Chemical mediators of inflammation/ dental implant courses

INDIAN DENTAL ACADEMY
Leader in continuing Dental Education
www.indiandentalacademy.com

Inflammation is defined as a complex
reaction to injurious agents such as microbes and
damaged, usually necrotic, cells that consists of
vascular responses, migration and activation of
leukocytes, and systemic reactions

 3000 BC – signs of inflammation described by
PAPYRUS ( Egyptian)
 1st AD – CELSUS, roman writer listed 4 Cardinal
signs
RUBOR - redness
TUMOR - swelling
CALOR - heat
DOLOR - pain
 VIRCHOW – added 5th Cardinal sign
FUNCTIOLAESA - loss of function

 1793 – JOHN HUNTER (Scottish) – it is not a
disease, but non specific response, which has
salutary effect on its Host
 1839 – 1884 – JOHN COHNHEIN observed
Inflamed blood vessels (frogs) – Increased vascular
permeability and Leukocyte emigration

 1882 – ELIE METCHNIKOFF (Russian) observed
PHAGOCYTOSIS . Purpose of inflammation is to
get phagocytes in injured area to engulf the bacteria
 Same time –– PAUL EHLICH Neutralize the
infectious agent by serum factors ( antibodies)
 1908 – METCHNIKOFF and PAUL EHLICH got
NOBLE prize for their work.
 Both PHOGOCYTES (CELLULAR) and SERUM
FACTORS ( ANTIBODIES) are responsible to
defense against MICROBES

The Triple Response:
 SIR THOMAS LEWIS (1927), established the Concept that
Histamine locally induced by injury mediate the vascular
changes;
 This concept underlies the use of anti- Inflammatory agents
in clinical medicine.
 Firmly stroking the fore arm with a Blunt instrument, evokes
this response.
 Within one min. a red line appears; (because of dilatation of
arterioles, capillaries & venules).
 A red flare develops (because of vasodilation of the tissue
surrounding injury);
 A wheal forms because of exudation fluid
 The flare, which is a minor component is mediated by local
axon reflex;

 The major components, red line & wheal were
shown to be independent of neural connections

 Unique feature of the inflammatory process is the
reaction of blood vessels, leading to the
accumulation of fluid and leukocytes in
extravascular tissues.
 The inflammatory response is closely intertwined
with the process of repair.
 Inflammation serves to destroy, dilute, or walloff the
injurious agent, and it sets into motion a series of
events that try to heal and reconstitute the damaged
tissue

 Inflammatory response consists of two main
components
1. Vascular Events
2. Cellular Events

 Many tissues and cells are involved in these
reactions, including the fluid and proteins of plasma,
circulating cells, blood vessels, cellular and
extracellular constituents of connective tissue.

 Inflammation is divided into
1. Acute Inflammation
2. Chronic Inflammation

 Rapid in onset (Seconds or Minutes)
 Short duration
 Lasting for minutes to several hours or a few days
 Exudation of fluid and plasma proteins (edema) and
the emigration of leukocytes, predominantly
neutrophils

 Longer duration and
 Associated histologically with the presence of
lymphocytes and macrophages, the proliferation of
blood vessels, fibrosis and tissue necrosis.

 Stimuli for Acute inflammation
 Trauma
 Physical and chemical agents
 Tissue necrosis
 Foreign bodies
 Immune reactions
 Infection

Acute Inflammation
 Alteration in vascular caliber
 Structural changes in the microvasculature
 Emigration of the leukocytes from the microcirculation

Vascular changes:
 Change in vascular flow and caliber
 Increased vascular permeability(vascular leakage)

Change in vascular flow & caliber:

Increased vascular permeability:
 Formation of Endothelial gaps in Venules
 Direct endothelial injury
 Delayed prolonged leakage
 Leukocyte – mediated endothelial injury
 Increased transcytosis
 Leakage from new blood vessels

Cellular Events
 Neutrophils form the first line of defence;
 The multi step process of leucocyte migration:
- Neutrophils first roll,
- Then become activated,
- Adhere to endothelium,
- Transmigrate along the endothelium,
- Pierce the Basement membrane
- Migrate toward the chemoattractants
- Emanating from the source of injury.

Molecules that play predominent role in each step:
 SELECTINS:- E-Selectin &P-Selectin; In rolling
(tumbling along the endothelium)
 CHEMOKINES: Act on the rolling cells & activate
them. Activation results from several signaling
Pathways that result in increase in cytosolic Ca++,&
activation of enzymes such as Protein kinase C &
Phospholipase A2.
 INTEGRINS: (Beta 1 & Beta2 ) In firm
adhesion;Integrin superfamily Consisting of 30
proteins,that promote Cell to cell or cell to matrix
inter action. They coordinate signals with
cytoskeleton dependent motility, Phagocytic
response ect.

 CD 31 (PECAM-1)- Adhesion molecule in trans-
migration, Leukocyte migration occurs
predominantly. In venules; they pierce the BM by
Secreting collagenases.

Importance Of Adhesion Molecules:
Genetic defects in adhesion molecules result in
 Recurrent bacterial infections;
 LAD-Type-I- have defect in biosynthesis of Beta
chain;
 LAD-TYPE-2-have defects in Fucosyl transferase
enzyme ;

LAD-I (CD11/CD18 Deficiency):
 Rare; inherited disorder; Detected in early
childhood; delayed umbilical cord separation may be
Life threatening. Infections of middle ear,
oropharynx ect.
 Neutrophils roll, but do not adhere or migrate.
LAD-2:
 Short stature &distinct facial appearance;
 Recurrent bacterial infections—including
Pneumonias, cellulitis without pus & Periodontitis
 Surface CD18 expression is normal;
 Lack of CD15 expression seen;
 Neutrophils do not roll on endothelial Cells, & do
not adhere

Emigrating Leukocytes:
 Varies with the age of the response & With the type
of stimulus;
 In most forms, Neutrophils predominate during the
first 6-24 hrs;
 After entering the tissue, they undergo Apoptosis &
disappear; In certain infections (Eg. Pseudomonas
inf.), they predominate over 2-4 days;
 In viral inf. lymphocytes are the first cells to arrive.

 Chemotaxis
Defined as locomotion oriented along a
Chemical gradient.
 All granulocytes, monocytes, & to a lesser extent
lymphocytes respond to stimuli with varying rates of
speed.
 Exogenous agents- bacterial products,
 Endogenous- 1.C5a,
2.Leucotriene (LTB4)
3. Cytokine (IL-8).

Defects In Chemotaxis:
 Localised Juvenile Periodontitis: Is characterised by
alveolar bone loss, most prominently of the incisors
& first Molars.
 They don’t have extra oral infections;
 Abnormal Chemotaxis to FMLP & C5a has been
reported; Neutrophils in these Pts express CR2 on
surface in contrast to control cells;
 Normally, CR2 is present only on immature cells &
lost during Maturation, before release from the
marrow.

Leukocyte Activation:
 Results from several signals passing through & trigger
leucocytes; result in Increase in cytosolic Ca++ &
activates Enzymes such as Protein kinase C &
Phospholipase A2;
 As a result the following responses occur;
1 Production of AA metabolites from Phospholipids;
2 Degranulation & secretion of lysosomal enzymes &
activation of Oxidative Burst.
3 Secretion of Cytokines which amplify & Regulate
inflammatory reactions;
4 Modulation of adhesion molecules allowing firm
adhesion of activated Neutrophils to the endothelium.

 Neutrophils express a no. of surface receptors involved
in the activation:
1. Toll like receptors (TLRs) (which play a role in
adhesion & response to LPS)
2. 7mem Gprotein receptors (recognize
chemokines,C5a,PAF,LTB4 &Prosta.E)

 Neutrophils

Phagocytosis (Cell Eating):
 When a neutrophil meets a particle, it envelops it
with pseudopodia which flow around it forming a
phagolysosome that rapidly fuse with Azurophilic &
Specific granules.
Granule Release:
 Neutrophil contains 4 types of intracellular
Granules: Azurophilic,specific, Gelatinase(Tertiary)&
Sec.Ves.

Oxygen dependent mechanisms
 Free O2 radicals:
 Phagocytosis initiates HMP shunt; causing a burst in
O2 consumtion, glucose oxidation & Production of
reactive O2 metabolites;
 O2 is reduced to Superoxide ion which is then
converted to H2O2 by spontaneous dismutation.
 This H2O2 is not powerful bactericidal.

 Production of reactive O2 Species

O2 Independent Mechanisms
 LYSOZYME-in neutrophil granules can lyse the
cellwall of some bacteria, -gram +ve cocci;
 Lactoferrin-a protein that binds Iron &inhibits
bacterial growth by depriving them of it;
 BPI-Bactericidal permeability increasing factor.
 Elastase (found in granules)
 Defensins Ect.contribute for killing the bacteria.

Mediators originate from either –
 Plasma – e.g. complement proteins & kinins -
These are present in precursor forms that must be
activated by series of proteolytic cleavage →
acquire biologic properties
 Cells – present in intracellular granules that need to
be secreted (e.g. Histamine in mast cells) or
synthesized denovo in response to stimulus (e.g.
Prostaglandins, cytokines)

Mediators perform activity by –
 Mostly by binding to receptors on target cells
 Direct enzymatic activity e.g. Lysosomal proteases
 Mediate oxidative damage e.g. reactive oxygen
species & nitrogen intermediates
Mediators can act on –
 One or few target cells Can have diverse targets
 Have different effect on different cell types

 Once activated & released from the cell the mediators
are short lived.
They either –
 Quickly decay e.g. Arachidonic acid metabolites
 Inactivated by enzymes e.g. kininase inactivates
Bradykinin
 Scavenged e.g. antioxidants scavenge toxic oxygen
metabolites
 Inhibited e.g. complement regulatory proteins breakup
& degrade activated complement components

Vasoactive amines:
 First mediators to be released during
inflammation are-
Histamine
Serotonin

Histamine:
 Richest source –mast cells
-also in platelets & Basophils
Stimuli for degranulation of Mast cells –
 Physical injury such as trauma , cold or heat
 Immune reactions involving binding of antibodies
to Mast cells
 Fragments of complement called Anaphylotoxins
(C3a & C5a )
 Neuropeptides (substance P )
 Cytokines (IL – 1 & IL – 8 )

Action of Histamine
 Dilation of arterioles ( but constriction of large
arterioles )
 Increased permeability of venules
 Principle mediator of immediate transient phase of
increased vascular permeability
 Acts on microcirculation mainly via binding to H1
receptor on endothelial cells

Serotonin:
 Action similar to that Histamine
 Source – platelets & Enterochromaffin cells
 Release from platelets occurs when platelets aggregate
after contact with –
Collagen
Thrombin
ADP
Ag- Ab complexes

 Plasma proteins that mediate inflammatory response
belong to 4 interrelated systems
 Complement system
 Kinin system
 Clotting system
 Fibrinolytic

Complement system-
 Complement system consists of 20 component proteins
that are found in greatest concentration in plasma
Complement components causes –
 Increasing vascular permeability
 Chemotaxis
 Opsonisation
Activation of complement cascade consists of 2 steps i.e.
early step & late step
 Early steps consists of 3 different pathways & lead to
proteolytic cleavage of C3
 Late steps – all 3 pathways converge & major
breakdown products of C3, C3b activate a series of
other complement components

 The early steps in complement activation consists of
3 pathways i.e. –
Classical pathway
Alternate pathway
Lectin pathway

 classical pathway

 Alternate pathway

 Lectin pathway

 PLASMA PROTEINS
Late pathway

PLASMA PROTEINS
Regulation of complement activation
 Regulation of C3 & C5 convertase by enhancing
dissociation of convertase complex e.g. Decay
accelerating factor
 Binding of active complement components by
specific proteins in plasma
 C1 inhibitor interferes with enzymatic activity of C1
 Proteins that inhibit MAC formation e.g. CD59
inhibit excessive complement activation

The biologic function of complement system
 Cell lysis by MAC
 Vascular phenomenon – increased vascular
permeability & vasodilatation
 Leukocyte adhesion, chemotaxis & activation
 Phagocytosis

Disorders of complement system
 Deficiency of complement components lead to
increased susceptibility to infections
 Deficiency of C4 & C2 – autoimmune diseases e.g.
SLE
 Genetic defeciency of complementary regulatory
protein – significant disease – e.g. Paroxysmal
Nocturnal Hematuria
 Defeciency of C1 inhibitor – Hereditory
angioneurotic edema

 Kinin & Clotting system

Protease activated receptors
 These are 7- Transmembrane G – protein receptors
present on platelets, endothelial cells, smooth muscle
cells, etc.
 Engagement of PAR by proteases particularly
Thrombin triggers several responses like-
 Mobilization of P- selectin
 Production of chemokines
 Expression of endothelial adhesion molecule
 Production of Prostaglandins, PAF, & NO
 Changes in endothelial shape

ARACHIDONIC ACID METABOLITES
Membrane lipids
↓
Biologically active lipid products
(Autocoids – short range of hormones- formed
rapidly – exert their effects locally – either decay
spontaneously or destroyed enzymatically )
↓
Serve as extracellular or intracellular signals to affect
variety of biologic process including inflammation &
hemostasis

Cell membrane phospholipids
↓ phospholipases
Dietary sources → Arachidonic acid
↓ Cyclooxygenase
Lipooxygenase
Eicosanoids

 Eicosanoids + G-protein coupled receptors on
various cell types – mediate steps of inflammation

LIPOXINS
 Lipoxins are generated by transcellular biosynthetic
mechanisms involving two cell population
 Leukocytes produce intermediates in Lipoxin
synthesis which are converted to Lipoxin by platelets
interacting with leukocytes

 Biosynthesis of Leukotrienes & Lipoxins

The principle action of Lipoxins are –
 Inhibit leukocyte recruitment & cellular components
of inflammation
 Inhibit neutrophil chemotaxis & adhesion to
endothelium
 Lipoxins may be endogenous negative regulators of
Leukotrienes leading to resolution of inflammation

 Anti inflammatory therapy can be directed at many
targets along the Eicosanoids biosynthetic pathway
 Cyclooxygenase inhibitors – (COX 1, COX 2) e.g.
NSAIDS like Indomethacin inhibit Prostaglandin
synthesis by irreversibly acetylating & inhibiting
Cyclooxygenase
 Lipoxygenase pathway – used in treatment of Asthma
 Broad spectrum inhibitors – e.g. Glucocorticoids.
They act by down regulating the expression of genes like
genes encoding for COX2, Phospholipase A2, NO
synthetase e.t.c. They also up regulate the genes encoding
for anti-inflammatory proteins like Lipocortin-1

PLATELET ACTIVATING FACTORS
 PAF is bioactive phospholipid derived mediators
 PAF is derived from antigen stimulated IgE
sensitized Basophils that cause platelet aggregation
Sources – Neutrophils, Platelets, Basophils, Mast cells,
Endothelial cells.

Functions –
 Platelet stimulation
 Vasoconstriction ( in low conc. It induces
vasodilatation & increased venular permeability)
 Increased leukocyte adhesion to endothelium
 Chemotaxis
 Degranulation
 Increased synthesis of other mediators by leukocytes
& other cells

CYTOKINES & CHEMOKINES
 Cytokines are proteins produced by many cell types
principally activated Lymphocytes, Macrophages,
Endothelium, Epithelium & Connective tissue cells

TUMOR NECROSIS FACTOR & INTERLEUKIN-1
 They are produced mainly by activated macrophages &
they mediate inflammation
 Secretion of TNF & IL-1 is stimulated by – endotoxins,
microbial products, immune complexes, physical injury
e.t.c.
Functions –
 Effects on Endothelium, leucocytes, & fibroblast
 Induction of systemic & acute phase reactants

ENDOTHELIAL EFFECTS
 Increased synthesis of endothelial adhesion
molecules & chemical mediators like cytokines,
chemokines, growth factors, eicosanoids & NO.
 Production of enzymes associated with matrix
remodeling
 Increase in the surface thrombogenecity of the
endothelium
 Increased procoagulant activity, Decrease in
anticoagulant activity

EFFECTS ON FIBROBLAST
 Increased proliferation
 Increased collagen synthesis
 Increased collagenase
 Increased protease
 Increased PGE synthesis

LEUKOCYTE EFFECT
 Increased cytokine secretion ( IL-1, IL-6 )
IL-1 & TNF induces systemic acute phase
response which include-
 Fever
 Loss of appetite
 Release of Neutrophils into circulation
 Hemodynamic effects like hypotension, decreased
vascular resistance, increased heart rate e.t.c.
 Regulates body mass by regulating lipid & protein
mobilization & by suppressing appetite

CHEMOKINES
 Chemokines are a family of small proteins that
act primarily as chemoattractant
 They are classified into 4 major groups based on
the arrangement of conserved cysteine residues
in the mature proteins
 C-X-C chemokines (Alpha chemokine)
 C-C chemokines (Beta chemokines)
 C chemokines (Gamma chemokines)
 CX,C chemokines


 NITRIC OXIDE

LYSOSOMAL CONSTITUENTS OF
LEUKOCYTES
 Neutrophils & monocytes contain granules that
produce inflammatory response
 Neutrophils contain 2 main types of granules-
 Small specific granules
 Large Azurophilic granules

Smaller specific
granules contain
 Collagenase
 Gelatinase
 Lactoferrin
 Plasminogen activator
 Histaminase
 Alkaline phosphatase
 Phospholipase A2
Large Azurophilic
granules contain
 Myeloperoxidase
 Bactericidal factors
(lysozyme, defensins)
 Acid hydrolases
 Variety of neutral
proteases (Elastases,
Cathepsin G, Non-
specific collagenase,
proteinase – 3 )
 Phospholipase A2
 Bacterial permeability
increasing
protein(BPI)

OTHER MEDIATORS
 Hypoxia induced factor 1 alpha
 Uric acid which is break down product of DNA in
necrotic cells

Applied Anatomy

 Acute inflammation-Morphology
1. Pseudomembranous inflammation
 It is the response of mucous membrane (Oral,
respiratory, bowel) to toxins of the diphtheria, or
irritant gases. Due to denudation of epithelium,
plasma exudes on the surface, where it coagulates &
together with Necrosed epithelium, forms false
membrane that gives the name.

2. Ulcer
 Ulcers are local defects on surface of an organ
produced by inflammation, i.e. discontinuity of the
lining epithelium.
 Common sites are stomach, intestines(e.g. Typhoid
fever), intestinal Tuberculosis, Bacillary & Amoebic
dysentery etc.
 Ulcers of legs due to Varicose veins.
 May be acute or chronic

3.Abscess formation (Suppuration-Purulent
inflammation)
 Abscesses are focal collections of pulse that may be
caused by deep seeding of Pyogenic organisms or by
secondary infection of necrotic foci. They have a central
necrotic region rimmed by a layer of preserved
neutrophils with a zone of dilated vessels & Fibroblastic
proliferation.
Abscess
 The purulent exudate or pus is creamy & or opaque in
appearance & is composed of numerous dead as well as
living neutrophils, red cells, tissue debris & fibrin.
 In old pus macrophages & Cholesterol crystals may be
present.
 It may discharge to the surface due to increased pressure
inside or may require drainage.

4.Cellulitis
 It is a diffused inflammation of soft tissues resulting
from spreading effects of substances like
Hyaluronidase released by some bacteria.

Fate of acute inflammation
 Acute inflammatory process can result in one of the
following outcomes
1.Resolution
2.Healing by scarring
3.Progression to suppuration
4.Progression to chronic inflammation.

Resolution
 It means complete return to normal tissue following
acute inflammation.
 This occurs when the injury is limited or with
minimal tissue damage & when the tissue is capable
of replacing the injured cells.
E.g Resolution in Lobar Pneumonia

Healing by Scarring
 This takes place when the tissue destruction is
extensive; there is no regeneration, extensive
fibrinous exudate occurs which cannot be
completely absorbed.
 There is healing by Fibrosis.
E.g Healing of Abscess(In certain bacteria or fungal
infections due to Pyogenic infections)

Progression to Suppuration
 When Pyogenic bacteria cause acute inflammation
resulting in severe tissue necrosis, Suppuration sets
in.
 Initially, there is intense neutrophilic infiltration.
Subsequently mixture of neutrophils, bacteria,
fragments of Necrotic tissue, cell debris & Fibrin
comprise “pus” which is contained in a cavity
forming an Abscess. If it is not drained, it may get
organised & in time get calcified.

Progression to Chronic inflammation
 Acute inflammation may progress to chronic
inflammation in which the process of inflammation
& healing proceed side by side.
 Depending on the extent of initial injury & the
capacity of the tissue, there may be regeneration or
Scarring.

THANK YOU

Chemical mediators of inflammation/ dental implant courses

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