2. DEFINITIONS
Exudation: Escape of fluid, proteins and blood cells
from the vascular system into the interstitial tissue or
body cavities.
Exudate: an inflammatory extra vascular fluid that
has high protein concentration and much cellular
debris.
Edema: an excess of fluid in the interstitial tissue or
serous cavities.
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3. Introduction
Inflammation is the reaction of vascularized living
tissue to local injury.
It is evoked by:
Microbial infections
Physical agents
Chemicals
Necrotic tissue
Immunologic reactions
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4. Introduction
The roles of inflammation are:
To contain and isolate injury
To destroy invading microorganisms
To inactivate toxins
To prepare the tissue or organ for healing and repair
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5. Acute Inflammation
Acute inflammation is a rapid response to an injurious
agent that serves to deliver mediators of host
defense—leukocytes and plasma proteins—to the site
of injury.
When a host encounters an injurious
agent, phagocytes that reside in all tissues try to get rid
of these agents.
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6. Acute Inflammation
At the same time, phagocytes and other host cells react
to the presence of the foreign or abnormal substance
by liberating cytokines, lipid messengers, and the
various other mediators of inflammation.
Some of these mediators act on endothelial cells in the
vicinity and promote the efflux of plasma and the
recruitment of circulating leukocytes to the site where
the offending agent is located.
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7. Acute Inflammation - continued
As the injurious agent is eliminated and anti-
inflammatory mechanisms become active, the
process subsides and the host returns to a normal
state of health.
If the injurious agent cannot be quickly
eliminated, the result may be chronic
inflammation.
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8. Acute Inflammation
Acute inflammation has three major components:
alterations in vascular caliber that lead to an increase in
blood flow;
structural changes in the microvasculature that permit
plasma proteins and leukocytes to leave the circulation;
and
emigration of the leukocytes from the
microcirculation, their accumulation in the focus of
injury, and their activation to eliminate the offending
agent
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9. Acute Inflammation
These changes produce the classic clinical signs of
inflammation:
Heat (Calor)
Redness (Rubor)
Edema (tumor)
Pain (dolor)
Loss of function
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11. Acute inflammatory reactions are triggered by a
variety of stimuli:
Infections (bacterial, viral, parasitic) and microbial
toxins
• Trauma (blunt and penetrating)
• Physical and chemical agents (thermal injury, e.g.,
burns or frostbite; irradiation; some environmental
chemicals)
• Tissue necrosis (from any cause)
• Foreign bodies (splinters, dirt, sutures)
• Immune reactions (also called hypersensitivity
reactions)
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12. Changes in vascular flow and
caliber
Initially, transient vasoconstriction of arterioles occurs
Vasodilation follows, causing increased flow; it
accounts for the heat and redness
Eventually slowing of the circulation occurs as a result
of increased vascular permeability, leading to stasis.
(edema)
With slowing, leukocytic margination appears.
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14. Vasodilation
Brief arteriolar vasoconstriction followed by
vasodilation
Accounts for warmth and redness
Opens microvascular beds
Increased intravascular pressure causes an early
transudate (protein-poor filtrate of plasma) into
interstitium (vascular permeability still not increased
yet)
15. Increased vascular permeability
Leads to escape of protein rich fluid into the
intestitium.
There is increased hydrostatic pressure, caused by
vasodilatation, decreased osmotic pressure due to
leakage of a high protein fluid, resulting in marked
outflow of fluid and edema formation.
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16. Vascular leakage
Five mechanisms known to cause vascular
leakiness
Histamines, bradykinins, leukotrienes cause an
early, brief (15 – 30 min.) immediate transient
response in the form of endothelial cell
contraction that widens intercellular gaps of
venules (not arterioles, capillaries)
17. Vascular leakage
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, detachment)
making them leaky until they are repaired
(immediate sustained response), or may cause
delayed damage as in thermal or UV injury,
18. Vascular leakage
(cont’d) or some bacterial toxins (delayed
prolonged leakage)
Marginating and endothelial cell-adherent
leukocytes may pile-up and damage the
endothelium through activation and release of
toxic oxygen radicals and proteolytic enzymes
(leukocyte-dependent endothelial cell injury)
making the vessel leaky
19. Vascular leakage
Certain mediators (VEGF) may cause increased
transcytosis via intracellular vesicles which
travel from the luminal to basement membrane
surface of the endothelial cell
All or any combination of these events may occur
in response to a given stimulus
20. Cellular events: Leukocyte
extravasation and phagocytosis
Delivers leukocytes to the site of injury.
Sequence of events can be divided into:
Margination, rolling and adhesion to the lumen
Diapedesis
Migration in the endothelial tissues towards a
chemotactic stimulus.
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21. Adhesion and Transmigration
Occurs as a result of interaction between adhesion
molecules on the leukocytes and endothelium.
Major ligand-receptor pairs include:
Selectins (E, P and L)
Immunoglobulins family: ICAM and VCAM-1
The integrins
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26. Chemotaxis and leukocyte
activation
Adherent leukocytes emigrate through
interendothelial junctions, traverse the basement
membrane and move towards the site of injury along a
gradient of chemotactic agents.
Neutrophils emigrate first and they are followed by
monocytes and lymphocytes.
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27. Chemotaxis and leukocyte
activation
Chemotactic agents include: bacterial
products, complement fragments
(C5a), leukotrienes, and chemokines (IL-8).
These agents bind to specific receptors on
leukocyte, resulting in signal transduction
process, which results in assembly of the contractile
elements responsible for cell movement.
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29. Chemotaxis and leukocyte
activation
Chemotactic agents also cause leukocyte activation
characterized by:
Degranulation and secretion of enzymes
Activation of an oxidative burst
Production of arachidonic acid metabolites
Modulation of leukocyte adhesion molecules
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30. Phagocytosis
Involves 3 steps:
Recognition and attachment of the paricle to be
ingested. Facilitated by opsonization e.g. Fc fragment of
IgG.
Engulfment by pseudopods, with formation of a
phagocytic vesicle, which fuses with membrane of the
lysosome to form a phagolysosome.
Killing and degranulation of bacteria.
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31. Phagocytosis
There are 2 types of bactericidal mechanisms:
Oxygen dependent mechanisms: this involves
production of reactive oxygen species catalysed by
enzymes such as: NADPH oxidase and
myeloperoxidase
Oxygen independent mechanisms: these cause
increased permeability of the bacterial cell membrane.
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33. 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 + 2H+ H2O2 (dismutase)
34. Reactive oxygen species
Hydrogen peroxide alone insufficient
Myeloperoxidase oxidase (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
35. 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
36. Leukocyte granules
Other antimicrobials in leukocyte granules:
Bactericidal permeability increasing protein (BPI)
Lysozyme
Lactoferrin
Defensins (punch holes in membranes)
37. Leukocyte induced tissue injury
Leukocytes also release some of their products into the
extracellular space. These include:
Lysosomal enzymes
Oxygen derived active metabolites
Products of arachidonic acid metabolism such as
prostaglandins and leukotrienes.
these may cause tissue damage and if persistent may
result in chronic inflammation.
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38. Defects in leukocyte function
May interfere with inflammation and increase
susceptibility to infection.
They may be :
Acquired such as neutropenia
Genetic such as:
Defects in leukocyte adhesion
Defects in phagocytosis such as Chediak-Higashi syndrome
Defects in microbicidal activity
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39. Defects of leukocyte function
Defects of adhesion:
Defect in E- and P-selectin sugar epitopes (LAD-2)
Defects of chemotaxis/phagocytosis:
Microtubule assembly defect leads to impaired
locomotion and lysosomal degranulation (Chediak-
Higashi Syndrome)
Defects of microbicidal activity:
Deficiency of NADPH oxidase that generates
superoxide, therefore no oxygen-dependent killing
mechanism (chronic granulomatous disease)
40. Outcome of acute inflammation
Complete resolution with restoration of the site to
normal
Abscess formation
Healing by connective tissue replacement (fibrosis)
and scarring.
Progression to chronic inflammation.
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