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ACUTE INFLAMATION

Inflammatio-Latin word("inflammo",
meaning "I set alight, I ignite".
Not a disease !
Is usually a manifestation of disease.

DEFINITION
Reaction of a tissue & its microcirculation to a
pathogenic insult.
It is a complex reaction in vascularized
connective tissue. It is characterized by
movement of fluid and leucocytes from blood
into extra vascular tissues by generation of
chemical mediators

CLASSIFICATION OF INFLAMMATION

1. ACUTE INFLAMMATION Initial and for


short duration( Mins - hrs-days)

Exudation of fluid + plasma proteins


Polymorphs

2. CHRONIC INFLAMMATION- Subsequent,


often prolonged.
Lymphocytes + Macrophages
Proliferation of BV + CT + necrosis

Suffix - itis

CAUSES:Microbes(e.g. pyogenic bacteria, viruses)


Infections (bacterial, viral, fungal, parasitic) and microbial
toxins are among the most common and medically important
causes of inflammation. Mammals possess many mechanisms
for sensing the presence of microbes. Among the most
important receptors for microbial products are the family of
Toll-like receptors (TLRs), which can detect bacteria, viruses,
and fungi .Engagement of these receptors triggers signaling
pathways that stimulate the production of various mediators

* Hypersensitivity(e.g. parasites, tubercle bacilli)


*

Physical agents(eg:trauma, ionising radiation)


Irritant and corrosive chemicals
Tissue necrosis(e.g. ischaemic infarction.)
Several molecules released from necrotic
cells are known to elicit inflammation; uric
acid, adenosine triphosphate, HMGB-1; and
even DNA.
Hypoxia, which often underlies cell injury,
is also itself an inducer of the inflammatory
response. This response is mediated largely
by a protein called HIF-1 (hypoxia-induced
factor-1), which is produced by cells
deprived of oxygen and activates the

CELLS INVOLVED IN INFLAMMATION

ACUTE INFLAMMATION
Neutrophils mainly
Macrophages
CHRONIC INFLAMMATION
Mononuclear cells, which include
macrophages, lymphocytes, and
plasma cells

Aims

Eliminate pathologic insult


Remove injured tissue components
Protective response
Hand in hand with repair

ESSENTIAL MACROSCOPIC
APPEARANCE OF ACUTE
INFLAMMATION/PHYSICAL SIGNS OF
INFLAMMATION
Formulated by Celsus
Rubor- redness
Calor- heat
Tumor-swelling
Dolor- pain
Functio laesa- loss of function, was added by Virchow

Acute
Inflammation
Vascular
events
Cellular
events

EARLY STAGES OF ACUTE


INFLAMMATION
1. Changes in vessel calibre and blood
flow
2. Increased vascular permeability and
formation of fluid exudate
3. Cellular exudate formation

Neutrophil granulocytes [also known as


neutrophils or polymorphonuclear
leukocytes (PMNs)] are the most
abundant type of white blood cells in
mammals and form an essential part of the
innate immune system. They form part of
the polymorphonuclear cell family (PMNs)
together with basophils and eosinophils.
Neutrophils are so named because of their
neutral staining with Wright stain

Neutrophil granulocytes have an


average diameter of 1015
micrometers (m),cytoplasm is pink.
Nucleus has a characteristic lobed
appearance (25), the separate lobes
connected by coarse
Chromatin
After entering tissues, neutrophils are
short-lived; they undergo apoptosis and
disappear after 24 to 48 hours.

NEUTROPHIL GRANULES
GRANULES

CONTENT

Primary(azurophilic)

myeloperoxidase,
bactericidal/permeability-increasi
ng protein
(BPI), Defensins, and the
serine proteases neutrophil
elastase and cathepsin G

Secondary(specific)

alkaline phosphatase, lysozyme,


NADPH oxidase, collagenase,
Lactoferrin and Cathelicidin

Tertiary

gelatinase

EARLY STAGES OF ACUTE


INFLAMMATION

1. Changes in vessel calibre and blood


flow
2. Increased vascular permeability and
formation of fluid exudate
3. Cellular exudate formation

1. CHANGES IN VESSEL
CALIBRE
*Dilatation of blood vessels and increased
blood flow (hyperemia).
*Microcirculation : capillary network between
arterioles and venules.
Pre-capillary sphincters regulate blood flow.
# They open during acute inflammation
causing blood flow through the capillaries.

MECHANISMS OF
INFLAMMATION

TRIPLE RESPONSE TO INJURY (LEWIS)


Initial momentary white line arteriolar
vasoconstriction
The Flush- dull red line due to capillary
dilatation
The Flare- red, irregular, surrounding zone
due to arteriolar dilatation
The Wheal- Fluid exudation or oedema
Vasoconstriction Momentary
Vasodilatation 15 mins to hours

2. INCREASED VASCULAR
PERMEABILITY
Small blood vessel walls act as
microfilter.
Ultrafiltration (Starling)
In acute inflammation, more fluid and protein
leaves the vessel.
The net escape of protein rich fluid
EXUDATION

FLUID EXUDATE
Proteins escape from vessels.
Hence, exudate has high
proteins upto 50g/l.
* Immunoglobulins
* Coagulation factors
Turnover of inflammatory
exudate is high.
Lymphatics drain exudate

EXUDATE

TRANSUDATE

Definition

Escape of fluid,
proteins, and blood
cells from the
vascular system
into the interstitial
tissue or body
cavities

Ultrafiltrate of
blood plasma that
results from
osmotic or
hydrostatic
imbalance across
the vessel wall
without an increase
in vascular
permeability

Specific gravity

High

Low

Protein
concentration

High

Low

Cellular material

Abundant

Little/absent

Acute Enteritis

CAUSES FOR INCREASED


VASCULAR PERMEABILITY
1. IMMEDIATE TRANSIENT :
In venules and small veins
Endothelial cell contraction and
opening of transient pores
No damage to endothelial cells
Histamine acts on actin
Other chemical mediatorsbradykinin, nitric oxide,
leukotriene B4 etc.

2. IMMEDIATE SUSTAINED
Direct vascular injury (trauma)
3. DELAYED PROLONGED
Heat, cold, X-rays, chemicals, bacterial
toxins.
Due to injury to endothelial cells.
Tissue sensitivity to chemical mediators
causing increased vascular permeability
varies.
Skin, conjunctiva, bronchial mucosa very
sensitive.
Vessels in CNS relatively insensitive.

3. FORMATION
EXUDATE

OF

CELLULAR

Neutrophil polymorph within extracellular


space- HALLMARK OF ACUTE INFLAMMATION
STAGES IN LEUKOCYTE (NEUTROPHIL)
EMIGRATION
1. Margination / Rolling into plasmatic zone.
2. Adhere to endothelial cells (Pavementing).
3. Pass between endothelial cells.
4. Pass through basal lamina, migrate into
adventitia.

What causes margination?


* Loss of intravascular fluid.
* Increase in plasma viscosity.
* Slowing of blood flow.

MARGINATION OF NEUTROPHILS

What causes adhesion?


Neutrophils come in contact
with the endothelium
* Adhesion = pavementing
*Paired adhesion molecules
on leukocytes and endothelial
surfaces interact.

Endothelial / Leukocyte adhesion


molecules belong to 4 molecular
familiesSelectins, Immunoglobulins, Integrins
and Mucin-like glycoproteins.
Chemical mediators enhance the
expression of adhesion molecules on
the surface of endothelial cells and
leukocyte.

Enhancement of leukocyte surface


adhesion molecules (eg. L-selectin,
VLA-4 integrin) expression by
chemical mediators like:
Complement C5a
Leukotriene B4
Tumour necrosis factor

Enhancement of endothelial surface


adhesion molecules like ELAM-1
(Endothelial leukocyte adhesion
molecule-1), ICAM-1 (Intercellular
adhesion molecule-1) by:
Interleukin-1
Endotoxins
Tumour necrosis factor

Neutrophil Emigration:
Through walls of venules, small
veins.
By active amoeboid movement.
Pseudopodia between endothelial
cells.
Migrate through gap in vessel wall.
Gap is self-healing.
No damage to endothelium.

DIAPEDESIS
Passive escape of RBCs from vessels
into extravascular space.
Hydrostatic pressure causes
diapedesis.

Chemotaxis

of

neutrophils

The process of movement of leukocytes


towards the site of injury in tissues is called
as chemotaxis.
Defined as locomotion oriented along a
chemical gradient.
Chemotactic compoundsComplement components
Cytokines (Interleukin-8)
Neutrophil products
Bacterial products

ACUTE PYOGENIC MENINGITIS: x10

Why neutrophils come


1st ???
They are more numerous in the
blood
They respond more rapidly to
chemokines
They may attach more firmly to
the adhesion molecules.

The nature of the leukocyte


infiltrate varies with the age of
the inflammatory response and
the type of stimulus. In most
forms of acute inflammation
neutrophils predominate in the
inflammatory infiltrate during
the first 6 to 24 hours and are
replaced by monocytes in 24 to
48 hours

After entering tissues,


neutrophils are short-lived; they
undergo apoptosis and
disappear after 24 to 48 hours..

Monocytes not only survive


longer but may proliferate in the
tissues, and thus become the
dominant population in chronic
inflammatory reactions

Exceptions to this pattern of cellular infiltration.

Eg: Pseudomonas bacterial infection


the cellular infiltrate is dominated by
continuously recruited neutrophils for
several days
Viral infections-lymphocytes may be
the first cells to arrive.
In some hypersensitivity reactions,
eosinophils may be the main cell
type.

ROLE OF NEUTROPHIL
The cell of acute inflammation.
Neutrophil
Polymorphonuclear
Leukocyte, PMN, PML
Leukocyte
Granulocyte, Neutrophilic
granulocyte
Polymorph

ACTIONS OF NEUTROPHIL
* Movement
* Adhesion to micro-organisms
* Phagocytosis
* Intracellular killing of micro-organisms
* Release of lysosomal products

MOVEMENT

Amoeboid movement
-Contraction of cytoplasmic
microtubules
-Gel-Sol cytoplasmic changes
-Dependent on calcium ions
-Controlled by intracellular
concentration
of cyclic nucleotides
Movement is DIRECTIONAL
(Chemotaxis)

ADHESION TO MICROORGANISMS
Neutrophils bind to microorganisms before ingestion.
First, micro-organisms are
OPSONISED
(made more prone to ingestion)
Immunoglobulins, Complement
components (C3b) have
opsonising properties.

PHAGOCYTOSIS
Process of ingestion of solid particles.
By neutrophils, macrophages.
STEPS:
* opsonisation
* adhesion
* pseudopodia is put out
* fusion of pseudopodia
* phagosome formation
* phagolysosome formation

INTRACELLULAR KILLING
OF MICRO-ORGANISMS

Neutrophils contain microbicidal agents.


OXYGEN DEPENDENT
Hydrogen peroxide- It reacts with
myeloperoxidase in the cytoplasmic
granules, in the presence of a halide to
produce potent microbicidal agent.
Peroxide anions
Hydroxyl radicals
Singlet oxygen

OXYGEN INDEPENDENT
lysozyme (muramidase)
lactoferrin
cationic proteins
low pH

Release of lysosomal products, which


damages local tissues and also
attracts other leukocytes into the
area.

CHEMICAL MEDIATORS OF ACUTE


INFLAMMATION

Endogenous; released from injured


tissues, from cells or plasma factors
VASCULAR DILATATION

Histamine
Prostaglandins
Nitric oxide
INCREASED VASCULAR PERMEABILITY

Histamine ( Transient )
Bradykinin, Leukotriene B4
( Prolonged )

UPREGULATION OF ADHESION
MOLECULES
Interleukin-1(IL-1), IL-8
Tumour necrosis factor
Leukotriene B4
EMIGRATION OF LEUKOCYTES
Complement- C5a
Leukotrienes
Cationic proteins

CHEMOTAXIS

Complement components
Cytokines
Neutrophil products
PAIN

Prostaglandins
Bradykinin
Serotonin

CHEMICAL MEDIATORS RELEASED


FROM CELLS
HISTAMINE
Stored in mast cells, basophils,
eosinophils, platelets.
Stimuli for release :
Complement components- C3a, C5a
Lysosomal components from
neutrophils.

PROSTAGLANDINS
Long chain fatty acids derived from
arachidonic acid in the cell membrane
of
neutrophils.
LEUKOTRIENES
From arachidonic acid esp. in
neutrophils
SRS-A (involved in Type-I
hypersensitivity reactions) is a

PLASMA
1.
2.
3.
4.

FACTORS

Coagulation system
Fibrinolytic system
Kinin system
Complement system

All are enzyme cascade system which


are
inter-related and produce inflammatory
mediators

Coagulation system

Coagulation system ends in the


activation of thrombin and formation
of fibrin
(a major component of the acute
inflammatory exudate. )
Hageman factor (factor xii), when
activated (factor xii a) by contact
with basal lamina and bacterial
enzymes, can activate other

Fibrinolytic

system

* Plasmin breaks fibrin to fibrin


degradation products
* It affects vascular permeability

KININ SYSTEM
Peptides ( 9 11 amino acids )
Bradykinin
* Vascular permeability
* Pain

COMPLEMENT SYSTEM
Cascade of enzymatic proteins
activated by:
* Tissue necrosis ( enzymes of dying
cells)
* InfectionAg-Ab complexes (classical
pathway)
Endotoxins (alternative
pathway)
* Products of other systems (like
fibrinolytic system etc).

The products of complement activation


most important in acute inflammation
include:
C5a: chemotactic for neutrophils;
increases vascular permeability;
releases histamine from mast
cells
C3a: similar properties to those
of C5a, but less active
ocytosis by macrophages).

C567: chemotactic for neutrophils

C56789: cytolytic activity (the


'membrane attack complex')

C4b, 2a, 3b: opsonisation of bacteria


(facilitates phag

SPECIAL MACROSCOPIC APPEARANCES


OF ACUTE INFLAMMATION

Depends onprovoking agent, tissue involved


Types:
Serous
Membranous
Catarrhal
Pseudomembranous
Fibrinous
Necrotising
(Gangrenous)
Hemorrhagic
Suppurative (purulent)

Serous inflammation
Is marked by the outpouring of a
thin fluid that may be derived
from the plasma or from the
secretions of mesothelial cells
lining the peritoneal, pleural,
and pericardial cavities.
Accumulation of fluid in these
cavities is called an effusion.
There is abundant protein-rich
fluid exudate with a relatively

The skin blister resulting from a


burn or viral infection represents
a large accumulation of serous
fluid, either within or
immediately beneath the
epidermis of the skin

Serous effusion

Serous Inflammation

Catarrhal inflammation
When mucus hypersecretion
accompanies acute inflammation of a
mucous membrane, the appearance is
described as catarrhal. The common
cold is a good example.

Fibrinous inflammation
When the inflammatory exudate
contains plentiful fibrinogen, this
polymerises into a thick fibrin
coating. This is often seen in acute
pericarditis and gives the parietal
and visceral pericardium a 'bread
and butter' appearance.

Fibrinous
pericarditis

Fibrinous pericarditis

Fibrinous pericarditis

Haemorrhagic inflammation
Haemorrhagic inflammation indicates
severe vascular injury or depletion of
coagulation factors. This occurs in
acute pancreatitis due to proteolytic
destruction of vascular walls, and in
meningococcal septicaemia due to
disseminated intravascular
coagulation

Haemorrhagic pericarditis

Suppurative (purulent) inflammation

The terms 'suppurative' and


'purulent' denote the production of
pus, which consists of dying and
degenerate neutrophils, infecting
organisms and liquefied tissues.

The pus may become walled-off by


granulation tissue or fibrous tissue to
produce an ABSCESS (a localised
collection of pus in a tissue).
If a hollow viscus fills with pus, this is
called an EMPYEMA, for example,
empyema of the gallbladder or of the
appendix

Purulent exudate

Abscess lung

Empyema
of gall
bladder

Purulent pericarditis

Gangrene

MEMBRANOUS
INFLAMMATION
In acute membranous inflammation, an
epithelium becomes coated by fibrin,
desquamated epithelial cells and
inflammatory cells. An example is the grey
membrane seen in pharyngitis or laryngitis
due to Corynebacterium diphtheriae.

PSEUDOMEMBRANOUS
INFLAMMATION
The term 'pseudomembranous' describes
superficial mucosal ulceration with an
overlying slough of disrupted mucosa, fibrin,
mucus and inflammatory cells. This is seen
in pseudomembranous colitis due to
Clostridium difficile colonisation of the
bowel, usually following broad-spectrum
antibiotic treatment

NECROTISING (GANGRENOUS)
INFLAMMATION
High tissue pressure due to oedema may
lead to vascular occlusion and thrombosis,
which may result in widespread septic
necrosis of the organ. The combination of
necrosis and bacterial putrefaction is
gangrene.
Gangrenous appendicitis is a good example.

Systemic effects of
inflammation
Pyrexia
Polymorphs and macrophages produce
compounds known as endogenous
pyrogens which act on the hypothalamus
to set the thermoregulatory mechanisms
at a higher temperature. Interleukin-2
probably has the greatest effect. Release
of endogenous pyrogen is stimulated by
phagocytosis, endotoxins and immune
complexes.

Constitutional symptoms
include malaise, anorexia and
nausea.
Weight loss
Weight loss, due to negative nitrogen
balance, is common when there is
extensive chronic inflammation. For
this reason, tuberculosis used to be
called 'consumption'.

Reactive hyperplasia of the reticuloendothelial system


Local or systemic lymph node
enlargement commonly accompanies
inflammation, while splenomegaly is
found in certain specific infections
(e.g. malaria, infectious
mononucleosis).

Haematological changes
Increased erythrocyte sedimentation
rate.
An increased erythrocyte
sedimentation rate is a non-specific
finding in many types of
inflammation and is due to
alterations in plasma proteins
resulting in increased rouleaux

Leukocytosis.
Neutrophilia occurs in pyogenic infections
and tissue destruction; eosinophilia in
allergic disorders and parasitic infection;
lymphocytosis in chronic infection (e.g.
tuberculosis), many viral infections and in
whooping cough; and monocytosis occurs
in infectious mononucleosis and certain
bacterial infections (e.g. tuberculosis,
typhoid).

Anaemia.
This may result from blood loss in the
inflammatory exudate (e.g. in
ulcerative colitis), haemolysis (due to
bacterial toxins), and 'the anaemia of
chronic disorders' due to toxic
depression of the bone marrow.

Amyloidosis

Longstanding chronic inflammation


(for example, in rheumatoid arthritis,
tuberculosis and bronchiectasis), by
elevating serum amyloid A protein
(SAA), may cause amyloid to be
deposited in various tissues, resulting
in secondary (reactive) amyloidosis

SEQUELAE OF
ACUTE INFLAMMATION

Depends on ,
Type of tissue involved
Amount of tissue destruction
Nature of injurious agent

RESOLUTION
Complete restoration of tissues to
normal
Conditions favouring resolution are,
Minimal tissue damage
Regenerative capacity of the organ
Rapid destruction of causal agent
Rapid removal of fluid and debris
Eg. In acute lobar pneumonia

Acute lobar pneumonia

Complete resolution

SUPPURATION

Pus
Abcess
Empyema
Sinus tract
Fistula

ORGANISATION
Conditions favouring this are,
Large amounts of fibrin which cannot
be removed by fibrinolytic enzymes
Large volumes of tissue necrosis or
dead tissue not easily digested
Exudate and debris cannot be removed
or discharged
Replacement by granulation
tissue.. .fibrosis and scar
formation

PROGRESSION TO CHRONIC
INFLAMMATION
Due to persistence of causal agent
Neutrophils are replaced by
lymphocytes, plasma cells and
macrophages

Beneficial effects

Beneficial effects of the fluid exudate


are: Dilution of toxins, such as those
produced by bacteria, allows them to
be carried away in lymphatics.

Entry of antibodies, due to increased


vascular permeability into the
extravascular space, where they may lead
either to lysis of micro-organisms, through
the participation of complement, or to
their phagocytosis by opsonisation.
Antibodies are also important in
neutralisation of toxins.

Transport of drugs such as antibiotics


to the site where bacteria are
multiplying.

Fibrin formation from exuded


fibrinogen may impede the
movement of micro-organisms,
trapping them and so facilitating
phagocytosis, and serves as a
matrix for the formation of
granulation tissue.

Delivery of nutrients and oxygen, essential


for cells such as neutrophils which have
high metabolic activity, is aided by
increased fluid flow through the area.

Stimulation of immune response by


drainage of this fluid exudate into the
lymphatics allows particulate and soluble
antigens to reach the local lymph nodes,
where they may stimulate the immune
response

Harmful effects
The release of lysosomal enzymes by
inflammatory cells may have harmful
effects:
Digestion of normal tissues. Enzymes such
as collagenases and proteases may digest
normal tissues, resulting in their
destruction. This may result particularly in
vascular damage, for example in type III
hypersensitivity reactions in some types of
glomerulonephritis and in abscess cavities.

Swelling. The swelling of acutely


inflamed tissues may be harmful: for
example, in children the swelling of
the epiglottis in acute epiglottitis due
to Haemophilus influenzae infection
may obstruct the airway, resulting in
death.

Inflammatory swelling is especially serious


when it occurs in an enclosed space such
as the cranial cavity. Thus, acute
meningitis or a cerebral abscess may raise
intracranial pressure to the point where
blood flow into the brain is impaired,
resulting in ischaemic damage, or may
force the cerebral hemispheres against the
tentorial orifice and the cerebellum into
the foramen magnum

Leukocytes are important causes of injury to


normal cells and tissues under several
circumstances:

As part of a normal defense reaction


against infectious microbes, when
adjacent tissues suffer collateral
damage. In some infections that are
difficult to eradicate, such as
tuberculosis and certain viral
diseases, the prolonged host
response contributes more to the
pathology than does the microbe
itself.

When the inflammatory response is


inappropriately directed against host
tissues, as in certain autoimmune
diseases.
When the host reacts excessively
against usually harmless
environmental substances, as in
allergic diseases, including asthma

Clinical Examples of Leukocyte-Induced Injury[*]

Disorders
Acute respiratory distress
syndrome
Acute transplant rejection

Cells and Molecules Involved in


Injury
Neutrophils
Lymphocytes; antibodies and
complement

Asthma

Eosinophils; IgE antibodies

Glomerulonephritis

Neutrophils, monocytes;
antibodies and complement

Septic shock

Cytokines

Lung abscess

Neutrophils (and bacteria)

WHAT ARE TOLL-LIKE RECEPTORS


WHAT ARE ADHESION MOLECULES
AND EXAMPLES