host modulation, pathogenesis, HMT, agents, host response, NSAIDs, perioceutics

1. 1

2. HOST
MODULATION
THERAPY- Part 1
PRESENTED BY: - DR K. ABHILASHA
MODERATED BY: - DR FOUZIA TARANNUM
DEPARTMENT OF PERIODONTICS
M. R. AMBEDKAR DENTAL COLLEGE
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3. CONTENT
 INTRODUCTION
 HISTORICAL PERSPECTIVE
 MODELS OF PERIODONTAL
PATHOGENESIS
 HOST RESPONSE AND
PERIODONTAL DISEASE
 HOST MODULATION THERAPY
– Definition
– History
 RATIONALE
 CLASSIFICATION
 MODULATION OF ARACHIDONIC
ACID METABOLITES
PART
1
3

4. CONTENT
 MODULATION OF BONE REMODELLING
 MODULATION OF MATRIX METALLOPROTEINASES
 MODULATION OF CYTOKINE
 MODULATION OF OTHER HOST INFLAMMATORY MEDIATORS
 LOCAL HOST MODULATING AGENTS
 FUTURE DIRECTIONS
 CONCLUDING COMMENTS
 REFERENCES
PART
2
4

5. TERMINOLOGIES
Host: It is defined as “ the organism” from which parasite obtains its
nourishment.
OR
in the transplantation of tissue , the individual who receives the graft .
OR
In relation with Periodontal Diseases, an individual who harbors pathogens
associated with periodontal diseases.
Host defense mechanisms: A group of body-protective systems that guard
the body against infection.
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6. 6
Host response: The reactions of the immune system to infective microorganisms
(or) their products.
Immune system: The body’s most important line of defense against attacks by
bacteria, viruses, fungi and parasite.
‘MODULATION’ is defined as “alteration of function or status of something in
response to a stimulus or an altered chemical or physical environment”
PERIOCEUTICS : It is the use of pharmacological agents specifically
developed to better manage periodontitis

7. INTRODUCTION
HOST
BACTERIA
ENVIRONMENT
P.D
As is the case with any other disease, Periodontal disease is also,
basically the end result of interaction between 3 factors
e.g. smoking, medication,
faulty dentistry etc 7

8. PAST ERA
 Understanding of the etiology and pathogenesis of periodontal
disease focussed on the ‘MICROBIAL ASPECT’
 Periodontal disease was inevitable consequence of aging and
was uniformly distributed in the population
 Disease severity directly corelated with plaque levels.
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9. 9
NON-SPECIFIC PLAQUE HYPOTHESIS

10. 10
SPECIFIC PLAQUE HYPOTHESIS
Disease Progression
Continuous, Linear Manner Through Out Life
Therapeutic effects Focus Mainly On Mechanical Or
Chemotherapeutic Removal Of Bacteria Flora

11. FACT
TWO categories of patients
Periodontal disease resistant Periodontal disease susceptible
 Abundant plaque, calculus
 Gingivitis, some shallow pockets
 No signs of deep pocket,
 No mobility, and
 No aggressive bone loss
 Good oral hygiene
 Minimal plaque
 Deep pockets
 Mobility
 Early tooth loss
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12. WHY THIS DIFFERENCE??
WHY IS THE RESPONSE SO DIFFERENT IN THE INDIVIDUALS????
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13. PRESENT ERA
o Periodontal disease is not a natural consequence of ageing.
o Periodontal disease is not related to the plaque level as far as
severity is concerned.
o Pathogenesis of periodontal disease focuses not only on just
microbial aspect but an important role is being given to
HOST RESPONSE
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14. HOST RESPONSE
ROLE IN PROTECTION ROLE IN DESTRUCTION
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15. MODELS OF PERIODONTAL
PATHOGENESIS
1. Linear Model (Mid 1960s Loe et. Al.)
2. Basic Conceptual Model (CIRCA MODEL 1981, Ivanyi L, Lehner)
3. Critical Pathway Model ( Offenbacher 1996)
4. Non-Linear Model ( Basic conceptual model revised, 1997, Page &
Kornman)
5. Multilevel Hierarchal model
6. Biologic system model
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16. Pathogenesis of periodontitis
1960 – BACTERIAL MODEL
• Implicated bacterial plaque deposits as the primary
direct factor in the development of periodontitis
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17. MODELS OF PERIODONTAL
PATHOGENESIS
1. Linear Model (Mid 1960s Loe et. Al.)
2. Basic Conceptual Model (CIRCA MODEL 1981, Ivanyi L, Lehner)
3. Critical Pathway Model ( Offenbacher 1996)
4. Non-Linear Model ( Basic conceptual model revised, 1997, Page &
Kornman)
5. Multilevel Hierarchal model
6. Biologic system model
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D
(Modified from Kornman KS: Host modulation as a therapeutic strategy in
the treatment of periodontal disease. Clin InfectDis 28:520, 1999.)
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19. HOST RESPONSE AND PERIODONTAL
DISEASE
o Periodontal disease does not appear to act as a classic infection, but more as
opportunistic infections.
o There is no way to eliminate bacteria from the oral cavity, so bacteria are
always present in the periodontal milieu.
o With more virulent species in the environment, there is an opportunity for
periodontal destruction to occur.
o Although bacterial pathogens initiate periodontal inflammation, host response
to these pathogens is equally, if not more, important in mediating connective
tissue breakdown, including bone loss.
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20. 20
Events in host response to bacteria
Accumulation of subgingival plaque bacteria and release
of bacterial substances
As a result of toxins from bacteria, gingival vasculature
dilates and becomes permeable to fluid and cells
Defense cells migrate from circulation towards the
source of chemotactic stimulus in the crevice
Neutrophils or PMNL predominate in the early stages of
gingival inflammation to phagocytosize bacteria

21. 21
Events in host response to bacteria
As bacterial products penetrate circulation, committed
lymphocytes return to the site of infection
B – lymphocytes are transformed to plasma cell which
produces antibodies against specific bacterial antigens
Antibodies are released in gingival tissues and in presence of complement
facilitate and enhance PMN phagocytosis and bacterial killing
Thus, host immune-inflammatory response is
established in the gingival tissues
CLINICAL SIGNS OF GINGIVITIS TO DEVELOP

22. HOST
Disease
resistant
Disease
susceptible
Primary defense mechanisms
control the infection
Inflammatory events extends
laterally and apically to involve
deeper connective tissue
22

23. Further defense cells are recruited to the area, including macrophages and
lymphocytes
These lymphocytes secrete excessive quantities of destructive enzymes and
inflammatory mediators
Destruction of
periodontal ligament
and bone
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24. COMPREHENSIVE TREATMENT FOR
PERIODONTITIS
 Mechanical (SRP, surgical management)
 Risk factor modification
 Host Modulatory Therapy
24

25. HOST MODULATION THERAPY
Host modulatory therapy (HMT) is a treatment
concept that aims to reduce 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 response.
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DEFINITION

26. 26
 The concept of host modulation was first introduced to dentistry by
Williams (1990) and Golub et al (1992).
 In 1990, Williams concluded, "There are compelling data from studies in animals and
human trials ; that pharmacologic agents that modulate the host responses believed to
be involved in the pathogenesis of periodontal destruction may be efficacious in slowing
the progression of periodontitis.“
 In 1992, Golub and colleagues discussed "host modulation with tetracyclines
and their chemically modified analogues”.
HISTORY

27. RATIONALE OF HOST MODULATION
27
1. To restore the balance of pro-inflammatory and anti-inflammatory mediators
2. As Adjunctive treatment options
3. To decrease patient susceptibility
4. To aid in risk assessment & risk reduction strategy
5. To facilitate regeneration

28. 28
 HMT is a means of treating the host side of the host bacteria interaction.
 HMTs do not switch off normal defense mechanism or inflammation;
instead, they ameliorate excessive or pathologically elevated
inflammatory processes to enhance the opportunities for wound healing
and periodontal stability.

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NEWMAN AND CARRANZA’S, CLINICAL PERIODONTOLOGY, 13TH ED

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31. 31
NEWMAN AND CARRANZA’S, CLINICAL PERIODONTOLOGY, 13TH ED

32. CLASSIFICATION
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33. 33
Microbial
Challenge
Host
Immuno-
inflammatory
response
Cytokines
Prostanoids
MMPs
Bone & CT
Metabolism
Clinical
Bone Level
Clinical
Attachment
Level
Blocks Regulators
of host defenses
(PGE2, Cytokines)
Blocks
regulator of
bone & CT
metabolism
Blocks tissue
destruction

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35. 35
One pathway involved in pathogenesis of periodontal disease involves the synthesis and
release of prostaglandins and arachidonic acid metabolites within the periodontal tissues.
Prostaglandins are synthesized from arachidonic acid by all mammalian tissue cells
except ERYTHROCYTES

36. 36
Two isoforms of COX are recognized
 COX-1 is expressed ‘constitutively’ and
known as a "housekeeping" enzyme.
 Functions include
1. Gastric cytoprotection
2. Vascular homeostasis
3. Platelet aggregation
4. kidney function
 Stimulated by hormones or growth factors
 COX-2 is usually undetectable in
most tissues
 Its expression is ‘inducible’ during
states of inflammation
 Upregulated by pro- inflammatory
cytokines, endotoxin
COX -1 COX-2

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 Prostaglandins were first discovered by VON EULER in 1939
 PGE2 has been studied in periodontal disease and is considered as one of the most potent
prostaglandins that upregulates bone resorption by osteoclasts.
Goldhaber (1971) while studying mechanisms of bone resorption in mouse calvaria found
that resorptive process could be stimulated by prostaglandins (PG).
Klein and Raisz in 1970 reported that prostaglandin and PGE2 specifically had the potential
to induce bone resorption directly in organ culture.
Goodson et al. in 1974 demonstrated with in vivo experiments that prostaglandins were
implicated in the bone resorption process.

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 PGE2 also inhibits fibroblast function and has inhibitory and modulatory effects on the
immune response.
 In addition to prostaglandins, other AA metabolites such as
• Prostacyclin
• LT
• LTB4
has been shown to stimulate bone resorption both in vitro and in animal models including
rheumatoid arthritis and periodontal diseases.

39. Arachidonic Acid metabolite levels in
periodontal tissues and GCF
Another line of evidence for a role of prostaglandins in the
pathogenesis of periodontal disease came from examining the
levels of arachidonic acid metabolites in crevicular fluid and
gingival tissue samples.
The data clearly indicate that in periodontally diseased tissues,
the levels of prostaglandins are elevated significantly when
compared with levels in healthy tissues.
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40. 40
AUTHOR RESULTS OF THE STUDY
Goodson and
colleague in 1974
Examined a ten fold elevation of PGE2 levels in the diseased
gingival tissue compared with healthy gingiva excised around
the third molars.
Wong and co-
workers in 1980
Examined the ability of excised human gingival tissues to
synthesize 6-keto-PGF1α, the stable hydrolytic product of
prostacyclin. They found a significant formation of
prostacyclin in the inflamed gingival tissues when compared
with the healthy tissues

41. 41
ARACHIDONIC ACID
METABOLITE
PRODUCTION
NSAIDS
TRICLOSAN
LIPOXINS
&other PRMs

42. MODULATION OF ARACHIDONIC ACID
METABOLITES
NON-STEROIDAL ANTI-INFLAMMATORY DRUGS
 COX-1 INHIBITORS- Indomethacin, Naproxen, etc
 COX-2 INHIBITORS- Rofecoxib
 COX and LOX INHIBITORS- Triclosan
 LOX INHIBITORS- Lipoxin
42

43. Non-steroidal Anti-inflammatory drugs
The development of all periodontal disease is a consequence of the
inflammatory and immunological reaction of the host to bacterial plaque.
Any drug that has anti-inflammatory properties, therefore, should be
capable of modifying the host’s reactions to the bacterial insult & so have
clinical effect upon the progression of disease.
NSAIDs act by blocking the enzyme CO and reduce prostaglandin synthesis.
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44. 1. INDOMETHACIN
• A specific inhibitor of cyclooxygenase
• One of the most potent NSAIDs available in the early 1970s.
• Indomethacin, reduces the release of prostaglandins from human
polymorphonuclear leukocytes and macrophages, and was found to be a
significant inhibitor of bone resorption in tissue culture and animal
model systems.
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45. 45
Nyman et al. in 1979 reported that the daily administration of
indomethacin to beagle dogs with ligature-induced periodontal disease
suppressed the magnitude of the acute inflammation, delayed the
onset of the acute inflammatory reaction, and reduced alveolar
bone resorption
Bezerra et al in 2000 studied the effect of systemic indomethacin and
systemic meloxicam on alveolar bone loss during experimental
periodontitis in rats and found that both NSAID significantly inhibited
bone loss and inflammation

46. 2.FLURBIPROFEN
 Flurbiprofen, a phenylalkanoic acid.
 It is known to be a very potent cyclooxygenase inhibitor.
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47. 47
Jeffcoat et al
1988
15 refractory
periodontitis patients
Systemic
Flurbiprofen
50 mg bid
Decreased bone loss
over 2 months
compared to placebo
Williams et al
1989
44 adult periodontitis
subjects monitored for
3 years
Systemic
Flurbiprofen
50 mg bid
Lower bone loss rates
at 12 & 18 months
Heasman et al
1993
Chronic periodontitis
patients
Topical
flurbiprofen
Found no adjunctive
effect of the
medication on plaque
and bleeding scores
HUMAN STUDIES

48. 3. KETOPROFEN
Ketoprofen, an NSAID which can block both the CO and LO pathways.
Its administration as a
 Racemic cream (1%),
 (S)-enantiomer dentifrice (0.3%, 3.0%) or
 (S)-enantiomer capsule (10.0 mg)
was noted to prevent the progression of alveolar bone loss in ligature-
induced periodontitis models.
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49. 49
HUMAN STUDY
Paquette et al in
2000
Used systemic and topical ketoprofen in untreated
chronic periodontitis patients for 22 days and found
that topical as well as systemic ketoprofen
administration reduced GCF PGE 2 but not GCF- LTB 4

50. 4. COX-2 INHIBITORS
 Meloxicam, Nimesulide, Etoricoxib, Celecoxib, Rofecoxib,
Valdecoxib
 They have potencies, 10 -1000 fold higher than for COX 1
 Long term use has been linked to development of hypertension,
edema and congestive cardiac failure
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Drawbacks of use of NSAID :
o “Rebound effect”: Return to or even an acceleration in the
rate of bone loss was seen after NSAID therapy.
o Gastric ulceration by producing mucosal ischaemia.
o Renal and hepatic impairment.
o Hemorrhage (decreased platelet aggregation)
Currently, FDA has not approved any NSAID formulation for host modulation
therapy in periodontics and future research is required to determine its
suitability as a host modulating agent.

52. 52
ARACHIDONIC ACID
METABOLITE
PRODUCTION
NSAIDS
TRICLOSAN
LIPOXINS
&other PRMs

53. TRICLOSAN
 An antibacterial and anti-inflammatory agent .
 Triclosan (2, 4, 41-trichloro-2-hydroxy-diphenyl ether) is a
non-ionic antimicrobial agent.
 Triclosan also inhibits CO and LO and thus may interfere with
the production of AA metabolites.
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54. 54
Gaffar et al – 1995
To elucidate the effect of triclosan on the production of pro-inflammatory
metabolites of arachidonic acid.
Triclosan has a direct inhibitory effect on primary enzymes –
cyclooxygenase and 5 – lipooxygenase
Leads to the reduction in formation of pro-inflammatory cytokines – PGE2
and leukotrienes B4
Coleman et al – 1992- Triclosan blocked the production of prostaglandin E2 in
human gingival fibroblast cultures which were stimulated by interleukin 1β.

55. 55
 Triclosan inhibits release of PGE2 from IL- 1β stimulated fibroblasts
 Effect is relevant since gingival fibroblasts is an important target cell for
IL-1 during the process of gingival inflammation
 Also been experimented for topical application
Lin et al – 1994- Favorable partition co-efficient , triclosan can readily penetrate
the skin and also penetrates the tissue following topical application

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ACUTE
INFLAMMATION FAILS TO RESOLVE CHRONIC
INFLAMMATION
RESOLUTION OF INFLAMMATION

57. RESOLUTION OF INFLAMMATION
ANTI INFLAMMATORY & PRO RESOLVING MOLECULES
 LIPOXINS (LX)
 ASPIRIN TRIGGERED LIPOXINS (ATL)
 RESOLVINS OF THE E SERIES (RvE)
 RESOLVINS OF THE D SERIES (RvD)
 THE NEUROPROTECTINS/PROTECTINS
57
Charles N Serhan J Periodontol 2008 ; 70 :1520-1526

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59. 59
The active termination of inflammation to the “non inflamed
state” is accompanied by LIPID MEDIATOR CLASS
SWITCHING from pro inflammatory mediators to biosynthesis
of lipoxins (Levy et al 2001) & pro resolving mediators (Serhan
et al 2000)
PGE2 & PGD2 promote the switch in enzyme expression by
neutrophils, thus changing their phenotype to pro resolution
(Levy et al 2001)

60. 1. LIPOXIN
 Lipoxins are members of the eicosanoid family produced within
the vascular lumen, primarily via platelet-leukocyte
transcellular biosynthesis.
 First identified by Serhan and colleagues in 1984
 Act as endogenous “braking signals” in inflammation.
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61. Lipoxins In Modulation Of Inflammation
 Evidence suggests that LXs are a class of both structurally and functionally
unique eicosanoids involved in counter-regulation of inflammatory
responses (Kantarci & Van Dyke 2003).
 Metabolically stable analogues of both LXA4 and its epimer 15-epi LXA4
are active in the nanomolar range and inhibit PMN adhesion and
diapedesis, thus representing counter-regulatory signals involved in the
resolution of inflammatory processes (Serhan et al. 1995, Takano et al.
1997).
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62. 62
Author Results
Pouliot & Serhan 1999 Investigated the impact of metabolically stable LX and ATL analogues
on TNF-α induced neutrophil response in murine air pouches, their
findings indicated that both analogues down regulated the release of
cytokines (e.g. IL-1β) and stimulated IL-4 involved in the pathogenesis of
periodontitis.
Pouliot et al. 2000 Investigated the potential protective contribution of lipoxins in murine
air pouches, results indicated that administration of stable analogues of LX
and of ATL blocked neutrophil migration and decreased PGE2 levels within
cellular exudates.
Kim et al. 2007 Studied the effect of aspirin on gingival crevicular fluid (GCF) levels of
inflammatory and anti-inflammatory mediators in patients with
gingivitis. They concluded that after administration of aspirin for seven
days, GCF levels of 15-epi-lipoxin-A4 were 500-fold higher than the
concentration of naturally occurring lipoxin A4

63. 63
Author Results
El-Sharkawy H
J Periodontol 2010
The goal of this study was to test an innovative strategy of low
dose aspirin and omega -3 fatty acid
for periodontal treatment in a clinical experiment. The results of
this preliminary clinical study suggest that dietary supplementation
with ω-3 PUFAs and 81 mg aspirin may provide a sustainable, low-
cost intervention to augment periodontal therapy
Elkhouli AM
J Periodont Res
2011
The findings suggested that the combination therapy of low
dose aspirin and omega -3 fatty acid demonstrated successful
reduction of gingival inflammation, reduction of pocket depth and
attachment level gain, accompanied by a trend for modulation of
the cytokines profile in gingival crevicular fluid.
M Faizuddin,F
Tarannum
Aust dent journal
2012
This study evaluated the periodontal attachment level of
subjects on long-term low dose aspirin therapy. The results of
this study suggested that low dose aspirin may reduce the risk of
periodontal attachment loss. This hypothesis needs to be tested by
larger sample sized prospective cohort studies.

64. RESOLVINS (Resolution Phase Interaction Products)
 Lipid mediators that are induced endogenously in the resolution
phase following inflammation
 Synthesized from omega 3 PUFA – EPA (Eicosapantaenoic acid) &
DHA (Docosahexaenoic acid)
 Demonstrate potent anti inflammatory and immunomodulatory
actions in the nanogram dose range invivo
64

65. RESOLVINS (Resolution Phase Interaction Products)
Resolvin stimulate resolution of inflammation through:
Preventing neutrophil penetration
Phagocytosing apoptotic neutrophil to clear the lesion
Enhancing clearing of inflammation within the lesion to promote
tissue regeneration
Such pro resolving function result in a shift in
inflammatory response to a shorter resolution interval
65

66. RVE1 & PERIODONTITIS
 Topical application of RvE1 in experimental model of periodontitis in
rabbits prevented the progression of periodontitis as
 No neutrophils and tissue damage was evident
 Histologically there was lack of osteoclast proliferation
 Radiographic evidence of decreased % of bone loss
66
Petasis N A et al 2006

67. RVE1 & PERIODONTITIS
 Effect of RvE1 on biofilm composition in rabbit model showed reversal
in P.gingivalis count to negligible levels and overall composition
approximated that observed in healthy tissues
67
Hastruk et al 2006
 In established periodontitis model, application of RvE1 was shown to restore
interproximal tissues and bone with formation of new PDL, cementum and
connective tissue

68. PROTECTINS
 Endogenous DHA is converted in to another family of lipid
mediators – Protectins
 Owing to its potent protective activity in inflammatory and
neural system, it is known as protectin D1(Hong et al 2003)
 Known as neuroprotectin D1, when produced by neural tissues
(Serhan et al 2005)
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69. 69
STUDIES
 Protectin D1 promotes human T-cell apoptosis via lipid raft clustering
and blocks T-cell migration in vivo( Ariel et al 2005 )
 Protectin D1 promotes upregulation of chemokine receptor type 5
expression on apoptotic T-cells leading to terminating signals during
resolution phase of inflammation (Areil et al 2005)

70. 70
 Protectin D1 is active in human retinal pigment epithelial cells to protect against oxidative
stress induced apoptosis (Mukherjee et al 2004) and in glial cells to block cytokine
production (Hong et al 2003)
 Together with D and E series resolvins ,Protectin D1 has been described to inhibit
transendothelial migration of neutrophils , and enhance macrophage phagocytosis of
apoptotic neutrophils (Shwat et al 2007 , Serhan et al 2011) .
STUDIES

71. END OF PART-1
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TO BE CONTINUED....

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