GOOD AFTERNOON

Presented by
K.V.Chalapathi
I MDS
Department of Oral and Maxillofacial Pathology
Vishnu Dental College

Inflammation
Etymology : latin inflammare meaning to set

afire.
Inflammation is an injurious stimuli causing a
protective vascular connective tissue reaction.
Injury can be due to any agent.
It is a body defense reaction in order to
eliminate or limit the spread of the injurious
agent as well as to remove a consequent
necrosed cells and tissues.

Cellular Injury

Acute Inflammation

Healing
Chronic Inflammation

Healing
Granuloma formation

Healing

Agents causing
Inflammation
Physical agents
Infective agents
Chemical agents
Immunological agents.

Historical Highlights
Inflammation was first described in an

Egyptian papyrus in around 3000 BC.

Celsus, a Roman of I century AD, listed out the
4 cardinal signs.
Rubor (redness)
Tumor (swelling)
Calor (heat)
Dolor (pain)

In 19th century Rudolf Virchow given the fifth

cardinal sign Functio laesa (loss of function).

John Hunter in 1793 revealed the fact that

inflammation is not a disease but a non specific

response that has a salutary effect on its host.
Phagocytosis was discovered by Elie
Metchnikoff in 1880 s.
Sir Thomas Lewis has given the concept that
chemical substances, such as histamine
(produced locally in response to injury),
mediate the vascular changes of inflammation.

Classification
According to the duration:
Acute Chronic (+ subacute, hyperacute)

According to predominant component:

1. Alterative (predominance of necrosis - diphtheria)
2. Exudative (pleuritis)
3. Proliferative (cholecystitis - thickening of the wall by

fibrous tissue)

According to histological features:

Nonspecific (not possible to trace the etiology) - vast

majority
Specific (e.g. TB)

According to causative agent:

Aseptic (sterile) - chemical substances, congelation,

radiation - inflammation has a reparative character.

Septic (caused by living organisms) - inflammation has a
protective character.

Acute inflammation
Acute inflammation is a rapid response to an

injurious agent that serves to deliver mediators of

host defenseleukocytes and plasma proteinsto
the site of injury.
Main features
Accumulation of fluid and plasma at the affected

site.
Intravascular activation of platelets.
PMNs as inflammatory cells.

Chronic Inflammation
Chronic inflammation is considered to be

inflammation of prolonged duration (weeks or

months) in which active inflammation, tissue
destruction, and attempts at repair are proceeding
simultaneously.
Main features
Presence of chronic inflammatory cells such as
lymphocytes, plasma cells and macrophages.
Associated with vascular proliferation and
scarring.

ACUTE INFLAMMATION
Acute inflammation is a rapid host

response that serves to deliver

leukocytes and plasma proteins,
such as antibodies to the site of
infection or tissue injury.
3 major components are:

Alterations in vascular caliber that

lead to an increase in blood flow.

(erythema and warmth)
Extravasation and extravascular
deposition of plasma fluid and
proteins. (edema)
leukocyte emigration and
accumulation at the site of injury.

Stimuli of Acute Inflammation

Infection
Trauma
Physical and chemical injuries
Tissue necrosis
Foreign bodies
Hypersensitivity reactions

Changes in Acute Inflammation

Vascular Events
Cellular Events

Vascular Events: Alteration in the

microvasculature is the earliest response to

the tissue injury. This includes
Haemodynamic changes
Changes in Vascular permeability

Hemodynamic changes

Change in vascular permeability

Vascular leakage
Five mechanisms are known to cause the

vascular leakiness.
Histamines, Bradykinins, Leukotrienes : cause an

early, breif (15 30 min) immediate transient

response in the form of endothelial cell contraction
that widen intercellular gaps of venules.
Cytokine mediators (TNF, IL-1) induce endothelial
cell junction retraction through cytoskeleton
reorganization (4 6 hrs post injury, lasting 24 hrs
or more)
Severe injuries may cause immediate direct
endothelial cell damage (necrosis, detatchment)
making them leaky until they are repaired.

Role of Histamine in vascular leakage:

Histamine has an ability to induce phosphorylation of
an intercellular adhesion protein (called (VE)cadherin) found on vascular endothelial cells
(Andriopoulouet al1999).That is why histamine is
known as being vasoactive.
Gaps between the cells in vascular tissue are created
by this phosphorylation, allowing blood fluids to seep
out into extracellular space.
Indirectly, histamine contributes to inflammation by
affecting the functions of other leukocytes in the area.
It has been suggested by Maroneet althat histamine
release triggers the release of cytokines and
inflammatory mediator by some neighboring
leukocytes.

Bradykinins : Bradykinin is a potentendothelim-

dependentvasodilator, increases
vascularpermeability, causes dilation of nonvascularsmooth muscle.
Leukotriene B4may play a pivotal role in the
induction of neutrophil-endothelial cell
adherence. Leukotriene B4-induced endothelial
cell hyperadhesiveness for neutrophils depends
on increased CD11/CD18 expression on the
neutrophil surface and possibly a specific domain
of the adhesion molecule CD54 found on
endothelial cells
Bradykinin triggers the production of other

chemicals such asHistamines and Prostaglandins.

Cellular Events
The processes involving leukocytes in

inflammation consists of their:

Recruitment from the blood into extravascular

tissues.
Recognition of microbes and necrotic tissues.
Removal of the offending agents.

Recruitment of leukocytes to the

site of infection and injury
Journey of leukocytes from the vessel lumen

to interstitial tissue

extravassation.

Leukocytes margination rolling adhesion

transmigration
Emigration of:

Neutrophils (1-2 days)

Monocytes (2-3 days)

Chemotaxis

Endogenous signaling molecules - lymphokines

Exogenous - toxins

Margination and Rolling

With increased vascular permeability, fluid leaves

the vessel causing leukocytes to settle-out of the

central flow column and marginate along the
endothelial surface.
Early rolling adhesion mediated by selectin family
of adhesion molecules.
Endothelial cells and leukocytes have
complementary surface adhesion molecules which
briefly stick and release causing the leukocyte to
roll along the endothelium like a tumbleweed until
it eventually comes to a stop as mutual adhesion
reaches a peak.

Margination, Rolling and

Adhesion

Adhesion

Rolling comes to a stop and results in

adhesion.
Other sets of adhesion molecules participate,
such as the integrins.
Ordinarily down-regulated or in an inactive
conformation.

Diapedesis

Transmigration across
Endothelium

Occurs after firm adhesion within the

systemic venules and pulmonary
capillaries via other adhesion
molecules (CD31)
Must then cross basement membrane
collagenases
integrins
Early in inflammatory response
mostly PMNs, but as cytokine and
chemotactic signals change with
progression of inflammatory
response, alteration of endothelial
cell adhesion molecule expression
activates other populations of
leukocytes to adhere (monocytes,
lymphocytes, etc)

Chemotaxis
Chemotaxis: A reaction by which the direction of

locomotion of cells or organisms is determined

by substances in their environment along the
chemical gradient.
If the direction is towards the stimulating
substance, chemotaxis is said to be positive, if
away from the stimulating substance, the
reaction is negative.
If the direction of movement is not definitely
towards or away from the substance in question,
chemotaxis is indifferent or absent.

Chemotaxis

Leukocytes follow chemical gradient to site of

injury (chemotaxis)
Soluble bacterial products
Complement components (C5a)
Cytokines (chemokine family e.g., IL-8)
LTB4 (AA metabolite)

Chemotactic agents bind surface receptors

inducing calcium mobilization and assembly of

cytoskeletal contractile elements.
chemotaxis
endogenous signaling molecules - lymphokines
exogenous - toxins

Chemotaxis and Activation

Leukocytes:
Extend pseudopods with overlying surface

adhesion molecules (integrins) that bind ECM

during chemotaxis
undergo activation:
Prepare AA metabolites from phospholipids.
Prepare for degranulation and release of
lysosomal enzymes (oxidative burst).
Regulate leukocyte adhesion molecule affinity
as needed.

Recognition of Microbes and Dead

Tissues
Once leukocytes reaches the site of infection

2 sequential set of events occurs:

Recognition of offending agents which delivers

the signals

Activates the leukocytes to ingest and destroy

the offending agents

Various receptors
Receptors for the microbial products: TLRs
These are present on the cell surface and in the

endosomal vesicles of leukocytes. They function

through receptor-activated kinases to stimulate the
production of microbial substances and cytokines by
the leukocytes.

G protein-coupled receptors:
Found on neutrophils, macrophages and other

leukocytes recognize short bacteria peptides containing

N-formylmethionyl residues. These receptors induce
migration of the cells from the blood through the
endothelium and the production of the microbicidal
substances.

Receptors cntd
Receptors for opsonins:
Leukocytes express receptors for proteins that
coat the microbe. This process of coating for
ingestion is called as opsonisation and
substances are opsonins. The substances
include antibodies, complement proteins and
lectins
Receptors for cytokines:
Interferon secreted by natural killer cells. It is

the major macrophage-activating cytokine.

Phagocytosis
It involves 3 sequential steps
Recognition and attachment of the particle to
be ingested by the leukocyte.

Engulfment with subsequent formation of

phagocytic vacuole.

Killing or degradation of the ingested material.

Recognition and Binding

Opsonized by serum complement,

immunoglobulin (C3b, Fc portion of IgG)

Corresponding receptors on leukocytes (FcR,
CR1, 2, 3) leads to binding

Phagocytosis and Degranulation

Triggers oxidative burst, engulfment and

formation of vacuole which fuses with

lysosomal granule membrane
(phagolysosome).
Granules discharge within phagolysosome
and extracellularly (degranulation).

Oxidative Burst
Reactive oxygen species formed through

oxidative burst that includes:

increased oxygen consumption

glycogenolysis
increased glucose oxidation
formation of superoxide ion

2O2 + NADPH 2O2-rad + NADP+ + H+

(NADPH oxidase)
O2-rad + 2H+ H2O2 (dismutase)

Reactive oxygen species

Hydrogen peroxide alone insufficient
MPO (azurophilic granules) converts hydrogen

peroxide to HOCl- (in presence of Cl- ), an

oxidant/antimicrobial agent.
Therefore, PMNs can kill by halogenation, or
lipid/protein peroxidation.

Degradation and Clean-up

Reactive end-products only active within

phagolysosome.
Hydrogen peroxide broken down to water and
oxygen by catalase.
Dead microorganisms degraded by lysosomal
acid hydrolases.

Leukocyte-induced Tissue Injury

Destructive enzymes may enter extracellular

space in event of:

Premature degranulation
Frustrated phagocytosis (large, flat)
Membranolytic substances (urate crystals)
Persistent leukocyte activation (RA,

emphysema)
Eg.:
Acute ARDS, Asthma, Glomerulonephritis, Septic
shock, Vasculitis.
Chronic Arthritis, Asthma, Atherosclerosis, Chronic
lun disease.

Defects of Leukocyte Function

Defects of adhesion:
LFA-1 and Mac-1 (integrins) subunit defects lead
to impaired adhesion (LAD-1)
Recurrent bacterial infections with impaired
wound healing
Absence of sialyl-Lewis X, and defect in E- and
P-selectin sugar epitopes (LAD-2)
Clinically milder than LAD-1, but recurrent
bacterial infections

Defects of Leukocyte Function

Defects of chemotaxis/phagocytosis:
microtubule assembly defect leads to impaired
locomotion and lysosomal degranulation
neutropenia, defective neutrophil
degranulation, delayed microbial killing,
recurrent bacterial infections
Defects of microbicidal activity:
deficiency of NADPH oxidase that generates

superoxide, therefore no oxygen-dependent

killing mechanism (Chronic Granulomatous
Disease)
recurrent bacterial infections

Chemical Mediators

Cell derived mediators

Vasoactive Amine : Histamine and Serotonin.
Arachidonic acid derivatives : PGs,

Leukotrines, Lipoxins.
Platelet-aggrevating factor (PAF).
Reactive Oxygen Species.
Nitric Oxide.
Cytokines and Chemokines.
Neuropeptides.

Vasoactive Amines
Histamines :
Stored as preformed molecules in cells.
First mediators to be released during inflammation.
Richest source of histamine are Mast cells.
Also in basophils and platelets.
Histamine is released by mast cell degranulation in
response to various stimuli, including physical
trauma; binding of antibodies to mast cells which
underlies allergic reactions; fragments of
complement called anaphylotoxins (C3a,C5a);
histamine releasing proteins derived from
leukocytes; neuropeptides (e.g., substance P); and
cytokines (IL-1, IL-8).

Histamines cntd..
Action
Vaodilatation.
Increased vascular permeability thus
interendothelial gaps in vennules.
Microvascular endothelial cells activation.

Serotonin (5-hydroxytryptamine)
Source is platelets.
Actions similar to histamine.
Release of serotonin from platelets is

stimulated when platelets aggregate after

contact with collagen, thrombin, adenosine
diphosphate and antigen-antibody complexes.
Thus platelet release reaction, which is a key
component of coagulation, also results in
increased vascular permeability.

Arachidonic acid derivatives

AA is a 20-carbon polyunsaturated fatty acid

(5,8,11,14-eicosatetraenoic acid) derived from

dietary sources or by conversion from the
essential fatty acid linolenic acid.
Any stimuli or other mediators (like C5a) release
AA from the membrane phospholipids through
the action of phospholipases.
The biochemical signalling includes an increase in
cytoplasmic Ca and activation of various
kinases.
AA derived mediators are also known as
eicosanoids, which are synthesised by
cyclooxygenases and lipoxygenases.

Prostaglandins nd Thromboxane : via

cyclooxygenase pathway; cause vasodilation,

fever and prolong edema ; COX blocked by
aspirin and NSAIDS.
but also protective (gastric mucosa)

Leukotrienes : via lipoxygenase pathway; are

chemotaxins, vasoconstrictors, cause increased

vascular permeability, and bronchospasm;
inhibited by lipoxygenase inhibitors,either by
inhibiting the production or by blocking the
leukotriene receptors.
Lipoxins : via lipoxygenase pathway; these inhibit
the leukocyte recruitment and the cellular
components of the inflammation.

Platelet Activating Factor

Source platelets, leukocytes, mast cells and

endothelial cells.
It increases the activity of synthesis of other
mediators, particularly eicosanoids, by leukocytes.
It causes
Platelet aggregation
Vasodilatation
Increased vascular permeability
Leukocyte adhesion
Chemotaxis
Degranulation
Oxidative burst

Nitric Oxide
These are alo known as endothelium-derived

relaxing factor.
It is produced by endothelium, macrophages,
and some neurons in brain.
NO is synthesized from L-arginine by an enzyme
nitric oxide synthetase (NOS).
It has a dual role in inflammation :
Relaxes the smooth muscle and promotes

vaodilatation, thus contributing to vascular

reaction.
Inhibitory on cellular component of inflammatory
reponses.

Cytokines and Chemokines

Cytokines are proteins produced by many cell

types that modulate the functions of other cell

types.
Cytokines in inflammation
In Acute Inflammation

Tumor Necrosis Factor (TNF)

Interleukins IL-1,IL-6
Chemokines

In Chronic Inflammation

Interleukins IL-12, IL-17

Interferon

Chemokines
These are the family of small proteins (8-10kD)

which acts primarily as chemoattractants for

specific type of leukocytes.
According to the arrangement of the conserved
cysteine (C) residues in the mature proteins
these are classified into 4 major groups.
C-X-C chemokines ( chemokines)
C-C chemokines ( chemokines)
C chemokines ( chemokines)
CX3C chemokines

Chemokines
C-X-C chemokines :
Have one amino acid residue separating two conserved

cysteine residues.
They act primarily on neutrophils.
Secreted by activated macrophages, endothelial cells and
causes activation and chemotaxis of neutrophils.
Inducers are microbial products and other cytokines mainly IL1, TNF.

C-C chemokines :
Have the first two conserved residues adjacent.
They act by monocyte chemoattractant protein (MCP-1),

eotaxin, macrophage inflammatory protein 1 (MIP-1), and

RANTES (regulated and normal T-cell expresedand secreted),
on monocytes, eosinophils, basophils and lymphocytes but not
on neutrophils.

Chemokines
C chemokines :
They lack two ( the first and third) of the four conserved
cysteines.
They act on lymphocytes by lymphotactin.
CX3C chemokines :
These contain three amino acids between two cysteines.
The only known member of this family is fractalkine.
They exists in two forms cell surface bound proteins that

promotes strong adhesion of monocytes and T-cells, and

a soluble form, derived by proteolysis of the membrane
bound protein which have chemoattractant activity for
same cells.

Neuropeptides
These are secreted by sensory nerves and

various leukocytes and play a major role in

initiation and propagation of an inflammatory
response.
Subtance P and neurokinin A of family
tachykinin neuropeptides are produced in the
central and peripheral nervous system.
Substance P has many functions, including the
transmission of pain signals, regulation of blood
pressure, stimulation of secretion by endocrine
cells, increasing vascular permeability.

Plasma Derived Mediators

A variety of phenomena in the inflammatory

response are mediated by plasma proteins

that belong to three interrelated systems :
The Complement system
The Kinin system
The Clotting system

Complement system

Components C1-C9 present in inactive form

activated via classic (C1) or alternative (C3) pathways to

generate MAC (C5 C9) that punch holes in microbe

membranes.

In acute inflammation
Vasodilation, vascular permeability, mast cell
degranulation (C3a, C5a)
Leukocyte chemotaxin, increases integrin avidity (C5a)
As an opsonin, increases phagocytosis (C3b, C3bi)

Kinin system

Leads to formation of bradykinin from

cleavage of precursor (HMWK)

Vascular permeability
Arteriolar dilation
Non-vascular smooth muscle contraction (e.g.,

bronchial smooth muscle)

Causes pain
Rapidly inactivated (kininases)

Kinin and Coagulation

System

Clotting System
Cascade of plasma proteases
Hageman factor (factor XII)
Collagen, basement membrane, activated
platelets converts XII to XIIa (active form)
Ultimately converts soluble fibrinogen to
insoluble fibrin clot
Factor XIIa simultaneously activates the
brakes through the fibrinolytic system to
prevent continuous clot propagation
Endothelial activation, leukocyte recruitment

Outcomes of Acute
Inflammation
Complete resolution
little tissue damage
capable of regeneration
Scarring (fibrosis)
in tissues unable to regenerate
excessive fibrin deposition organized into fibrous

tissue

Abscess formation occurs with some bacterial

or fungal infections
Progression to chronic inflammation (next)

Outcome of inflammation
Fibrosis / Scar

Resolution

Injur
y

Acute
Inflammation

Chronic
Inflammation
Fungal
Viral
TB etc

Abscess

Ulcer

Sinus

Fistula

Chronic Inflammation
Chronic inflammation is inflammation of

prolonged duration (weeks or months) in

which inflammation, tissue injury and
attempts at repair coexist in varying
combinations.
Chronic inflammation follows the acute
inflammation or it may be as a result of the
tissue damage in some disabling human
diseases like rheumatoid arthritis,
atherosclerosis, tuberculosis and pulmonary
fibrosis.

Causes of chronic inflammation

When acute phase cannot be resolved
Persistent injury or infection (ulcer, TB) leads to

delayed hypersensitivity. Inflammatory

response sometimes takes a specific pattern
called a granulation tissue.
Prolonged toxic agent exposure (exogenous like
silica, endogenous in Atherosclerosis).
Autoimmune disease states (RA, SLE)

Morphologic features
Infiltration with mononuclear cells, which

include macrophages, lymphocytes and

plasma cells.
Tissue destruction, induced by the persistent
offending agent or by the inflammatory cells.
Healing by connective tissue replacement of
damaged tissue, accomplished by proliferation
of small blood vessels (angiogenesis) and in
particular fibrosis.

Mononuclear/Phagocyte System
Macrophages
scattered all over (microglia, Kupffer cells,
sinus histiocytes, alveolar macrophages)
circulate as monocytes and reach site of injury
within 24 48 hrs and transform
become activated by T cell-derived cytokines,
endotoxins, and other products of inflammation.

T and B Lymphocytes
Antigen-activated (via macrophages and

dendritic cells).
Release macrophage-activating cytokines (in
turn, macrophages release lymphocyteactivating cytokines until inflammatory
stimulus is removed).

Plasma Cells
Terminally differentiated B cells.
Produce antibodies.

Eosinophils
Found especially at sites of parasitic infection,

or at allergic (IgE-mediated) sites.

Granulomatous inflammation
Distinctive chronic inflammation type.
Cell mediated immune reaction (delayed).
Macrophage is the major player
Granuloma is a focal area of inflammation made

up of macrophages, lymphocytes and plasma cells

Aggregates of activated macrophages
epithelioid cell multinucleated giant cells (of
Langhans type x of foreign body type).
NO agent elimination but walling off.
Intracellulary agents (TB).

Granulomatous inflammation
1. Bacteria
TBC
leprosy
syphilis (3rd stage)

2. Parasites + Fungi
3. Inorganic metals or dust
silicosis
berylliosis

4. Foreign body
suture (Schloffer tumor), breast prosthesis

5. Unknown - sarcoidosis

Lymph Nodes and Lymphatics

Lymphatics drain tissues
flow increased in inflammation.
antigen to the lymph node.
toxins, infectious agents also to the node:
lymphadenitis, lymphangitis.
usually contained there, otherwise bacteremia
ensues.
tissue-resident macrophages must then prevent
overwhelming infection.

Patterns of acute and chronic

inflammation
Serous
Watery, protein-poor effusion (e.g., blister)
Fibrinous
Fibrin accumulation
Either entirely removed or becomes fibrotic
Suppurative
Presence of pus (pyogenic staphylococci spp.)
Often walled-off if persistent
Ulceration
Necrotic and eroded epithelial surface
Underlying acute and chronic inflammation
Trauma, toxins, vascular insufficiency

Systemic effects
Fever
One of the easily recognized cytokinemediated(esp.IL-1, IL-6, TNF) acute-phase
reactions including
Anorexia
Skeletal muscle protein degradation
Hypotension

Leukocytosis
Elevated white blood cell count
Bacterial infection (neutrophilia)
Parasitic infection (eosinophilia)
Viral infection (lymphocytosis)

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