhibitors most extensively investigated are the family of tetracycline antibiotics which can inhibit host-derived MMPs by mechanisms independent of their antimicrobial properties.

•In vivo animal and human studies have demonstrated that tetracyclines inhibit MMP levels in gingival tissue and GCF with concomitant improvements in periodontal status.

•Tetracycline appear to inhibit MMP activity and extracellular matrix destruction by multiple non-antimicrobial mechanisms (e.g., chelation, inhibition of activation of pro-MMP molecules) (Golub et al., 1998).

•The development of HMT utilizing tetracyclines has primarily involved the use of a reduced dose of doxycycline (20 mg bid).

•This dose has been reported not to exhibit antimicrobial effects, but can effectively lower MMP levels (Golub et al., 1997).

•This reduced dose has been referred to as sub-antimicrobial dose doxycycline (SDD).

• FDA approved for depressing host enzymes – collagenases

• 20mg capsule given 2 times daily

• Duration: 3-9 months

• No bacterial resistance has been reported.

• Decrease probing depth & increase attachment gain

DURATION OF THERAPY (GOLUB ET AL)

2 week regimen: reduced collaenase in gcf

1 month: after cessation, a rapid rebound of collagenase activty to placebo levels; hence 1 month insufficient.

3 months: prolonged effect without rebound

But, it is reasonable to speculate that levels will increase again in patients with more risk factors. Hence more frequent HMT with SDD in such patients.

1. EFFECTS OF DOXYCYCLINE

2. Direct inhibition of active MMPs by cation chelation (dependent on Ca2+- and Zn2+-binding properties)

3. Inhibits oxidative activation of latent MMPs (independent of cation-binding properties)

4. Downregulates expression of key inflammatory cytokines (interleukin-1, interleukin-6 and tumor necrosis factor-a) and prostaglandin E2

5. inhibits production of reactive oxygen species produced by neutrophils

6. Inhibits MMPs and reactive oxygen species thereby protecting a1-proteinase inhibitor, and thus indirectly reducing tissue proteinase activity

7. Stimulates fibroblast collagen production

8. Reduces osteoclast activity and bone resorption

9. Inhibits osteoclast MMPs.

10. Improving osteoblastic activities

With regard to the issue that low dose antibiotics could result in microbial resistance, several in vivo human studies have indicated that long-term (i.e., 9 to 18 months) administration of SDD does not result in emergence of resistant organisms or alteration of the subgingival microflora.

(Walker et al., 2000)

NEW -Modified release subantimicrobial dose doxycycline

“ORACEA” approved by FDA commonly used in dermtology communityo 40 mg once daily with SRP rather than 20 mg b. d

o (Preshaw et al (2008) : 9 month double blind randomized placebo controlled multicenter study on 266 subjects

o There was statistical significance decrease in the probing pocket depth and reduction in the B.O.P

o Showed similar results in their earlier study using 20 mg b.i.d

SDD FOR SPECIAL PATIENT POPULATION

SDD in periodontitis – associated genotype patient (IL-1 polymorphism)

Variation in genes that regulate IL-1o Al Shammari et al (2001) treated above

patients with SRP alone and SRP with SDD for 2 to 4 months

o They assessed the IL-1 b and MMP-9 level as biochemical marker

o There was no reduction in the above markers with the SRP alone, but 50 -61% decrease in this after SDD

SDD – Generalized Aggressive periodontitis patients

o Novak MJ et al(2002) – studied 70 patients , in a 9 month, double blind, placebo controlled study

o There was significant gain in probing depth reduction in pockets of 7 mm or greater at base line as early as 1 month after therapy

o This effect was maintained 3 months after the stopping the drug therapy, demonstrating the no rebound effect

SDD in Smokerso Preshaw et al(2005) evaluated SDD in smokers and

non smokers and compared with the placebo for 9 months along with SRP

o Non smokers with SDD showed greatest improvement

o Smokers with SDD and nonsmokers with the placebo showed the intermediate improvement

o Smokers with the placebo showed the poorest treatment response

o Concluded that even patient considered traditionally resistant for the SRP will benefit from the SDD

SDD along with local drug delivery antibiotics

o Preshaw et al (2006) did a clinical trial of SDD + SRP along with the Atridox and compared with the SRP alone

o Patients in the test group showed more than 2 mm improvement in mean attachment gain and probing depth reduction compared to SRP alone

o They concluded that combined therapy maximize the treatment benefit and they also said that it is safe to use with LDD without untoward effect

Indications Chronic periodontitis Disease resistant

patients Patients with

generalized aggressive periodontitis

Smokers and PST positive patients

Contraindications H/o allergy or

hypersensitivity to tetracyclines

Pregnant or lactating women

Children less than 12 years

Patient who are on OC

SEQUENCING PRESCRIPTION WITH PERIODONTAL TREATMENT

o SDD not to be used as a stand alone therapyo It is combined with the first episode of SRP for 3

months up to a maximum of 9 monthso For patient demonstrating the good response

after the first 3 months plaque control therapy to be continued

o Risk category patients and patients do not respond to the initial treatment SDD to be continued

o Patients may cycle between phases of active treatment ( SRP +SDD ) and long term periodontal maintenance

CONTRAINDICATION

Pregnant and lactating females Children younger than 12 years With oral contraceptives Allergic to tetracyclines

Golub et al (1987) recognizing that the antimicrobial and anticollagenase properties of tetracycline may reside in different parts of the molecule

That this newly discovered property of tetracyclines could provide a new approach to the treatment of diseases, such as periodontal disease.

Chemically modified tetracyclines

o Golub et al (1987) produced the first of the chemically modified tetracyclines now called CMTs by removing the dimethyl amino group from the carbon-4 position [this side chain is required for the antimicrobial activity of tetracyclines] and found that the resulting compound 4-de-dimethyl amino tetracycline, or CMT-1 had lost its antimicrobial property but retained

o (actually showed enhanced anti-collagenase activity both in vitro and in vivo.)

Chemical name- 4 de dimethyl amino

tetracycline (CMT)

CMT 1- 10 are found, among this

o CMT 1,3, 6, 7,8 – are effective inhibitors

o CMT- 3 is the most potent compound

o CMT -5 is ineffective

o CMT – 2, 4 inhibits MMP- 8, but not MMP -13

Beneficial effect

Potent inhibitor of proinflammatory mediators,

Increases the level of IL-10, an anti-inflammatory mediator

Inhibit osteoclastic bone resorption and promote bone formation

Enhance wound healing Inhibit proteinase produced by periodontal

pathogens

REGULATION OF ARACHIDONIC ACID

METABOLITES

•Both bacterial and host factors initiate tissue damage.

•This damage allows phospholipids in plasma membranes of cells to become available for action by phospholipase A2 and thereby results in production of free arachidonic acid (AA).

•This AA can be metabolized via the cyclooxygenease (CO) or lipoxygenase (LO) pathways.

•Two isoforms of cyclooxygenase are now recognized.

•Cyclooxygenase 1 (COX-1) is constitutively (i.e., continuously) expressed and is important for physiologic functions including gastric cytoprotection.

•Cyclooxygenase 2 (COX-2) is inducible, upregulated by proinflammatory cytokines, and thought to be involved in inflammation.

•The final products of the CO pathway include prostaglandins, prostacyclin, and thromboxane, whereas the end results of the LO pathway include leukotrienes and other hydroxy-eicosa-tetraenoic acids.

Tissue damage

Membrane Phospholipids

Arachidonic Acid

Prostaglandins (PGE2)ProstacyclinsThromboxane

Lipoxygenase

5-HETELeukotrienes (LTB4)

Lipoxins

COX-1& COX-2

Cell-cell andEnzyme

Interactions

ENZYMATIC SYNTHESIS OF ARACHIDONIC ACID METABOLITES IN RESPONSE TO TISSUE DAMAGE

•Mean crevicular PGE2 concentrations are also significantly elevated in patients who exhibit disease progression compared to periodontally stable individuals.

•One proposed approach to modulate the host response is inhibition of enzymes responsible for the release of these destructive products.

•The discovery that non-steroidal anti-inflammatory durgs (NSAIDs) block the enzyme CO and reduce prostaglandin synthesis led to in vitro studies evaluating NSAIDs as inhibitors of bone resorption.

•

•Inhibition of periodontal disease progression utilizing a NSAID was first demonstrated with indomethacin in a ligature-induced canine periodontitis model.

•Multiple NSAIDs including indomethacin, flurbiprofen, ibuprofen, naproxen, meclofenamic acid, and piroxicam have demonstrated the ability to inhibit gingivitis and progression of periodontitis in both ligature induced and naturally occurring periodontal disease animal models.

Following Vane’s landmark discovery in 1971 that aspirin and NSAIDs blocked cyclooxygenase as their mechanism of action, various NSAIDs have been studied in regulating periodontal disease.

1. Goldhaber et al. (1973) – Indomethacin

2. Nyman et al. (1979) – Indomethacin

3. Weaks-Dybvig et al (1982) – Systemic Indomethacin

4. Offenbacher et al (1987) – Flurbiprofen

5. Jeffcoat et al (1991) – Ibuprofen

6. Howell et al (1991) – Naproxen

7. Willams et al (1988) – Topical Flurbiprofen

8. Kornman et al (1990) – Ibuprofen/Meclofenamic acid

9. Howell et al 1991 – Piroxicam gel

•The most extensive clinical trial that investigated a systemically administered NSAID (flurbiprofen) demonstrated significantly lower bone loss rates over an 18-month period.

•However, disease progression returned upon withdrawal of the agent.

•“Rebound effect”

•Therefore, it appears that the drug did not provide any residual effect and would require prolonged administration to maintain periodontal status.

•Extensive data acquired in animal and human clinical trials have demonstrated the potential clinical utility of NSAIDs in the management of periodontitis.

•However, adverse effects associated with prolonged systemic administration of non-selective NSAIDs that possess both COX-1 & COX-2 inhibitory activity include gastrointestinal upset and hemorrhage, renal and hepatic impairment.

•These adverse events associated with systemic use of NSAIDs have precluded their incorporation into treatment regimens.

•Selective COX-2 inhibitors :

•selectively block the isoenzyme associated with inflammation (COX-2) and spare COX-1 that has a homeostatic function

•Initial results were encouraging.

•Later, singnificant and life threatening side effects observed, hence withdrawal.

•Safety and efficacy evaluations continue for these drugs.

•However, at this time no NSAID formulation is FDA approved for the management of periodontal diseases.

•Lipoxins are a series of oxygenated arachidonic acid derivatives formed by interactions between individual LO and appear to function as endogenous anti-inflammatory mediators.

•Recently, it was demonstrated that lipoxins are produced by peripheral blood neutrophils from patients diagnosed with aggressive periodontitis.

•In addition, lipoxins have also been found in the GCF of these individuals.

•In a mouse model, it was shown that administration of metabolically stable analogues of lipoxins blocked P.gingivalis elicited neutrophil infiltration and also reduced PGE2 levels.

•These results support the concept that lipoxins may be involved in the regulation of local acute inflammatory responses in periodontal disease.

•However additional studies are needed to elucidate the role of lipoxins in the pathogenesis of periodontitis.

MODULATION OF BONE REMODELLING

THE TARGET-OSTEOCLAST : BISPHOSHONATES IN HMT

o Overproduction of osteoclast by the fusion of their precursors or their activation by proinflammatory cytokines responsible for the bone loss

o Therefore use of a drug that inhibit osteoclast function/and or formation- promising

BISPHOPHONTATES- ANTIRESORPTIVE AGENTS

BPs are synthetic

chemical drugs similar to

endogenous regulators of

bone pyrophoshates,

which have capacity to

chelate calcium and to

regulate the bone

mineralization process

GENERATION OF BPS First- has alkyl side

chains- Eg : Etidronate

Second – has aminoterminal side chain-Eg : Alendronate

Third – cyclic side chain- Eg: Zolendronate

CELLULAR EFFECT OF BISPHOSPHONATES

systemic administration of BPs BPs are adsorbed selectively on bone surfaces and

present in all areas of high bone resorption activity areas

Then they are possibly endocytosed in the osteoclast and they interfere with various intracellular biochemical process

CELLULAR EFFECT OF BISPHOSPHONATES

Non nitrogenous containing BPs (clondronate and etidronate) –inhibit osteoclast proton pumping vacuolar ATPase- which plays a crucial role in the resorption process by pumping protons in the resorption lacunae

More potent BPs(zolendronate & pamidronate) cause loss of the ruffled border as well as alteration of the cell morphology, disrupting the key regulatory protein – leads to loss of osteoclast activity

o BPs found to be inducing apoptosis of osteoclasto It reduces RANKL\OPG ratio by increasing the level of OPGo It also inhibits differentiation and maturation of

osteoclastso Gun-Im et al(2006)- suggested that BPs may have

osteogenic action promoting osteoblast differentiation and maturation.

Antiinflammatory effect BPs seem to have inhibitory effect on inflammatory

mediators and MMPs New BP (TRK- 530) showed this anti-inflammatory

property, in mice(Takeyamaa et al 2006) This effect has been enhanced further in the presence of

doxycycline

ADVERSE EFFECTS

High dose of BPs – may cause increased periodontal destruction and inflammation

High dose may stimulate the proinflammatory cytokines such as IL-1 and IL-6

Nitrogen containing BPs – could reduce the collagen production thus reconstitution of the Extracellular matrix of the injured periodontal tissue is prevented

AVASCULAR OSTEONECROSIS OF JAW

Also called as osteochemonecrosis or bisphophonate associated osteonecrosis

Most commonly seen after oral surgery or dental extraction procedure

First reported cases seen only with the IV use of zolendronate and palmidronate (2003)

Also seen with oral administration of alendronate in 0.7% 1/100,000

Reasons for AONJo Severe suppression of bone turnover that may impair

bone biomechanics and reparative capacityo BPs has antiangiogenic propertyo Hoefert et al (2006) said that it is due to sequestra

formation and is initiated by the passage of oral microorganisms to bone tissue

DISRUPTION OF THE RANKL/RANK/OSTEOPROTEGERIN AXIS

The RANKL/RANK/osteoprotegerin axis

RANKL mediates a signal for osteoclastogenesis through RANK on pre-osteoclast cells.

The RANKL/RANK interaction is responsible for differentiation and maturation of osteoclast precursor cells to activate osteoclasts.

Osteoprotegerin (OPG) acts as a decoy receptor, expressed by osteoblastic cells, which binds to RANK and inhibits osteoclast development.

MECHANISMS OF DOWNREGULATION OF RANKL

DIRECT THERAPEUTIC APPROACHES (i) Interference with co-stimulatory molecules

required for RANKL production.

(ii) Control of signaling pathways regulating RANKL expression in immune cells,

(iii)Down- regulation of lymphocytic RANKL expression by manipulation of cytokine balance.

INDIRECT THERAPEUTIC APPROACHES

(iv) Physiological blockade of RANKL–RANK interaction,

(v) Deactivation of the enzyme that releases soluble RANKL from membrane-bound RANKL

(vi) By interfering with lymphocyte-derived

RANKL mediated osteoclastogenesis.

ROLE OF OSTEOPROTEGRIN

The use of osteoprotegerin as a therapeutic agent was first evaluated by Simonet et al. when they treated ovariectomized rats with murine osteoprotegerin-Fc protein and protected them against losses of bone volume associated with deficiencies of estrogen.

Other studies demonstrated that OPG blocked increased osteoclast formation responsible for resorptive processes in rheumatoid arthritis patients and periprosthetic bone tissue.

An OPG mimetic drug called “DENOSUMAB” has been introduced which has high affinity for RANKL and affects osteoclasts by inhibiting their formation, function and survival.

Denosumab inhibits this maturation of osteoclasts by binding to and inhibiting RANKL. This mimics the natural action of osteoprotegerin

 It was developed by the biotechnology company Amgen.

In June 2010, became the first RANKL inhibitor to be approved by the FDA for use in postmenopausal women with risk of osteoporosis under the trade name Prolia.

Hesham El-Sharkawy (2012) in a clinical trial consisiting of 36 post menopausal women taking the drug observed that Densumab (DNS) treatment improved periodontal disease and reduced bone turnover markers.

Based on pre-clinical animal studies and on preliminary human clinical studies, the osteoprotegerin/RANKL/RANK axis is a new target for the treatment of destructive periodontal disease and other bone resorption-related diseases.

Further studies are necessary to determine the most efficacious therapeutic approach on that molecular interaction.

CYTOKINES

Key mediators of inflammation Soluble proteins Bind to sp. Receptors on target cells to

activate intracellular pathway and result in changes in cell function by expression of altered protein.

Act as messengers to transmit signals from one cell to another

Act locally, at very low concentrations Have pleotropic effects Two types1. proinflammatory 2. anti-inflammatory

•IL-1 and TNF- are the most important pro-inflammatoty cytokines which can induce connective tissue and alveolar bone destruction.

•These cytokines are present in diseased periodontal tissues and gingival crevicular fluid (GCF)

(Gemmell et al., 1997).

•The catabolic activities of these cytokines are controlled by endogenous inhibitors that include IL-1 and TNF receptor antagonists.

•When administered for therapeutic purposes, these antagonists can reduce inflammation.

•The use of cytokine receptor antagonists to inhibit periodontal disease progression has been investigated in a ligature-induced periodontitis non-human primate model.

•It was demonstrated that IL-1/TNF blockers partially inhibited disease progression.

•Infliximab and etanercept are two TNF antagonists currently under study

•However, the use of cytokine antagonists to treat human periodontal disease needs to be evaluated

(Delima et al., 2001).

Anti-inflammatory cytokines:

•include IL-4, IL-10, IL-11 and TGF-.

•Both IL-4 and IL-10 can target macrophages and inhibit the release of IL-1, TNF, reactive oxygen intermediates, and NO.

•IL-4 also induces programmed cell death (apoptosis), which reduces the number of infiltrating inflammatory macrophages.

•It can also upregulate the production of IL-1 receptor antagonists (Wong et al., 1993)

The evidence that IL-4 is deficient in diseased periodontal tissues, and the finding that exogenous IL-4 administration in experimental arthritis reduces inflammation, suggest that use of this cytokine may provide a therapeutic benefit in the treatment of periodontal diseases.

Recently, recombinant human IL-11, which inhibits productions of TNF-, IL-1, and NO, was also shown to reduce disease progression in a ligature-induced periodontitis canine model.

(Howell et al., 2000)

Another cytokine, granulocyte colony stimulating factor (G-CSF), which enhances neutrophil production, was used to treat cyclic neutropenia and improved periodontal disease status over a 15-year period

(Baer and Lacono,1994).

INTERLEUKIN-11

Interleukin-11 has shown to have anti-inflammatory effects by inhibition of tumor necrosis factor-α and other pro-inflammatory cytokines.

Moreover, it indirectly minimizes tissue injury through stimulation of tissue inhibitor of metalloproteinases-1 (TIMP-1).

INTERLEUKIN-11

Based on these studies, Martuscelli et al. investigated the ability of recombinant human interleukin-11 (rhIL-11) to reduce periodontal disease progression in dogs with ligature-induced periodontitis.

Significant reduction in the rate of clinical attachment and radiographic bone loss were observed after an 8-week period of rhIL-11 administration, twice a week.

Thus new studies should be conducted towards the therapeutic use of rhIL-11 in periodontal treatment.

•However, unresolved issues regarding cytokine modulation therapy include identifying the ideal method to maintain or inhibit cytokines long term, and understanding the systemic implications associated with altering cytokine levels on tissue homeostasis.

•Therefore, additional animal and human studies are needed to determine the safety and efficacy of anti-inflammatory cytokines in the treatment of periodontitis.

OTHER HOST RELATED PRODUCTS AND THEIR MODUALTION

Antioxidants

o Larger upward shift in the pro-oxidant/

antioxidant ratio intracellularly bring about

direct damage to the vital biomolecules and

structures and cell death

DIFFERENT PROPORTION OF ROS AND ANTIOXIDANTS- TISSUE STATUS

Antioxidants There are several group of antioxidants,

among that at least few can be thought of in future for the host modulation or decrease the free radicals level

Vitamin c ,vitamin e,carotenoids, co-enzyme Q 10, uric acid, polyphenols, glutathione

Nitric oxide synthase (NOS) inhibitors have demonstrated protective effects against the bone resorption and inflammatory process in ligature induced periodontitis in rats

o Elevated quantity of NO has the cytotoxic effect towards the host cell

o Use of selective iNOS inhibitor – mercaptoethylguanidine has shown promising result in the management of periodontitis

MODULATION OF CELL SIGNALLING PATHWAYS

A “pathway” is a chain of proteins in the cell that communicates a signal from a receptor on the surface of the cell to the DNA in the nucleus of the cell.

The signal “starts” when a signaling molecule binds to the receptor on the cell surface and “ends” when the DNA in the nucleus expresses a protein and produces some change in the cell, e.g. cell division/ apoptosis.

Signal transduction pathways involved in inflammation:

1. MAPK pathway2. phosphatidylinositol-3 protein kinase

(PI3) pathway3. janus kinase-signal transducer and

activator of transcription (Jak-STAT)4. nuclear factor kappa B (NF-κB)

pathway

Activation activated by cytokines bacterial proteins lipopolysaccharide, environmental stress. These stimuli act on receptors that are coupled

to the signal transduction pathways, causing activation of transcription factors and other proteins that control the production of cytokines, proteases and many other compounds involved in the inflammatory process.

Inhibition

Inhibition of signal transduction pathways would be expected to abolish both cell activation by cytokines or other stimuli, and the production of pro-inflammatory cytokines.

The various pathways involved in inflammation thus present another target for modulation of the host response.

GROWTH FACTORS

GROWTH FACTORS -HMT

o Growth factors and differentiating factors are considered as a subset of cytokines with the anabolic physiological and pathophysiological roles in the regulation of tissue growth and healing

o A number of growth factors supplied externally for potential use as adjuncts to surgical procedures not only to improve healing but also to stimulate the periodontal regeneration

Among them Enamel matrix proteins(Emdogain), BMP-2 and BMP-7, Platelet derived growth factors are being commonly used

As we understand the molecular process better , more growth factors are likely to be available in recombinant forms for the use of periodontal regeneration, further boosting up the HMT

Current FDA approval:1. enamel matrix proteins2. recombinant human PDGF-BB (GEM 21S)3. rhBMP-2 (INFUSE)

TOPICAL NSAIDS

Topical application of NSAIDs using pastes, gels and biodegradable subgingival delivery systems have been shown to be efficacious in reducing attachment and bone loss.

Topical application of NSAIDs is possible because these drugs are lipophillic and are absorbed in gingival tissues.

In multi-centre placebo control trials both of these drugs were associated with reductions in rate of alveolar bone loss when used in conjugation with mechanical instrumentation

However at this time no topical NSAID formulation is FDA approved for the management of periodontal diseases.

1. Ketoprofen can block both the cyclooxygenase and

lipooxygenase pathways

Its administration as a racemic cream (1%), was noted to prevent the progression of alveolar bone loss in ligature-induced periodontitis models.

2. Piroxicam

It is found to have influence on the inflammatory process by modulation of PMN’s and monocytes.

Piroxicam can be applied topically in both liquid

and gel form with the conc of 2mg/ml with effect on gingivitis without any effect on plaque accumulation.

3. Triclosan is a lipid-soluble (phenol derivative) antibacterial agent which is included in dentifrices, mouthwashes etc.

In addition to its antibacterial activity, investigators are focusing on its anti-inflammatory activity in oral soft tissues and skin in vivo .

Waaler et al and Kjarheim et al demonstrated that topical application of triclosan to both intraoral and extraoral compartments reduced clinical signs of inflammation.

Ramberg et al showed in an experimental gingivitis study that triclosan incorporated in a mouthrinse inhibited or retarded gingival inflammation which would otherwise have developed in the presence of plaque.

Triclosan can penetrate skin and mucous membranes

Triclosan interrupts inflammatory pathways by inhibiting both cyclooxygenase and lipoxygenase pathways of arachidonic acid metabolisms that lead to the production of prostaglandins, luekotrienes and lipoxins.(Gaffar et al, Kim et al)

STATINS Statins are inhibitors of hydroxymethylglutaryl

coenzyme A (HMG-CoA) reductase.

They were developed for the reduction of serum cholesterol levels and have been used successfully in the prevention and treatment of coronary heart disease.

 In a study by Cruz et al, Lovastatin and Simvastatin have been shown to increase bone thickness in vitro and in mice by stimulating BMP-2.

Statins were shown to have immunomodulatory as well as anti-inflammatory property as it decreases level of MMP-9, C- reactive protein, TNF-α.

CONCLUSION

It is to be understood that excess inflammatory process is always harmful to the host and treating this excess response is essential, even though, it is difficult to decide what is to be considered as excess response

However there is group of patients, which shows hyper inflammatory response to minimal plaque, presence of active disease sites, resistant or recurrent disease sites, and such subjects may benefit from an adjuvant therapy like host modulation therapy

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