unit 3 Acute & Chronic Inflammation (1).pdf

Information needed for inflammatory response

1. PATHOLOGY
Acute and Chronic
inflammation.
MukukaB
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2. OUTLINE
1.OVERVIEW OF INFLAMMATION
2.ACUTE & CHRONIC INFLAMMATION
3.MEDIATORS OF INFAMMATION
4.CARDINAL SIGNS
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3. OVERVIEW
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ØDef: Inflammation is a protective response
intended to eliminate the initial cause of cell
injury as well as the necrotic cells and tissues.
ØIt accomplishes its protective mission by diluting,
destroying, or otherwise neutralizingharmful
agents (e.g., microbes and toxins).
ØIt then sets into motion the events that
eventually heal and repair the sites of injury.
ØIn the context of infections, inflammation is part
of a broader protective response referred to as
innate immunity.

4. COMPONENTS OF INFLAMMATION
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1. Vascular reaction
2. Cellular response
Both are activated by mediators
that are derived from plasma
proteins and various cells-
discussed later.

5. STEPS OF THE INFLAMMATORY
RESPONSE
Steps of the inflammatory remember as
the 5 Rs:
1. Recognition of the injurious agent
2. Recruitment of leukocytes
3. Removal of the agent
4. Regulation (control) of the response,
and
5. Resolution (repair).5/20/23

6. TYPES OF INFLAMMATION
Acute or Chronic
Acute: Rapid in onset, short duration (lasting from a few minutes to as long as a few days). Is characterized by fluid and plasma protein exudation and a predominantly neutrophilic leukocyte (PMNS) accumulation.
ChronicInsidious, longer duration (days to years), and is typified by influx of lymphocytes and macrophages with associated vascular proliferation and fibrosis (scarring)-The two types can overlap.
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7. EXTERNAL MANIFESTATIONS OF INFLAMMATION
•Often called “cardinal signs”, result from the
vascular changes and cell recruitment:
Heat (calor)
Redness (rubor)
Swelling (tumor).
Pain (dolor)
Loss of function (functiolaesa)
The last two occur as consequences of
mediator elaboration and leukocyte-mediated
damage.
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8. NOTE: The components of the inflammatory
reaction that destroy and eliminate microbes
and dead tissues are capable of also injuring
normal tissues Therefore, injury may accompany
entirely normal if the reaction is:
-Very strong (e.g., when the infection is severe),
-Prolonged (e.g., when the eliciting agent resists
eradication), or
-Inappropriate (e.g., when it is directed against
self-antigens in autoimmune diseases or against
usually harmless environmental antigens in
allergic disorders).
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9. ACUTE INFLAMMATION
•A rapid response to injury or microbes and other foreign
substances that is designed to deliver leukocytes and
plasma proteins to sites of injury.Once there, leukocytes
clear the invaders and begin the process of digesting and
getting rid of necrotic tissues. Acute inflammation has two
major components:
Vascular changes:alterations in vessel caliber resulting in
increased blood flow (vasodilation) and structural changes
that permit plasma proteins to leave the circulation
(increased vascular permeability).
Cellular events:emigration of the leukocytes from the
microcirculation and accumulation in the focus of injury
(cellular recruitment and activation). The principal leukocytes
in acute inflammation are neutrophils (polymorphonuclear
leukocytes).
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10. STIMULI FOR ACUTE INFLAMMATION
•Infections
•Trauma(blunt and penetrating) and physical and
chemical agents(thermal injury, e.g., burns or
frostbite; irradiation; some environmental chemicals)
injure host cells and elicit inflammatory reactions.
•Tissue necrosis(from any cause), including ischemia
(as in a myocardial infarct) and physical and chemical
injury.
•Foreign bodies(splinters, dirt, sutures). Immune
reactions(also called hypersensitivity reactions)
against environmental substances or against self
tissues.
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11. CHANGES IN VASCULAR CALIBER AND FLOW
•After vasoconstriction (lasting only for seconds), arteriolar vasodilationoccurs, resulting in locally increased blood flow 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. As the microvasculature becomes more permeable, protein-rich fluid moves into the extravascular tissues. This causes the red blood cells to become more concentrated, thereby increasing blood viscosity and slowing the circulation.
•As stasis develops, leukocytes (principally neutrophils) begin to accumulate along the vascular endothelial surface, a process called margination
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12. INCREASED VASCULAR PERMEABILITY
MECHANISMS
•Endothelial cell contraction leading to intercellular gaps in postcapillary
venules is the most common cause of increased vascular permeability. It is
a reversible process elicited by histamine, bradykinin, leukotrienes, and
many other chemical mediators. Endothelial cell contraction occurs rapidly
after binding of mediators to specific receptors, is usually short-lived (15-
30 minutes), and is called the immediate transient response.
•Endothelial injury results in vascular leakage by causing endothelial cell
necrosis and detachment. Direct injury to endothelial cells is usually seen
after severe injuries (e.g., burns and some infections). In most cases
leakage begins immediately after the injury and persists for several hours
(or days) until the damaged vessels are thrombosed or repaired.
•Leukocyte-mediated endothelial injury may occur as a consequence of
leukocyte accumulation along the vessel wall.
•Leakage from new blood vessels, tissue repair involves new blood vessel
formation (angiogenesis). These vessel sprouts remain leaky until
proliferating endothelial cells mature sufficiently to form intercellular
junctions.
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13. RESPONSES OF LYMPHATIC VESSELS
•In inflammation, lymph flow is increased and helps
drain edema fluid from the extravascular space.
•In addition to fluid, leukocytes and cell debris may
also find their way into lymph.
•The lymphatics may become secondarily inflamed
(lymphangitis), as may the draining lymph nodes
(lymphadenitis).
•Inflamed lymph nodes are often enlarged, because
of hyperplasia of the lymphoid follicles and increased
numbers of lymphocytes and phagocytic cells lining
the sinuses of the lymph nodes.
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14. CELLULAR EVENTS: LEUKOCYTE
RECRUITMENT AND ACTIVATION
•An important function of the inflammatory response is to
deliver leukocytes to the site of injury and to activate them.
•Leukocytes ingest offending agents, kill bacteria and other
microbes, and eliminate necrotic tissue and foreign
substances. A price that is paid for the defensive potency of
leukocytes is that, once activated, they may induce tissue
damage and prolong inflammation, since the leukocyte
products that destroy microbes can also injure normal host
tissues.
•Therefore, key to the normal function of leukocytes in host
defenseis to ensure that they are recruited and activated
only when needed.
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15. LEUKOCYTE RECRUITMENT
The sequence of events in the recruitment of leukocytes from the vascular lumen to the extravascular space consists of:
(1) margination, adhesion to endothelium, and rolling along the vessel wall.
(2) firm adhesion to the endothelium.
(3) transmigration between endothelial cells.
(4) migration in interstitial tissues toward a chemotactic stimulus.
CHEMOTAXIS
Chemical mediators-chemo-attractants and certain cytokines-affect these processes by modulating the surface expression or avidity of the adhesion molecules and by stimulating directional movement of the leukocytes.Check chemical mediators on the next slide.
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16. MECHANISMS OF INFLAMMATION

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18. LEUKOCYTE ACTIVATION
•Once leukocytes have been recruited to the site of infection or tissue
necrosis, they must be activated to perform their functions.
•Leukocytes express on their surface different kinds of receptors that
sense the presence of microbes. Engagement of these receptors by
microbial products or by various mediators of inflammation induces a
number of responses in leukocytes that are part of their normal
defensive functions and are grouped under the generic term leukocyte
activation. Leukocyte activation results in many enhanced functions:
-Phagocytosis of particles, an early step in the elimination of harmful
substances.
-Production of substances that destroy phagocytosed microbes and remove
dead tissues; these leukocyte products include lysosomal enzymes and
reactive oxygen and nitrogen species.
-Production of mediators that amplify the inflammatory reaction, including
arachidonic acid metabolites and cytokines.
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19. LEUKOCYTE-INDUCED TISSUE INJURY
Leukocytes are important causes of injury to normal cells and tissues under several circumstances:
-As part of a normal defensereaction against infectious microbes, when "bystander" tissues are injured.
-In some infections that are difficult to eradicate, such as tuberculosis and certain viral diseases, the host response contributes more to the pathology than does the microbe itself.
-As a normal attempt to clear damaged and dead tissues (e.g., after a myocardial infarction).
-Inflammation may prolong and exacerbate the injurious consequences of the infarction, especially upon reperfusion.
-When the inflammatory response is inappropriately directed against host tissues, as in certain autoimmune diseases, or when the host reacts excessively against non-toxic environmental substances, such as allergic diseases that induce asthma.
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20. 5/20/23
Mediator Source Principal Actions

Cell-Derived
Histamine Mast cells, basophils,
platelets
Vasodilation, increased vascular permeability,
endothelial activation
Serotonin Platelets Vasodilation, increased vascular permeability
Prostaglandins Mast cells, leukocytes Vasodilation, pain, fever
Leukotrienes Mast cells, leukocytes Increased vascular permeability, chemotaxis,
leukocyte adhesion and activation
Platelet-
activating factor
Leukocytes, endothelial
cells
Vasodilation, increased vascular permeability,
leukocyte adhesion, chemotaxis, degranulation,
oxidative burst
Reactive oxygen
species
Leukocytes Killing of microbes, tissue damage
Nitric oxide Endothelium,
macrophages
Vascular smooth muscle relaxation; killing of
microbes
Cytokines (e.g.
TNF, IL-1)
Macrophages,
lymphocytes, endothelial
cells, mast cells
Local endothelial activation (expression of
adhesion molecules), systemic acute-phase
response; in severe infections, septic shock
Chemokines Leukocytes, activated
macrophages
Chemotaxis, leukocyte activation

Plasma Protein-Derived

Complement Plasma (produced in liver) Leukocyte chemotaxis and activation,
opsonization, vasodilation (mast cell stimulation)
Kinins Plasma (produced in liver) Increased vascular permeability, smooth muscle
contraction, vasodilation, pain
Proteases
activated during
coagulation
Plasma (produced in liver) Endothelial activation, leukocyte recruitment

21. CONSEQUENCES OF ACUTE
INFLAMMATION
1.Resolution.
-When the injury is limited or short-lived, when there has been no or minimal tissue damage, and when the tissue is capable of replacing any irreversibly injured cells.
-Termination of the acute inflammatory response involves neutralization, decay or enzymatic degradation of the various chemical mediators, normalization of vascular permeability, and cessation of leukocyte emigration with subsequent death (by apoptosis) of extravasated neutrophils.
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22. CONSEQ. CONT.
2. Progression to chronic inflammation
3. Scarring or fibrosis results after substantial
tissue destruction or when inflammation occurs
in tissues that do not regenerate.
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24. Chronic inflammation
•May be more insidious, is of longer duration
(days to years), and is typified by influx of
lymphocytesand macrophages with
associated vascular proliferation and fibrosis
(scarring).
•However, as we will see later, these basic
forms of inflammation can overlap, and many
variables modify their course and histologic
appearance
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25. CHRONIC INFLAMMATION ARISES IN
THE FOLLOWING SETTINGS: •Persistent infections by microbes that are difficult to eradicate e.gThese mycobacteria, Treponema pallidum. These elicit a T lymphocyte-mediated immune response called delayed-type hypersensitivity.
•Immune-mediated inflammatory diseases (hypersensitivity diseases). Diseases that are caused by excessive and inappropriate activation of the immune system are increasingly recognized as being important health problems.
•Immune responses against common environmental substances are the cause of allergic diseases, such as bronchial asthma.
•Prolonged exposure to potentially toxic agents. Examples include nondegradable exogenous materials such as inhaled particulate silica, which can induce a chronic inflammatory response in the lungs (silicosis), and endogenous agents such as chronically elevated plasma lipid components, which may contribute to atherosclerosis.
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27. Another type of chronic inflammation
Granulomatous inflammation•A distinctive pattern of chronic inflammation
characterized by aggregates of activated
macrophages that assume an epithelioid
appearance.
•Granulomas are encountered in certain specific
pathologic states; consequently, recognition of
the granulomatous pattern is important because
of the limited number of conditions (some life-
threatening) that cause it.
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