inflammation-150818185203-lva1-app6891-converted.pptx

INFLAMMATION
• Inflammation is defined
as the local response of
living tissues to injury
due to any agent.
• Body defense reaction
– eliminate or limit the
spread of injurious
agent
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es

Cause of
Inflammation
1. Infective agents like bacteria, viruses and
their toxins, fungi, parasites.
2. Immunological agents like cell-mediated
and antigen antibody reactions.
3. Physical agents like heat, cold,
radiation, mechanical trauma.
4. Chemical agents like organic and
inorganic poisons.
5. Inert materials such as foreign bodies
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How Inflammation distinct
from Infection ??
es

Inflammation
• Protective response by the body to variety of
etiologic agents, while infection is invasion into
the body by harmful microbes and their resultant
ill-effects by toxins
• 2 basic processes with some overlapping
– early inflammatory response
– later followed by healing
• Sometimes it causes considerable harm to the
body as well
• anaphylaxis to bites by insects or reptiles, drugs, toxins,
• atherosclerosis,
• chronic rheumatoid arthritis,
• fibrous bands
• Adhesions in intestinal obstruction
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SIGNS OF
INFLAMMATION
–redness
–swelling
–heat
– pain
–loss of function
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TYPES OF
INFLAMMATION
• Mainly of 2 types i.e. acute and chronic
• Acute Inflammation
– short duration
– represents the early body reaction-
followed by healing
• Chronic inflammation
– longer duration
– causative agent of acute inflammation
persists for a long time
• Another variant, Chronic active
inflammation : stimulus is such that it
induces chronic inflammation from the
beginning
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ACUTE
INFLAMMATION
• The main features of
acute inflammation
are:
– accumulation of fluid
and plasma at the
affected site;
– intravascular activation
of platelets;
– polymorphonuclear
neutrophils as
inflammatory cells.
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ACUTE
INFLAMMATION
• Divided into
following two
events
– Vascular events
– Cellular events
• These 2 events are
followed intermittently
by release of
mediators of acute
inflammation.
es

VASCULAR
EVENTS
• Alteration in the
microvasculature
• This is again divide in 2 phases
– Hemodynamic changes
– Changes in the vascular
permeablity
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Hemodynamic changes
es
1. Transient vasoconstriction
: immediate vascular
response irrespective of the
type of injury, mainly
arterioles
– Mild injury - 3-5 seconds
– Severe injury - 5 minutes
2. Persistent progressive
vasodilatation : mainly
arterioles, others to a lesser
extent.
– obvious within half an hour of
injury
– increased blood volume in
microvascular bed of the area
– redness and warmth

Hemodynamic changes
3. Progressive vasodilatation elevate the
local hydrostatic pressure
– transudation of fluid into
the extracellular space
– swelling
4. Slowing or stasis increased concentration of red
cells, and thus, raised blood viscosity
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Hemodynamic
changes
5. Leucocytic Margination peripheral
orientation
of leucocytes (mainly neutrophils) along
the vascular endothelium
– stick to the vascular endothelium briefly
– move and migrate through the gaps between
the endothelial cells - extravascular space
– This is known is emigration
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Altered Vascular
Permeability
• Accumulation of oedema fluid - interstitial
compartment which comes from blood
plasma by its escape through the endothelial
wall of peripheral vascular bed.
• Escape of fluid is due to vasodilatation
and consequent elevation in hydrostatic
pressure - transudate.
• Subsequently, the characteristic
inflammatory oedema, appears by
increased vascular permeability of
microcirculation – exudate.
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MECHANISMS OF INCREASED
VASCULAR PERMEABILITY
1. Contraction of endothelial cells.
2. Retraction of endothelial cells
3. Direct injury to endothelial cells
4. Endothelial injury mediated by
leucocytes
5. Leakiness and neo-vascularisation
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MECHANISMS OF
INCREASED
VASCULAR
PERMEABILITY
es

Contraction of endothelial
cells
• Affects venules exclusively.
• Endothelial cells develop
temporary gaps
• Contraction resulting in
vascular leakiness.
• Mediated by the release of
histamine, bradykinin and
other chemical mediators.
• Short duration (15-30
minutes) - immediately
after injury.
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Retraction of endothelial
cells
• Structural re-organisation
of the cytoskeleton of
endothelial cells -
Reversible retraction at
the intercellular junctions.
• Mediated by cytokines
such as interleukin-1 (IL-
1) and tumour necrosis
factor (TNF)-α.
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Direct injury to endothelial
cells
• Causes cell necrosis and
appearance of physical gaps.
• Process of thrombosis is initiated at
the site of damaged endothelial
cells.
• Affects all levels of
microvasculature.
• Either appear immediately after
injury and last for several hours or
days – severe bacterial infections
• Or delay of 2-12 hours and last for
hours or days - moderate thermal
injury and radiation injury
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Endothelial injury mediated
by leucocytes
• Adherence of leucocytes to the
endothelium at the site of inflammation.
• Activation of leucocytes - release
proteolytic enzymes and toxic oxygen.
• Cause endothelial injury and
increased vascular leakiness.
• Affects mostly venules and is a late
response.
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CELLULAR EVENTS
• Cellular phase of inflammation consists
of 2 processes
1. Exudation of leucocytes
2. Phagocytosis.
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Exudation of leucocytes
1. Changes in the formed elements of blood.
2. Rolling and adhesion
3. Emigration
4. Chemotaxis
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CHANGES IN THE FORMED
ELEMENTS OF BLOOD
• Central stream of cells
comprised by leucocytes and
RBCs and peripheral cell free
layer of plasma close to
vessel wall.
• Later, central stream of cells
widens and peripheral
plasma zone becomes
narrower because of loss of
plasma by exudation.
• This phenomenon is known as
margination.
• Neutrophils of the central
column come close to the
vessel wall - pavementing
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ROLLING AND ADHESION
• Peripherally marginated and
pavemented neutrophils
slowly roll over the
endothelial cells lining the
vessel wall (rolling phase).
• Transient bond between the
leucocytes and endothelial
cells becoming firmer
(adhesion phase).
• The following molecules
bring about rolling and
adhesion phases
– Selectins
– Integrins
– Immunoglobulin gene
superfamily adhesion
molecule facebook.com/trigemclass
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EMIGRATION
• After sticking of neutrophils to
endothelium,
• The former move along the
endothelial surface till a
suitable site between the
endothelial cells is found
where the neutrophils throw
out cytoplasmic pseudopods.
• Cross the basement
membrane by damaging it
locally – collagenases and
escape out into the
extravascular space -
emigratio
n
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EMIGRATION
• Diapedesis - escape of red cells through
gaps between the endothelial cells
– passive phenomenon.
– raised hydrostatic pressure
– haemorrhagic appearance to the
inflammatory exudate
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CHEMOTAXIS
• This is the process by which leucocytes are
attracted to and move towards an attractant at the
site of injury.
• After extravasating from the blood, Leukocytes
migrate toward sites of infection or injury along a
chemical gradient by a process called
chemotaxis
• They have to cross several barriers - endothelium,
basement membrane, perivascular myofibroblasts
and matrix.
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Events of Exudation of leucocytes
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PHAGOCYTOSIS
• The process of engulfment of solid
particulate material by the cells.
• 2 main types of phagocytic cells
Polymorphonuclear neutrophils (PMNs)
Macrophages
– This phagocytic cells releases
proteolytic enzymes
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PHAGOCYTOSIS
• The microbe undergoes the
process of phagocytosis in
following 3 steps :
– Recognition and attachment
– Engulfment
– Killing and degradation
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RECOGNITION AND ATTACHMENT
• Phagocytosis is initiated by the expression of surface
receptors
on macrophages.
• Its further enhanced when the microorganisms are
coated with specific proteins, opsonins.
– Establish a bond between bacteria and the cell
membrane of phagocytic cell.
– Major opsonins are
• IgG opsonin .
• C3b opsonin
• Lectins
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Engulfment
• Formation of cytoplasmic pseudopods
around the particle which completely
surround the foreign particle.
• Eventually plasma membrane gets lysed
and fuses with nearby lysosomes –
phagolysosome.
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KILLING AND DEGRADATION
• OXYGEN DEPENDENT MECH. :
Contact between neutrophil and stimulus
leads to activation of NADPH oxidase.
This enzyme oxidizes NADPH to NADP+H
and this reduces O2 to superoxide anion, in
this phagosome superoxide anion is
converted into H2O2 production.
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O2 DEPENDENT MECH
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H2O2 reacts with chloride in the presence of
enzyme(myeloperoxidase) to form hypochlorous radical
which is a powerful antimicrobial agent.
The died microorganisms are then degraded by lysosomal
acid hydrolase enzymes

O2 INDEPENDENT
MECHANISM
es
In the absence of oxygen-dependent system
leukocytes can kill bacterial and other infectious
agents by the bactericidal agents (enzymes)
produced by leukocyte granules such as:
.1. Defensin.
2. Lysozyme.
3. Proteases
4. Lactoferrin
5.Hydrolases.

Stages of Phagocytosis
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Chemical
Mediators of
Inflammation
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Chemical Mediators of Inflammation
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INITIATE
&
REGULATE
INFLAMMATORY
REACTIONS

Chemical Mediators of Inflammation
• Chemical mediators that
are responsible for
vascular and cellular
events.
• Knowledge of this
mediators
– basis of anti-
inflammatory drugs.
• It may either of two types,
– Cell Derived - produced
locally by cells at the site
of inflammation
– Plasma derived –
mainly from liver
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Chemical Mediators of
Inflammation
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Vasoactive Amines
• Histamine
• Serotonin

Vasoactive
Amines
• Histamine
– Originates from mast cells , basophils and
platelets
– variety of stimuli
It is released by injury, by the action of histamine releasing agents,
by antigen if cells
have been sensitized by IgE, interleukin-1 and histamine releasing
factors
derived from neutrophils, macrophages and platelets.

Vasoactive
Amines
• Serotonin
– preformed vasoactive mediator - effects
similar to those of histamine but less potent
– Released from platelets and mast cells
– Serotonin (5-hydroxytryptamine) is a vasoactive mediator similar to
histamine found in mast cells and platelets in the GI tract and
CNS. Serotonin also increases vascular permeability, dilates
capillaries, and causes contraction of nonvascular smooth muscle
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Vasoactive
Amines
FUNCTIONS
1. Increase permeability of vessels
2. Vasodilatation
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PLASMA PROTEASES
1. Kinin system
2. Complement system
3. Coagulation fibrinolytic
system
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PLASMA PROTEASES
Kinin system
Bradykinin is the most important kinin.
Function:
• Increase vascular permeability,
• Vasodilatation.
• Contraction of smooth muscle.
• Pain.
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Complement system
The complement system, also known
as complement cascade, is a part of the
immune system that enhances
(complements) the ability of antibodies
and phagocytic cells to clear microbes
and damaged cells from an organism,
promote inflammation, and attack the
pathogen's cell membrane.
es

Complement system
This system consists of 25 component proteins which are
found in greatest concentration in plasma. Complement
system plays a key role in non specific immunity and
amplify the function of antibody-based immunity.
Function:
Helps in defense against microbial agents by:
• Increased vascular permeability.
• Chemotaxis.
• Opsonization.
• Lysis of target organism.
• Inflammation facebook.com/trigemclass
es

Complement system
es
Components of
complement system
C3a Increases vascular permeability.
C5a Increases vascular permeability.
Chemotactic for neutrophil and
monocyte.
C3b Opsonization
C5b Chemotactic
C5b, C6-8 Final lytic component (membrane
attack complex).

Complement system
es
C3a and C5b are also called
anaphylotoxins
because they increase vascular
permeability and
vasodilatation, characteristics of
anaphylaxis

Coagulation and fibrinolytic
system
• Coagulation system
The coagulation system stimulation leads to
fibrin
clot formation. Hagman factor XII synthesized by
liver circulates in an inactive form. This factor is
activated when it comes in contact of basement
membrane or activated platelets (as at a site of
endothelial injury)
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system
• Coagulation system
Activation of factor XII causes
activation of thrombin that causes formation of
fibrin from fibrinogen. Fibrinopeptides formed
from fibrinogen increase vascular permeability
and chemotaxis, helpful in inflammation
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system
• Fibrinolytic system
Factor XII activates fibrinolytic system at the same
time when it activates clotting system to counter
regulates the cloiting system. Without fibrinolysis,
initiation of clotting system even by a minor injury
would lead to continuous and uncontrolled
clotting of the entire vasculature.
es

system
• Mechanism:
Plasminogen activator causes formation of
plasmin from plasminogen (a plasma protein).
This plasmin degrades fibrin and therefore lysis
of clot. Fibrin split products increase vascular
permeability while the plasmin is involved in
vasodilatation and increased permeability
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ARACHIDONIC ACID
METABOLITES
es
ARACHIDONIC ACID METABOLITES FUNCTIONS
Prostaglandins Vasodilatation, pain.
Prostacyclin Vasodilatation, inhibition of Platelet
aggregation
Thromboxane A2 Vasoconstriction, platelet aggregation

ARACHIDONIC ACID
METABOLITES
es
Leukotrienes B4 Chemotaxis
Leukotrienes C4 Vasoconstriction
Leukotrienes D4 Bronchoconstriction
Leukotrienes E4 Increase vascular permeability
PRODUCTS OF LIPOGENASE PATHWAY

es
PRODUCTS OF LEUKOCYTES
PLATELET- ACTIVATING FACTOR
• Derived from membrane phospholipids of
neutrophils , monocytes , basophils ,
endothelium and platelets
FUNCTIONS
• Platelet aggregation
• Vasoconstriction
• bronchospasm

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Cytokines
• Cytokines are soluble proteins secreted by
activated lymphocytes and macrophage and
some other cells. They modulate the function
of other cells.

es
Cytokines
Important cytokines which participate in acute
inflammation are the following.
• Interleukin-1 (IL-1).
• Tumor Necrosis Factor(TNF).
• Chemokines
• Gamma Interferon (IFN-y)

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Cytokines
• Functions
Interleukin I and tumor necrosis factor
They are produced by activated macrophages.
Secretion is stimulated by endotoxin, immune
complexes, toxins, physical injury or some
chemical mediators.
They induce the systemic acute-phase response
including fever, lethargy, metabolic wasting,
excessive neutrophil release into the circulation
and release of adrenocorticotropic

es
Cytokines
Functions
hormone.
TNF also induces nitric oxide synthesis which
plays a major role in inducing hypotension due
to septic shock.

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Lysosomal constituents
Lysosomal granules of neutrophils and
monocytes contain a number of molecules
that can act as mediators of acute
inflammation e.g.
• Acid protease
• Neutral proteases e.g elastase and
collagenase.

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CLINICAL SIGNS OF ACUTE INFLAMMATION
Clinically acute inflammation is characterized by
five classic signs.
1.Heat (Calor): due to increased blood flow.
2. Redness (rubor): due to increased blood flow.
3. Swelling (tumor): due to accumulation of fluid.
4. Pain (dolar): due to accumulation of chemicals
that stimulate nerve endings
5.Loss of function (functio laesa).

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SYSTEMIC EFFECTS OF ACUTE
INFLAMMATION
The systemic effects of inflammation are
collectively identified as acute phase
reactions.
Interleukin 1, interleukin-6 and tumor
necrosis factor are the most important
mediators of the acute phase reactions.

es
INFLAMMATION
ACUTE PHASE REACTIONS INCLUDES :
• Anorexia, weight loss, hypotension.
• Fever: As the pyrogens and
prostaglandins enter the circulation,
they act upon the brainstem
thermostat to reset body temperature
resulting in fever.

es
INFLAMMATION
• Leukocytosis : Increased WBC (leukocyte)count is a
common feature of inflammatory reactions, especially
those induced by bacterial infection. This increase in
leukocytesis called leukocytosis. Due to rapid release of
leukocytes from the bone marrow, increased number of
immature neutrophils (band form)appear in the
peripheral blood. This increased number of immature
neutrophils in peripheral blood is called shift to the left.

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INFLAMMATION
• Leukocytosis :
 Most bacterial infections induce relatively increase in
neutrophils called neutrophilia.
 Parasitic infection and allergic reaction increase
eosinophils called eosinophilia.
 Certain viruses increase lymphocytes called
lymphocytosis, but most of the viral infections,
protozoal, rickettsial and some bacterial infections (e.g.
typhoid fever) are associated with a decreased number
of circulating white cells called leukopenia.

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INFLAMMATION
Raised ESR:
• The levels of certain plasma proteins typically increase
when acute inflammation is present. These acute phase
reactants include:
• C-reactive protein
• Fibrinogen
• Haptoglobin
• Ceruloplasmin.

es
INFLAMMATION
Raised ESR:
Increased levels of these substances in
turn lead toan increased erythrocyte
sedimentation rate (ESR)that is a simple,
useful (though non- specific) clue to the
presence of inflammation

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