periodontics periodontal disease inflammation inflammatory disease

2.  Introduction
 History
 Definition
 Types of inflammation
 Acute inflammation
Vascular events
Cellular events
 Chemical mediators of inflammation

3.  Chronic inflammation
 Inflammatory diseases
 Resolution of inflammation.
 References

4.  Inflammation- body defense reaction intended to eliminate the
initial cause of cell injury as well as necrotic cells and tissues
resulting from original tissues.
 vascular dilation, enhanced permeability of capillaries,
increased blood flow and leukocyte recruitment.

5.  CELSUS listed four cardinal signs in 1st century AD.
 VIRCHOW  Fifth clinical sign.

6.  JOHN HUNTER in 1793, explained about ‘salutary’ effect.
 JULIUS COHNMEIN (1839 – 1884 ) observed inflamed
blood vessels in mesentery and tongue of frog.
 ELIE METCHINIKOFF in 1885, discovered phagocytosis –
observed the ingestion of rose thorns by Amebocytes of star
fish larvae.
He shared noble prize with PAUL EHERLICH in 1908.
 THOMAS LEWIS established the concept of Vascular
changes in Inflammation.

7. HOW IS INFLAMMATION DIFFERENT FROM
INFECTION?
 Infection is invasion into the body by harmful microbes and their
resultant ill effects by toxins.
 Protective mechanism of body against various etiological agents.

8.  Inflammation is defined as the local response of living
mammalian tissues to any injury.
 Inflammation is a complex reaction to injurious agents
such as microbes and damaged necrotic cells that
consists of vascular response, migration and activation
of leukocytes and systemic reactions.
(Robins & Cortan: 7th
edition)

9.  Agents causing inflammation:
1. Infective agents
2. Immunological agents
3. Physical agents
4. Chemical agents
5. Inert materials

11.  Recognition of injurious agent
 Recruitment of leukocytes
 Removal of agent
 Regulation of the response
 Resolution

13. Vascular events:
- Alterations in microvasculature (arterioles,
capillaries and venules)-earliest response to
tissue injury.
- These alterations include hemodynamic and
altered vascular permeability.

14. Transient vasoconstriction of
arterioles(lasts for 5mins)
Persistent progressive
vasodilatation
Slowing or stasis
Leukocytes margination or
peripheral orientation of
leukocytes

15.  Lewis experiment:
- Induced the changes in the skin of inner aspect of the forearm by firm
stroking with a blunt point.
a)Red line
b) Flare
c) Wheal

16. - In and around the inflamed tissue , there is accumulation of
oedema fluid in the interstitial compartment which comes
from blood plasma by its escape through the endothelial wall
of peripheral vascular bed.
- Escape of fluid is because vasodilation and elevation in
hydrostatic pressure
-This fluid is transudate in nature but later changes to exudate
due to increased vascular permeability.
- The fluid balance maintained is described by Starling’s
hypothesis.

18.  Contraction of endothelial cells
 Retraction of endothelial cells.
 Direct injury to endothelial cells
 Leucocyte mediated endothelial injury
 Leakiness in neovascularisation

20.  Exudation
 Phagocytosis
 EXUDATION :
In acute inflammation, PMNs comprise the first line of
body defense, followed later by monocytes and
macrophages

21.  The changes leading to migration of leukocytes are as
follows:
1) Changes in the formed elements of blood.
Slowing/stasis-central stream widens-peripheral plasma
zone narrower- loss of plasma by exudation-
MARGINATION
-neutrophils comes close to vessel wall-PAVEMENTING

22. 2) ROLLING AND ADHESION
SELECTINS
• P selectin(preformed and
stored in endothelial cells
and platelets).
• E selectin(cytokine
activated endothelial cells)
• L selectin (expressed on
the surface of
lymphocytes and
neutrophils).
INTEGRINS
• Bring firm adhesion
of leukocyte to
endothelium.
IMMUMOGLOBULIN
• ICAM
• VCAM,PECAM-1/CD 31

23.  EMIGRATION
-Neutrophils throw out pseudo-pods.
-Neutrophils lodged between endothelial cells and BM cross the BM
and escapes into extra-vascular space-EMIGRATION.
-Neutrophils: 24hrs(short-lived)
monocytes and macrophages:24-48hrs(longer)
-Diapedesis gives haemorrhagic appearance to inflammatory
exudate.

24.  CHEMOTAXIS
- Chemotactic factor-mediated transmigration of leukocytes after
crossing several barriers to reach the interstitial tissue is called
chemotaxis.
- Potent chemotatic substances for neutrophils:
Leukotriene B4
C5a and C3a
Cytokines(Il-8)
Soluble bacterial products(formylated peptides)

25. -Process of engulfment of solid particulate material by cell
Two main types of cells involved in phagocytosis are
 PMNS also called microphages and
 Macrophages .
-This involves 3 steps:
Recognition and attachment
Engulfment
Killing and degradation

28. 1) Recognition and attachment:
Microorganisms get coated with opsonins which are naturally occurring
factors in the serum to form a bond between bacteria and phagocytic cell .
-IgG opsonin
-C3b opsonin
-lectins

29.  Also called as permeability factors or
endogenous mediators.
 Enhance vascular permeability.
 They are broadly classified into 2 groups:
mediators released by cells
mediators originating from plasma

31. Vasoactive amines:
Histamine: stored in the granules of mast cells, basophils and
platelets. Histamine is released from these cells by various
agents as under:
a) Stimuli or substances inducing acute inflammation etc.
b) Anaphylatoxins C3a, and C5a,.
c) Histamine-releasing factors from neutrophils, monocytes and
platelets.
d) Interleukins.
The main actions of histamine: vasodilatation, increased vascular
(venular) permeability, itching and pain.

32. ii) 5Hydroxytryptamine (5HT or serotonin):
It is present in tissues like chromaffin cells of GIT, spleen, nervous
tissue, mast cells and platelets.
The actions of 5-HT-similar-histamine but it is a less potent mediator
of increased vascular permeability and vasodilatation than
histamine.

33. iii) Neuropeptides:
Substance P, neurokinin A, vasoactive intestinal
polypeptide (VIP) and somatostatin.
Small peptides produced in central and peripheral nervous
systems.
The major proinflammatory actions of these neuropeptides
are as follows:
a) Increased vascular permeability.
b) Transmission of pain stimuli.
c) Mast cell degranulation.

34.  The inflammatory cells neutrophils and monocytes, contain
lysosomal granules which on release elaborate a variety of
mediators of inflammation.
 These are
i) Granules of neutrophils- Neutrophils have 3 types of
granules: primary or azurophil, secondary or specific, and
tertiary.
a) Primary or azurophil granules-functionally active
enzymes. myeloperoxidase, acid hydrolases, acid phosphatase,
lysozyme, defensin (cationic protein), phospholipase, cathepsin
G, elastase, and protease.

35. b) Secondary or specific granules- alkaline phosphatase,
lactoferrin, gelatinase, collagenase, lysozyme, vitamin-
B12 binding proteins, plasminogen activator.
c) Tertiary granules or C particles -contain gelatinase and
acid hydrolases.

36. ii) Granules of monocytes and tissue macrophages-
These cells on degranulation release mediators of
inflammation like acid proteases, collagenase, elastase
and plasminogen activator.
- more active in chronic inflammation than acting as
mediators of acute inflammation.

37.  PLATELET ACTIVATING FACTOR (PAF)- released
from IgE-sensitised basophils or mast cells, other
leucocytes, endothelium and platelets
The actions of PAF as mediator of inflammation are:
-increased vascular permeability.
-vasodilatation in low concentration and vasoconstriction
otherwise.
-bronchoconstriction.
-adhesion of leucocytes to endothelium.
- chemotaxis.

38. CYTOKINES:
1) Fundamental role in inflammation-key mediators.
2) Polypeptide substances produced by activated
lymphocytes and monocytes.
3)Soluble proteins that act as messenger to transmit
signals from one cell-another.
4)Molecularly defined cytokines are called
interleukins.

39.  INTERLEUKINS FAMILY:
1)IL1 is elaborated by several body cells-monocytes and
macrophages, B lymphocytes, fibroblasts, endothelial and
some epithelial cells. Similarly, it can target all body cells. Its
major actions are: - ”expression of adhesion molecules.
- emigration of neutrophils and macrophages; ”
- role in fever and shock.
- hepatic production of acute phase protein

40.  IL6 is similar in its sources and target cells of action.
Its major role are: ”hepatic production of acute phase protein; ”
differentiation and growth of T and B cells.
 IL8 is also elaborated by the same cells as for IL-1 and IL-6
except that it is secreted by T cells instead of B lymphocytes. Its
target cells-neutrophils, basophils, T cells, monocytes/
macrophages, endothelial cells.
 Chemokine-major actions are: ”
-induces migration of neutrophils, macrophages and T cells; ”
-stimulates release of histamine from basophils.
”
-stimulates angiogenesis.

41.  IL12 is synthesised by macrophages, dendritic cells and
neutrophils while it targets T cells and NK cells.
- Its major actions in chronic inflammation are as under: ”
induces formation of T helper cells and killer cells.
”increases production of IFN-g.
”decreases production of IL-17.
 IL17 is formed by CD4+T cells while it targets fibroblasts,
endothelial cells and epithelial cells. Its action in chronic
inflammation are: ”increased secretion of other cytokines; and ”
migration of neutrophils and monocytes.

42. c) Interferon (IFN)-g: It is produced by T cells and NK
cells and may act on all body cells. It acts as mediator
of acute inflammation as under:
”activation of macrophages and NK cells.
stimulates secretion of immunoglobulins by B cells. ”
role in differentiation of T helper cells.

43.  TUMOR NECROSIS FACTOR ALPHA:
1)Key mediator in periodontal disease.
2) Fundamental role in immune responses-increase neutrophil
activity-mediate cell tissue turnover by inducing MMP
secretion.
3) secreted by activated macrophages in response to bacterial
LPS.
4)Pro inflammatory effects-stimulation of endothelial cells-
leukocyte recruitment, activation of macrophage IL-1β.
5)TNF-α:↑ periodontitis.

44. II. PROSTANOIDS:
1) Prostanoids -PGs, thromboxanes & prostacyclins.
2) COX2-regulated by IL-1β, TNF-α & bacterial LPS results in
increased production of PGE2.
3) PGE2 results in induction of MMPs & osteoclast bone
resorption-major role-tissue damage-periodontitis & have a pro
inflammatory role.
4)These are inhibited by NSAIDSs

45.  Arachidonic acid metabolites or eicosanoids are the most
potent mediators of inflammation, much more than oxygen
free radicals.
 These can be derived from cyclo-oxygenase pathway or
lipoxygenase pathway.

49.  Resolution
 Healing by scarring
 Progression to suppuration
 Progression to chronic inflammation

50. -Defined as prolonged process in which tissue destruction and
inflammation occur at the same time.
-General features
MONONUCLEAR CELL
INFILTRATION:
Infiltrated by phagocytes
and lymphoid cells.
TISSUE DESTRUCTION
OR NECROSIS:
Brought about by activated
macrophages which release
protease, elastase,
collagenase, lipase,
cytokines etc.
PROLIFERATIVE
CHANGES:
Proliferation of small blood
vessels and fibroblasts is
stimulated inflammatory
granulation tissue.

51.  Fever
 Anaemia
 Leucocytosis
 ESR elevated
 Amyloidosis

52.  chronic inflammation is subdivided into 2 types:
1. Chronic nonspecific inflammation –
When irritant substance produces a nonspecific
chronic inflammatory reaction with formation of
granulation tissue and healing by fibrosis, it is
called chronic non-specific inflammation
e.g. chronic osteomyelitis, chronic ulcer, lung
abscess.

53. 2. Chronic granulomatous inflammation:
In this, the injurious agent causes a characteristic
histologic tissue response by formation of granulomas
e.g. tuberculosis, leprosy, syphilis, actinomycosis,
sarcoidosis etc.

54.  Monocytes and macrophages are the primary cells.
 Macrophages are the scavenger cells of body
 T-lymphocytes primarily involved in cellular
immunity.
 B-lymphocytes and plasma cells produce antibodies.
 Mast cells and eosinophils appear in response to
parasitic infestations and allergic reactions.

55. 1.Mononuclear cell infiltration – phagocytes and lymphoid cells
macrophages- most important cells
2. Tissue destruction or necrosis
proteases, elastases, cytokines etc released by activated
macrophages
3. Proliferative changes- blood vessels and fibroblasts proliferate
forming granulation tissue.
thereby healing by fibrosis and collagen laying.

56. -A granuloma is basically a collection of epithelioid
cells, it also usually contains multinucleated giant cell
& is usually surrounded by a cuff of lymphocytes and
occasional plasma cells.
-The word ‘granuloma’is derived from granule
meaning circumscribed granule-like lesion, and -oma
which is a suffix commonly used for true tumours

58.  Two forms: sub-gingival micro flora(microbial virulence factors)
host immune-inflammatory response
 MICROBIAL VIRULENCE FACTORS:
-Lipopolysaccharides
-Bacterial enzymes & noxious products
-Microbial invasion
-Fimbrae
-Bacterial DNA & extracellular DNA

59.  HOST DERIVED INFLAMMATORY MEDIATIORS
Can be broadly classified into: Cytokines
Prostanoids
MMPs
Inflammatory diseases :
• Gingivitis
• Periodontitis
• Pericoronitis
• Cellulitis
• Sialadenitis
• Glossitis
• Osteomyelitis

61. Stage 1
Stage 2

62. Stage 3
Stage 4

63.  Bleeding on probing is present
 Color : red to bluish red
 Consistency : soft, friable
 Texture : loss of stippling is seen
 Size : Swollen or ballooning of interdental papilla and/or
gingival margin.
 Shape and contour : Blunts the marginal and papillary tissues

64. Inflammatory disease of supporting structures of the teeth .
 Gingiva moderately swollen
 Deep red to bluish-red tissues
 Blunted and rolled gingival margin
 Cratered papilla
 Bleeding and/or suppuration
 Plaque/calculus deposits
 Variable pocket depths
 Loss of periodontal attachment
 Horizontal/vertical bone loss
 Tooth mobility

65. Pericoronitis is inflammation of the soft tissue associated
with the crown of a partially erupted tooth.
 Most commonly seen in relation to the mandibular
third molar.
 Common symptoms and signs are pain, swelling,
trismus, halitosis, bad taste, inflammation of
pericoronal flap and pus discharge from underneath it.

66. Treatment
-Acute phase – debridement of plaque and debris ,
drainage of pus, irrigation , elimination of occlusal
trauma and prophylactic antibiotics along with
analgesics.
-Surgical intervention will be after acute phase is
subsided
-Extraction of impacted 3rd molar or operculectomy .

67.  Osteomyelitis may be defined as “an inflammatory
condition of bone, that begins as an infection of
medullary cavity and haversian systems of the cortex
& extends to involve the periosteum of the affected
area.”

68. PREDISPOSING FACTORS
• Fractures due to trauma and road traffic accidents
• Gun shot wounds
• Radiation damage
• Paget`s disease
• Osteoporosis
• Systemic disease : Malnutrition, Acute Leukemia,
Uncontrolled diabetes, sickle cell anemia, Chronic alcoholism

69.  It is a diffuse inflammation of soft tissues which
tends to spread through tissue spaces and along the
facial planes
 Also called as phlegmon
 It occurs as a sequelae of an apical abscess or
osteomyelitis or periodontal infection.
 Other causes : infection following tooth extraction,
injection(infected needle or through infected area) or
following jaw fracture

70.  Fever
 Chills
 Erythema
 Painful swelling of the soft tissues involved that
are firm and brawny.
 Local tenderness and pain.
 Regional lymphadenopathy

71.  Extension towards eye may result in
cavernous sinus thrombosis
 Extension to cervical area results in
respiratory discomfort because of
constriction of pharyngeal spaces.
Treatment
 systemic antibiotics
 Intravenous fluids
 Surgical intervention

72.  Resolution-active class switch in the mediators such as classic
PG and leukotrienes, to the production of immunoresolvents.
Lipid mediators- Resolvins
Protectins
Lipoxins
Maresins
Lipoxins- Endogenous fatty acids
Resolvins, protectins, maresins-dietary fatty acids(ω-3 FA)

73. In
humans(git
, airways,
oral-
cavity)
Sequential
oxygenatio
n of AA
Enzymatic
hydrolysis
Natural pro-resolving
molecules. Lipoxins
A4 & B4-isolated
First pathway

74. In blood vessels
5-lipoxygensae
LIPOXIN A4
12-
lipoxygenase(plat
elets) lipoxin B4.
LA4-regulates
cellular function.
Activation of
specific receptors
present on
neutrophils and
monocytes.
Second pathway

75. Triggered by
aspirin.
Acetylation of
COX2.
Change in COX2
activity and in
chirality- products.
Third pathway

76.  Lipid mediators-biosynthesized from precursor
essential ω-3 PUFA, eicosapentaenoic acid and
docosahexanoic acid derived from diet.
 Categorised into
E- series & D- series
(EPA) (DSA)

77.  E-series:
produced-vascular endothelium via aspirin
modified cox2.(EPA)
18R-HPEPA and 18S- HPEPA
(taken up by human neutrophils- metabolised-
resolvin E1 E2)
Production of resolvin E1- increased - plasma-
individuals-aspirin-amelioration of clinical signs
of inflammation.

78.  D- series
-Reduce inflammation-decreasing platelet
leukocyte adhesion.

79.  Biosynthesized by lipoxygenase mediator pathway.
DHA 17S-hydroxy peroxide-containing
intermediate(leukocytes)
10,17-dihydroxyDHA(Protectin D1/Neuroprotectin)
 Produced -Humans peripheral blood lymphocytes with T-
helper 2 phenotype
 Reduces TNF-α, Ifγ secretion, blocks T-cell migration &
promotes T-cell apoptosis.

80.  Macrophage mediators-primordial
molecules-macrophages with homeostatic
function
 Macrophage phagocytosis of apoptotic cells
trigger biosynthesis of resolvin E1, protectin
D1, lipoxin A4 and maresin-1
 They effectively stimulate efferocytosis with
human cells

81.  Brinkmann et al in 2004 , discovered neutrophil
extracellular traps in innate immunity .
 NETs are DNA-based net like fibers that mediate an
antimicrobial function outside the cell.
 They are complexes of nuclear or mitochondrial DNA
together with proteins such as histones, cell-specific
enzymes (myeloperoxidase or elastase) and
antimicrobial peptides (e.g., cathelicidins).
 The DNA itself is not antimicrobial, it is the host
proteins bound to the DNA scaffold that give NETs
their antimicrobial activity .

82.  In the presence of various bacteria, neutrophils have
been shown to release their DNA in a net-like fashion
to create traps.
 Steinberg and Grinstein termed this novel cell death
which is morphologically distinct from the classical
cell death program (apoptois and necrosis) as
“NETosis” .
 NET formation by neutrophils helps in the
containment of the infection along with decreasing
the inflammation by releasing anti-inflammatory
lipoxins and lowering pathogen load.

84.  Neutrophil death can occur by apoptosis or
necrosis and also by another unique
mechanism called as NETosis.
 NETs are degraded by DNAse, an enzyme
found in the serum of healthy individuals .
The neutrophils switch from producing
proinflammatory mediators (such as
prostaglandins and leukotrienes) to
producing anti-inflammatory mediators such
as lipoxins.

85.  The lipoxins promote the phagocytosis of
apoptotic neutrophils by macrophages and
induce macrophages to synthesize
antiinflammatory cytokines such as TGF-beta
and lipid mediators (resolvins, protectins, and
maresins) that play a key role in inhibiting
neutrophil recruitment, their activation and
are responsible for clearing neutrophils from
the site of inflammation.

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Cotran Pathologic Basis of Disease, Professional
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