Hygiene Tribune Middle East & Africa No. 2, 2020
Periodontal inflammation simplified
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DTMEA_No.1. Vol.10_HT.indd
NL
Y
O
LS
NA
IO
SS
FE
O
PR
NT
AL
DE
www.dental-tribune.me
PUBLISHED IN DUBAI
Periodontal
inflammation simplified
March-April 2020 | No. 2, Vol. 10
DENTAL
CONFEXPO HYGIENIST
SEMINAR
CAPP DENTAL
1 3 - 1 4 N O V
DUBAI, UAE
2 0 2 0
By Dr Fay Goldstep, Canada
sors to resolvins. Therefore, diet
can affect the resolution of inflammation.
5. Inflammation is affected by
many risk factors, including genetics.
6. Overexpression of inflammation is a key aspect of ageing that
may influence and link diseases
in the older individual. Inflammatory mechanisms are critical in the
development and progression of
the diseases of ageing.
7. Treatment of periodontal disease should not only reflect the
bacterial stimulus, but must take
into account the inflammatory
component of the disease as well.
Inflammation has been studied since
ancient times. It was observed that,
as a result of irritation, injury or infection, tissues throughout the body
react by increased redness (rubor),
swelling (tumour), heat (calor) and
pain (dolour).1 Today, we know that
inflammation is a process driven by
cells responding to signals from the
body to fend off what it perceives as
an intrusion. This leads to the accumulation of fluid and leukocytes in
the extravascular tissue.2
The inflammatory response is a
beneficial process. In the healthy
periodontium, bacteria in the crevicular fluid enter the bloodstream
and elicit a protective response during chewing, toothbrushing and so
on. The inflammatory response occurs routinely to counteract microbial challenges and eliminate them,
without our awareness. We become
aware of inflammation only when
the response is prolonged and not
successful in resolving the microbial
challenge. Chronic inflammation is a
destructive process that occurs when
the response is not able to complete
its normal cycle of removing bacteria and restoring the situation to
health. The process continues for
an extended period while the body
continues trying to eliminate the
bacteria. Tissue damage occurs owing to the action of the cells involved
in inflammation and their products.
This article discusses these factors
and will attempt to bring simplicity
and clarity to a very complex topic.
Fig. 1: The acute response. Periodontal tissue: Bacteria initiate the immune response by
producing vascular dilation, increased permeability of capillaries and increased blood
flow. Cellular level: The crevicular fluid contains neutrophils, macrophages and other
inflammatory cells. Macrophages eliminate bacteria by phagocytosis. The inflammatory cells secrete cytokines that regulate the inflammatory response. Biochemical level:
Arachidonic acid (released primarily by neutrophils) produces prostaglandin.
Research on periodontal inflammation is extensive. The following provides a synopsis of current
knowledge:
1. Periodontal inflammation is initiated by a bacterial stimulus.
2. A cascade of events occurs in
response to the stimulus (first in-
nate and then adaptive responses).
3. The innate response must be actively resolved. This requires substances called lipoxins, resolvins
and protectins. Resolution is an
active process to restore healthy
equilibrium.
4. Omega-3 fatty acids are precur-
AD
AD
The bacterial challenge
The bacterial aetiology of periodontal disease has been established for
over a hundred years. Recent studies
have also shown that it is not just the
number of bacteria, but the specific
bacterial types that are implicated in
the pathogenesis of periodontal disease. By the 1980s, it was established
that sites with periodontal disease
contain predominantly Gram-negative organisms, whereas healthy
sites are populated with Grampositive bacteria.3 In the 1990s, the
particular inflammatory response
of the affected individual (the host),
as well as the presence of certain
specific bacteria, was found to be
associated with active periodontal
disease progression. The four major
species implicated were Porphyromonas gingivalis, Aggregatibacter
actinomycetemcomitans, Tannerellaforsythensis (renamed Tannerella
forsythia) and Treponema denticola.4 These pathogens are found in
ecological complexes (biofilm). An
ecological shift in the biofilm, such
as a change in available nutrients,
can lead to the emergence of these
specific microbial pathogens.5
Periodontal inflammation is initiated by the products of biofilm bacteria, such as lipopolysaccharide molecules—these are components of the
cell wall of Gram-negative bacteria;
they are not found in Gram-positive
bacteria. This creates a cascade of reactions.6 In healthy periodontium,
these products are eliminated, and
the inflammation is resolved. In
the compromised periodontium,
perio-pathogens such as P. gingivalis
suppress the innate host response
by paralysing a key step in the host
defence system. This permits both
P. gingivalis and the commensal
(benign or beneficial) bacteria in the
pocket to thrive and grow without
any recognition or resistance from
the host.7
P. gingivalis may be present in low
concentrations, but it still has a profound effect on the amount and
composition of the surrounding bacterial environment, leading to periodontitis. For this reason, P. gingivalis
has been called a “keystone pathogen”, a species which supports and
remodels a microbial community to
promote pathogenesis.8 Many of the
bacterial model studies have focused
on P. gingivalis, but the model applies to the other perio-pathogenic
species as well.
The scenario is as follows: in the deep,
inaccessible subgingival space of the
compromised periodontium, P. gingivalis impedes the defence system
of the body by blocking protective
host receptors.9 This creates a dysbiosis between the host and the plaque,
interrupting the status quo and tipping the balance towards inflammatory disease. Just a very small level of
P. gingivalis leads to increased numbers of normally benign bacteria.
This encourages a greater inflammatory response and tissue breakdown.
The breakdown products, such as
collagen fragments, flood the crevicular fluid and are a great source of
nutrition for P. gingivalis and other
perio-pathogens that require essential amino acids as a food source.
(Caries pathogens thrive on sugars.9)
In this way, keystone pathogens
manipulate their environment (the
periodontium) and their normally
docile neighbours into creating a
very comfortable environment and
abundant food supply for their own
benefit. The bacteria and the host
both contribute to disease, and the
affected periodontal sites contain a
unique microbial composition not
seen in health.10
Changes in the composition of gut
microbiota have also been implicated in the pathogenesis of other
inflammatory diseases, such as inflammatory bowel disease, as well
as colon cancer, obesity, diabetes
and coronary heart disease. Future
treatment and prevention of these
diseases may involve the identification and targeting of the keystone
pathogens.9
The healthy, beneficial
inflammatory response
The reaction to infection or any
other noxious stimulus in the body
precipitates two distinct and interconnected reactions: the innate and
the adaptive. The innate response
is an evolutionary defence mechanism that provides immediate protection. Phagocytic (ingesting) cells
such as neutrophils, monocytes and
macrophages identify and eliminate
ÿPage E2
[2] =>
DTMEA_No.1. Vol.10_HT.indd
E2
HYGIENE TRIBUNE
Dental Tribune Middle East & Africa Edition | 2/2020
◊Page E1
braking signal for neutrophils.14 Aspirin transforms lipoxin into a more
bioactive form with more powerful
pro-resolving properties.18
Resolvins
Resolvins are substances derived
from omega-3 dietary fatty acids.
Several clinical studies have shown
that diets rich in omega-3 are useful in the prevention and treatment
of arthritis, cardiovascular disease
(CVD) and other inflammatory conditions.
Fig. 2: The active resolution of the acute response. Periodontal
tissue: The stimulus (bacteria) is removed. Cellular level: The crevicular fluid contains fewer, weakened neutrophils and remnants
of bacteria. Biochemical level: Arachidonic acid produces lipoxins.
Dietary omega-3 produces resolvins. Lipoxins and resolvins actively stop inflammation.
foreign substances. These immune
cells also release chemical mediators
called cytokines that assist antibodies in clearing pathogens or marking
them for destruction by other cells.
The innate response is non-specific.1
The adaptive response is specific.
Pathogens are recognised so that a
stronger response will occur should
these pathogens return in the future.
The adaptive response is tailored to
remove specific pathogens and to remember the pathogen’s antigen signature. T cells recognise foreign antigens and specifically target them. B
cells produce antibodies against the
antigen, and they assist the phagocytic cells in mounting a response to
the noxious stimulus.1
In healthy periodontium, the innate response eliminates or neutralises foreign bodies, and is protective
against injury or infection. The sequence is as follows:11
1. There is vascular dilation, enhanced permeability of capillaries,
and increased blood flow.
2. Neutrophils (also known as polymorphonuclear leukocytes) are
dispatched to the site.
3. Macrophages and others are recruited to the site.
4. Cell mediators (cytokines) are
produced by these recruited immune cells and by local cells in
the area, such as fibroblasts and
osteoblasts. Cytokines are the
mechanism the body uses for cell
communication. They are biologi-
Fig. 3: Return to health.
cally active proteins that alter the
function of the cell that releases it
or the function of adjacent cells.12
They can act locally to regulate the
inflammatory process or can be
dispatched to distant sites.6
5. Chemokines (cytokines with
chemotactic properties) are released and play an important role
in further leukocyte recruitment.13
6. These cytokines work with the
body to defend it from attack. The
immune cells and their secreted
chemicals attempt to destroy,
dilute or wall off the injurious
agent.12
7. T and B cells mediate the adaptive response.
It is noteworthy that, although oral
bacteria live close to a highly vascularised periodontium, very few bacteria cause systemic infections in a
healthy individual. This is the result
of the highly efficient innate host defence system that monitors bacterial
growth and prevents bacterial intrusion into the local tissue. Dynamic
equilibrium (homeostasis) exists between the dental plaque bacteria and
the innate host defence system.7 This
is the situation as it occurs in health.
When there is a compromise in the
health of the individual, systemically
or locally, the process of inflammatory disease begins.
Resolution of the inflammatory
response
Complete resolution of an acute in-
Fig. 4: Early chronic lesion. Periodontal tissue: Increased plaque,
breakdown of the periodontal ligament and ulceration of the epithelial lining; start of bone resorption. Cellular level: An increased
number of neutrophils, macro phages and others. Biochemical
level: Increased pro-inflammatory cytokine activity; arachidonic
acid continues to produce prostaglandin; release of MMPs.
flammatory response and the body’s
return to homeostasis is necessary
for health. The leukocytes and invading bacteria must be removed
without leaving remnants of the
conflict.14 In the past, it was thought
that the innate response peters out
passively as the pro-inflammatory
signals decline.15 However, evidence
now suggests that the resolution of
inflammation and return to homeostasis is an actively regulated process,
not a passive one.16 There are specialised pro-resolving lipid mediators in
chemically distinct families that are
involved in this process. These are
lipoxins, resolvins and protectins.
These substances are actively biosynthesised during the resolution
phase of acute inflammation and act
to control the magnitude and duration of inflammation.11
Lipoxins
At the end of healthy inflammation, neutrophils stop secreting
pro-inflammatory cytokines and
begin synthesising compounds that
actively halt inflammation. These
compounds are called lipoxins. They
are derived from lipids (arachidonic
acid, a fatty acid found in cell membranes) released from neutrophils
and other inflammatory cells.17 During acute inflammation, arachidonic
acid is converted to pro-inflammatory mediators, including prostaglandin. In the healthy individual, the
elevated prostaglandin level signals
the need to resolve inflammation.
This triggers a switch in the action
of arachidonic acid to now produce
lipoxins.17 Lipoxins are essentially a
Fig. 5: Late chronic lesion. Periodontal tissue: Apical migration of
pathogenic bacteria, such as P. gingivalis, further breakdown of
the periodontal ligament and increased ulceration of the epithelial lining; severe bone resorption. Cellular level: More neutrophils,
macrophages, etc. Biochemical level: Increased pro-inflammatory
cytokines regulate release of MMPs (involved in bone resorption
and collagen degradation). Collagen fragments provide nutrition
Resolvins formed from omega-3
may be responsible for this.17 Resolvins act locally to stop neutrophil
recruitment and infiltration. Neutrophils are present in inflamed or injured tissue, and their effective elimination is a prerequisite for complete
resolution of the inflammatory response and return to homeostasis.19
Results from P. gingivalis-induced
periodontitis animal studies showed
topical resolvin treatment stopped
the progression of periodontal disease.20 Silk threads were tied around
rabbit teeth to trap bacteria, and then
P. gingivalis was added to induce periodontitis. One group received topical application of resolvin, the other
group received a placebo. The rabbits
that received the topical resolvin remained healthy; the placebo group
developed periodontal disease. Topical resolvin treatment stopped the
progression of disease, and there was
complete resolution of periodontal
inflammation. Treatment resulted
in bone regrowth to pre-disease levels. Histological evidence showed
both new collagen and new bone
deposition.20
The chronic maladaptive
inflammatory response
The primary aetiological basis for
periodontal disease is bacterial. However, the excessive host inflammatory response and inadequate resolution of inflammation are critical to
the pathogenesis of periodontitis.18
Periodontal disease results from the
body’s failure to turn off its inflammatory response to infection. The
result is chronic maladaptive inflammation.17
As discussed, keystone pathogens,
such as P. gingivalis, create a dysbiosis between the host and dental
plaque. An essential step in the innate mechanism is impaired, leading to growth in the number of
commensal bacteria and increased
inflammation. This produces an environment that exudes a rich source
of nutrients, such as degraded host
proteins, which are exactly what
P. gingivalis needs for survival and
growth. P. gingivalis continues to
exploit the environmental change,
leading to more bacteria, even
higher inflammation and bone resorption, and a perfect niche space
(deeper periodontal pockets) where
all the processes can continue undisturbed.9
Chronic periodontitis has multiple
aetiologies. The persistent bacterial
infection of P. gingivalis is just one of
these. Inflammatory disease represents a disruption of tissue homeostasis. Any factor (whether microbial
or host-based) that can destabilise
the homeostatic equilibrium can
tip the balance towards inflammatory disease.8 Acute inflammation
that is resolved within a reasonable
time frame prevents tissue injury.
Inadequate resolution and failure
to return to homeostasis result in
chronic inflammation and tissue destruction.18
In chronic, unresolved inflammation, the following applies:
1. Cellular and molecular responses to bacterial challenges involve
constant adjustment and regulatory feedback.21
2. Neutrophils, macrophages and
monocytes continue to secrete
cytokines. This creates a complex
chronic lesion that destroys the
periodontium.
3. Cytokines promote the release
of matrix metalloproteinases
(MMPs). (MMPs are proteolytic enzymes implicated in normal bone
remodeling. They include collagenases. Virtually all collagenases
found in periodontal disease are
derived from host cells and not
from bacteria.21 They are also the
key mediators in irreversible tissue destruction in periodontitis
and have been used as biomarkers
of disease progression. 22)
4. Tissue destruction is not unidirectional. It is constantly being
adjusted by host–bacteria interactions.21
5. Alveolar bone destruction is
the result of the uncoupling of
the normally tightly coupled processes of bone resorption and formation.21
6. Prostaglandin production plays
a role in alveolar bone resorption.
Cytokines are an intermediate
mechanism between bacterial stimulation and tissue destruction. They
were historically identified as leukocyte products, but many are also
produced by other cell types, such
as fibroblasts and osteoblasts.23 The
balance between stimulatory and
inhibitory cytokines, and the regulation and signalling of their receptors,
may determine the level of periodontal tissue loss.23
The host response is the major contributing factor to chronic maladaptive periodontal disease. A deficient
host response initiates the chronic
condition, and a too vigorous response leads to further tissue breakdown.23
Risk factors for
periodontal disease
Clinical observation has shown remarkable variations in host responses between individuals and in their
presentation of periodontal disease.
Though microbial challenge is a
primary initiating factor, there are
many other variables that modify
disease expression. These risk factors interfere with the way the body
responds to bacterial invasion. Without the risk factors, the host may be
capable of limiting periodontal tissue destruction. Disease modifiers,
such as smoking, in the presence of
bacterial accumulation may shift the
immune response beyond normal
parameters.24 Bacteria initiate periodontitis. They are essential, but they
are insufficient. What is required is a
susceptible host. Risk factors determine disease susceptibility, onset,
progression, severity and outcome.21
Through the 1990s, studies were
undertaken to establish specific risk
factors for periodontal disease. Clinical presentation, expected progression and responses to therapy were
found to be “a net integration of the
host response modified by patient
genetics and environmental factors”.
These factors may shift the balance
to more severe periodontal destruction.24 The various environmental,
acquired and inherited risk factors
were found to be diabetes, smoking,
poor oral hygiene, specific microflora, stress, race and sex.25
Diabetes increases risk through an
amplified inflammatory response
and depressed wound healing.26 Diabetics have cytokines that respond
to the bacterial challenge at a higher
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rate than normal. Gingival tissue and crevicular fluid contain elevated
concentrations of these cytokines, producing high levels of MMPs that
promote tissue destruction and disease severity.21
Environment
Smoking contributes to increased severity by the release of toxins into
the oral cavity. It is the identified environmental risk most strongly associated with periodontal disease. In some studies, the impact of smoking outweighed the effect of pathogenic bacteria as a determinant of
outcome.27
Genetics
Twin studies of adult periodontitis show greater concordance in periodontitis susceptibility between monozygotic twins than between dizygotic twins. It has been estimated that heredity accounts for about 50%
of the enhanced risk of severe periodontitis.21
Given the critical role of neutrophils in inflammation, genetic defects
in neutrophil function would be expected to affect periodontal disease,
and this is the case. Genetic abnormalities in neutrophil function have
been demonstrated in 75% of patients with juvenile periodontitis.21
Epigenetics
The control of how certain genes are expressed in specific tissues can
change throughout life through factors such as diet, stress, smoking and
bacterial accumulation.28 This is called epigenetics. Epigenetic alterations in DNA result in long-lasting changes in the expression of selected
genes.24 Rather than involving the variability of the genetic sequence itself, epigenetic regulation is a reversible modification in gene expression
determined by environmental exposure. It may also be inheritable.29
The exposure actually changes the DNA through methylation of genetic
sequences. The differential methylation of genes may contribute to the
diseased state. The changes that persist in the tissue increase the susceptibility to reinfection. In this way, a previous bout of periodontal inflam-
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mation may increase susceptibility to
subsequent bouts of infection.30
Of course, there are also anatomical
changes that result from periodontal disease, such as residual pockets and bony
defects. These may also predispose the
individual to further periodontal infection.31
Inflammation as a factor
in diseases of ageing:
The local–systemic link
Chronic diseases such as rheumatoid
arthritis, CVD, diabetes and periodontal
disease may develop because of unrestrained inflammatory responses that
have maladapted over decades.1,12 In
inflammatory diseases, the innate and
adaptive responses become unresolved
and chronic. The tissue does not return to
homeostasis.1
Chronic inflammation is characterised by
the continued production of cytokines,
arachidonic acid-derived modulators
(such as prostaglandin) and many other
products. Periodontitis, located in the
oral cavity and, thus, easily observable,
has been used as a model for other inflammatory diseases. Periodontitis is also
unique among the inflammatory diseases because the aetiology is well known
(bacterial plaque), and the pathogenesis is
so well characterised.20
The periodontitis–systemic disease relationship has been studied extensively.
There is substantial epidemiological
evidence to suggest that periodontal inflammation can influence the course of
systemic disease, especially CVD, diabetes
and low-birthweight infants.20 Epidemiological studies (indirect evidence) have
demonstrated statistical associations
between poor oral health and several
systemic diseases.32 This epidemiological
evidence continues to grow.
More direct evidence through experimental studies suggests that the local
inflammatory burden presented by periodontal infection causes an increased systemic inflammatory burden; that is, local
inflammation can be a modifier of systemic inflammation.20 Studies monitoring C-reactive protein (CRP) levels have
shown this connection. CRP is one of the
most reported biomarkers of systemic
inflammation. It is a protein whose production is triggered by infection, trauma,
necrosis and malignancy, and also linked
to heart disease and diabetes.6 CRP is synthesised in the liver in response to pro-inflammatory cytokines. It is a component
of normal serum, but an elevated serum
CRP level reflects an elevation in systemic
inflammation. An elevated CRP level has
been associated with an increased risk
of CVD20 and is also seen in periodontal disease.33 CRP produces biological actions that exacerbate the inflammatory
response and may also impact the initiation or progression of systemic diseases
such as atherosclerosis.34
A study on animals with induced periodontitis (ligature with P. gingivalis for six
weeks, producing periodontitis) showed
them to have elevated systemic CRP levels. After topical resolvin treatment, not
only was the periodontal tissue returned
to health, but the systemic level of CRP
was returned to that associated with
health. The resolvin treatment lowers the
inflammatory burden locally, which results in a lower systemic burden.20
Another study using the same model of
animals with periodontitis showed these
animals to have greater atherosclerosis
(measured by fatty plaque deposits in
their major blood vessels) than the control subjects did.17 Inflammation-resistant
subjects (with high lipoxin levels in their
blood) not only failed to develop periodontal disease, but their arteries were
almost completely free of plaque compared with the control subjects.17
Local inflammation from the periodontium may influence systemic inflamma-
Fig. 6: The local–systemic link: Local inflammation produces ulcerations in the pocket
epithelium, creating risks for distant-site infection or bacteraemia. Systemic dissemination of locally produced cytokines affects other organ systems. Bacterial diffusion releases biologically active molecules that trigger host responses in distant areas, elevating the
serum cytokine level. The resulting cytokines affect arteries and organs. CRP synthesised
in the liver as a result of circulating cytokines produces damage to organ systems.
tion through several distinct pathways:35, 36
1. Local inflammation produces
micro-ulcerations through the
pocket epithelium, promoting
risks for distant-site infections and
transient bacteraemia.
2. There is systemic dissemination
of locally produced inflammatory
mediators (cytokines). These then
begin to act systemically, affecting
other organ systems.
3. Bacterial diffusion releases a
variety of biologically active molecules, such as lipopolysaccharides (from the bacterial cell membrane), endotoxins, chemotactic
peptides, proteins and others, that
may enter the systemic circulation. These products trigger the
host inflammatory response in
areas far from the periodontium
and elevate serum concentrations
of cytokines.
4. The circulating cytokines produced by these responses affect
arteries and organs.
5. CRP is synthesised in the liver in
response to these circulating proinflammatory cytokines in the
acute phase of inflammation. CRP
can produce injurious effects on
other organs, leading to vascular
damage, CVD and stroke.
The bottom line is that unresolved
chronic local inflammation creates
a toxic systemic situation. Bacteria, pro-inflammatory mediators
and CRP cause damage at the local
level, and the dissemination of these
noxious substances causes damage
throughout the body. The oral–systemic link is an artificial construct.
The periodontal–systemic link is
simply a local–systemic inflammation link. The periodontium is an
integral part of the body’s systemic
ecosystem. It is obvious that the local
effect on one part of this ecosystem
will impact the entire organism.
Impact on patient care
Understanding inflammatory response mechanisms is essential in
developing innovative treatments
for periodontal inflammation.
Though scaling and root planing is
the gold standard in non-surgical
therapy for chronic periodontitis, it
only addresses the bacterial aetiology of the disease, not its inflammatory progression. Much of periodontal disease is the result of the host
response to the breaking down of the
surrounding structures.
The dynamic events of pathogenesis are determined primarily by
the signalling and regulating molecules that direct cell function, the
cytokines.21 Chronic inflammation
supports the growth of pathogenic
bacteria through the production of
tissue breakdown products. Resolution of inflammation effectively
eliminates the pathogen from the
lesion by removing its food source.20
Advances in treatment must address
the specific bacteriological factors,
that is, the host response and the systemic progression of disease. When
we are faced with new techniques
and products designed to promote
periodontal health, we should be
open to innovation, but also judicious in our assessment. This is only
possible if we are armed with a thorough knowledge of the mechanisms
of periodontal inflammation and
their sequelae. This knowledge supplies us with the tools to provide our
patients with the best possible clinical outcome.
Editorial note
A list of references can be obtained
from the publisher.
This article was originally published
in prevention-international magazine for oral health, Issue 1/2019.
About the author
Dr Fay Goldstep
She is a fellow of the American College of Dentists, International Academy for DentalFacial Esthetics and American Society for Dental Aesthetics. Dr Goldstep has been a contributing author to four textbooks and has published more than 100 articles. She has
been listed as one of the leaders in continuing education by Dentistry Today since 2002.
Dr Goldstep is a consultant to a number of dental companies and maintains a private
practice in Toronto in Canada.
She can be contacted at goldstep@epdot.com.
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