Inflammation
Dr. Nabila Hamdi
MD, PhD
ILOs
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Distinguish between acute and chronic inflammation with respect to causes, nature
of the inflammatory response, and tissue changes.
Describe the sequence of vascular changes in acute inflammation and their purpose
Know the mechanisms of increased vascular permeability
Define the terms edema, transudate, and exudate
Describe the steps involved in extravasation of leukocytes from the blood to the
tissues. Know the steps at which selectins and integrins act.
Describe the meaning and utility of chemotaxis. Understand the role that chemokines
play in inflammation
Describe the steps involved in phagocytosis and the role of opsonins
Understand the mechanism of degradation in the phagolysosomes.
Know the major effects of the chemical mediators of inflammation
Distinguish between fibrinous, purulent, and serous inflammation. Define an abscess.
Know the cells involved in, and causes of chronic inflammation
Understand the mechanism of granulomatous inflammation
Describe the systemic manifestations of inflammation
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Outline
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Overview Of Inflammation
Acute Inflammation
Definition
Cardinal signs
Vascular changes
Cellular events
Chemical mediators
Outcomes
Chronic Inflammation
Definition
Cells & mediators
Granulomatous Inflammation
IV. Morphological Patterns of Acute and Chronic Inflammation
V. Systemic Effects of Inflammation
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Overview
Inflammation is a protective response intended to eliminate the initial cause of
cell injury as well as the necrotic cells and tissues resulting from the original
insult.
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Overview
Players of Inflammation
The goal of the inflammatory reaction is to bring cells and molecules of host defense
(normally circulating in the blood) to the site of infection or tissue damage. These include
blood leukocytes and plasma proteins, cells of vascular walls, and cells and extracellular
matrix (ECM) of the surrounding connective tissue.
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Acute Inflammation
Definition:
Acute inflammation is a rapid response to injury or microbes and other foreign
substances that is designed to deliver leukocytes and plasma proteins to sites of
injury.
Stimuli:
• Infections (bacterial, viral, fungal, parasitic)
• Trauma (blunt and penetrating)
• Physical and chemical agents (thermal injury, e.g., burns or frostbite; irradiation or
some environmental chemicals)
• Tissue necrosis (from any cause)
• Foreign bodies (splinters, dirt, sutures)
• Immune reactions (also called hypersensitivity reactions)
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Acute Inflammation
Heat
(calor)
redness
(rubor)
Swelling
(tumor)
Pain
loss of function
(dolor) (functio laesa)
Cardinal Signs of Inflammation
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Acute Inflammation
The major local manifestations of acute inflammation, compared to
normal, are:
(1) Vascular dilation and increased blood flow (hyperemia), causing
erythema and warmth
(2) extravasation and deposition of plasma fluid and proteins
(edema)
(3) leukocyte (mainly neutrophil) emigration and accumulation in the
site of injury
Erythema
Warmth
Histamine
Swelling
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1.
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Vascular Changes
Hyperemia
Exudation
Start of emigration
Acute Inflammation
2. Cellular Events
• Margination
• Rolling
• Adhesion
• Transmigration
• Chemotaxis
• Activation
• Phagocytosis & killing
3. Chemical Mediators
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Vascular Changes
Formation of transudates and exudates. A, Normal hydrostatic pressure (blue arrows) is about 32 mm Hg at the arterial end of a capillary bed and 12 mm Hg
at the venous end; the mean colloid osmotic pressure of tissues is approximately 25 mm Hg (green arrows), which is equal to the mean capillary pressure.
Therefore, the net flow of fluid across the vascular bed is almost nil. B, A transudate is formed when fluid leaks out because of increased hydrostatic
pressure or decreased osmotic pressure. C, An exudate is formed in inflammation because vascular permeability increases as a result of increased
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interendothelial spaces.
Vascular Changes
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After transient vasoconstriction (lasting only for seconds), arteriolar vasodilation
occurs, resulting in locally increased blood flow (hyperemia) and engorgement of
the down-stream capillary beds. This vascular expansion is the cause of the
redness (erythema) and warmth characteristically seen in acute inflammation. The
increased volume of blood flow lead to a rise in intravascular hydrostatic pressure,
resulting in movement of fluid from capillaries into the tissues (transudate). This
fluid is essentially an ultrafiltrate of blood plasma and contains little protein.
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As the microvasculature becomes more permeable, protein-rich fluid moves into
the extravascular tissues (exudate). This causes the red blood cells to become
more concentrated, thereby increasing blood viscosity and slowing the circulation.
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Fluid accumulation in extravascular spaces is called edema; the fluid may be a
transudate or exudate. Whereas exudates are typical of inflammation, transudates
accumulate in various non-inflammatory conditions.
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Cellular Events
Leukocyte Recruitment
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Stasis
1.Margination
4. Diapedesis/
Transmigration
5. Chemotaxis
7. Killing
-Bacteria
-Cytokines
-Complement
-Arachidonic acid
metabolism
6. Phagocytosis
The leukocytes first roll, then become activated and adhere to endothelium, then transmigrate across the endothelium, pierce the basement
membrane, and migrate toward chemoattractants emanating from the source of injury. Different molecules play predominant roles in different
steps of this process - selectins in rolling; chemokines in activating the neutrophils to increase avidity of integrins, integrins for stable adhesion.
After extravasating from the blood, leukocytes migrate toward sites of infection or injury along a chemical gradient by a process called
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chemotaxis.
Cellular Events
Leukocyte Recruitment
• Margination: The process of leukocyte accumulation at the periphery
of vessels. Leukocytes are pushed out of the central axial column and thus
have a better opportunity to interact with lining endothelial cells,
especially as stasis sets in.
• Rolling: leukocytes tumble on the endothelial surface, transiently
sticking along the way. This weak and transient adhesion involved in rolling
is mediated by the selectin family of adhesion molecules.
• Adhesion: firm adhesion of leukocytes to endothelial surfaces. This
adhesion is mediated by integrins expressed on leukocyte cell surfaces
interacting with their ligands on endothelial cells
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Cellular Events
Leukocyte Recruitment
• Transmigration: After being arrested on the endothelial surface,
leukocytes migrate through the vessel wall primarily by squeezing
between cells at intercellular junctions (diapedesis)
• Chemotaxis: After extravasation from the blood, leukocytes migrate
toward sites of infection or injury along a chemical gradient. Both
exogenous and endogenous substances can be chemotactic for leukocytes,
including:
(1) bacterial products
(2) cytokines
(3) components of the complement system, particularly C5a
(4) products of the lipoxygenase pathway of arachidonic acid (AA)
metabolism, particularly leukotriene B4 (LTB4).
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Cellular Events
Leukocyte Recruitment
Leukocyte Response in Acute Inflammation: Extravasation
Medicine, By Ernest
In most forms of acute inflammation, neutrophils predominate in the inflammatory infiltrate during the first
6 to 24 hours.
Why?
Neutrophils are more numerous in the blood, they respond more rapidly to chemokines, and they may
attach more firmly to the adhesion molecules that are rapidly induced on endothelial cells (selectins). In
addition, after entering tissues, neutrophils are short-lived, they die by apoptosis and disappear within 24
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to 48 hours.
Cellular Events
Leukocyte Activation
See next slide
Different classes of cell surface receptors of leukocytes recognize different stimuli. The receptors
initiate responses that mediate the functions of the leukocytes.
Only some receptors are depicted. IFN-γ, interferon γ; LPS, lipopolysaccharide.
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Cellular Events
Leukocyte Activation
oxidative burst
Phagocytosis of a particle (e.g., a bacterium) involves (1) attachment and binding of the particle to receptors on the
leukocyte surface, (2) engulfment and fusion of the phagocytic vacuole with granules (lysosomes), and (3) destruction
of the ingested particle. iNOS, Inducible nitric oxide synthase; NO, nitric oxide; ROS, reactive oxygen species.
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Leukocyte Activation
Phagocytosis
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(1) Recognition and attachment: Leukocytes bind and ingest most microorganisms
and dead cells via specific surface receptors, which recognize either components
of the microbes and dead cells, or host proteins, called opsonins, that coat
microbes and target them for phagocytosis (a process called opsonization)
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(2) Engulfment: Pseudopods are extended around the object, eventually forming
a phagocytic vacuole. The membrane of the vacuole then fuses with the
membrane of a lysosomal granule, resulting in discharge of the granule's contents
into the phagolysosome.
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(3) killing and degradation of the ingested material: The key steps in this reaction
are the production of microbicidal substances within lysosomes and fusion of the
lysosomes with phagosomes. The most important microbicidal substances are
reactive oxygen species (ROS) and lysosomal enzymes (myeloperoxidase).
Phagocytosis stimulates an oxidative burst characterized by a sudden increase in
oxygen consumption, glycogen catabolism (glycogenolysis), increased glucose
oxidation, and production of ROS.
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Defects in Leukocyte Function
Leukocyte Adhesion Deficiency (LAD)
Defect in integrins/selectins
Defects in microbicidal activity
a genetic deficiency in one of the several components of the phagocyte oxidase responsible
for generating ROS. In these patients, engulfment of bacteria does not result in activation of
oxygen-dependent killing mechanisms.
Defects in phagolysosome formation
Impairment of the fusion of lysosomes with phagosomes
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Summary of Vascular & Cellular Events
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Vasodilation is induced by chemical mediators such as histamine (described later), and
is the cause of erythema and stasis of blood flow
Increased vascular permeability allows plasma proteins and leukocytes to enter sites
of infection or tissue damage; fluid leak through blood vessels results in edema
Leukocytes are recruited from the blood into the extravascular tissue where infectious
pathogens or damaged tissues may be located and are activated to perform their
functions
Leukocyte recruitment is a multi-step process consisting of loose attachment to and
rolling on endothelium (mediated by selectins); firm attachment to endothelium
(mediated by integrins); and migration through inter-endothelial spaces.
Neutrophils predominate in the early inflammatory infiltrate and are later replaced by
macrophages.
Leukocytes can eliminate microbes and dead cells by phagocytosis, followed by their
destruction in phagolysosomes. Destruction is caused by free radicals (ROS, NO)
generated in activated leukocytes and lysosomal enzymes.
Enzymes and ROS may be released into the extracellular environment, which may lead
to damage of normal tissues.
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1.
Which cells are responsible for initiating an inflammatory response?
2. What are the cardinal signs of inflammation?
3.
Which signs of inflammation are associated with histamine release?
4.
What are the vascular changes that occur during acute inflammation?
5.
What is the sequence of events in the cellular events of acute inflammation?
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What is the definition of chemotaxis?
7.
What is the mechanism of destruction of a bacteria by the neutrophils?
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