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PATHOLOGY: Inflammation and Repair | Aemil Q.

Liberato (June 29, 2015)


INFLAMMATION

Overview: Definitions and General Features

Inflammation
- a response of vascularized tissues to
infections and damaged tissues that brings
cells and molecules of host defense from the
circulation to the sites where they are needed
in order to eliminate the offending agents
- a protective response that rids the host cells of
both the initial cause of cell injury (microbes,
toxins) and the consequences of such injury
(necrotic cells and tissues)
Steps in a typical inflammatory response:
1. The offending agent (located in extravascular
tissues) is recognized by host cells and
molecules (macrophages, dendritic cells, mast Fundamental Properties of the Inflammatory
cells)
Response: A Review
2. Recruitment of leukocytes from circulation to
Components of the Inflammatory Response
site of injury leukocytes engulf and destroy
- Major participants:
bacteria, tissue, debris, and other particulate
blood vessels (vascular response), and
material
leukocytes (cellular response)
3. Leukocytes and proteins (chemical mediators)
are activated and work together to destroy
Harmful consequences of inflammation
and eliminate the offending substance
- Often accompanied by local tissue damage
(through proteolytic degradation).
and its associated signs and symptoms (pain
4. The reaction is controlled and terminated.
and functional impairment)
5. The damaged tissue is repaired/restored to its
- Typically, these harmful consequences are
normal structure and function. Limited by:
self-limited and resolve as the inflammation
extent
of
tissue
abates.
degradation, and
- There are many diseases in which the
regenerative capacity
inflammatory reaction is misdirected, for
of specific tissue
example:
- OR Autoimmune diseases against self
5 Rs of the inflammatory response
tissues
1. Recognition of the injurious agent
Allergies against normally harmless
2. Recruitment of leukocytes
environmental substances
3. Removal of the agent
Where inflammatory reaction is
4. Regulation (control) of the response
inadequately controlled
5. Resolution (repair/restoration)
- Anti-inflammatory drugs control the
harmful sequelae of inflammation yet not
interfere with its beneficial effects

Local vs. systemic inflammation


Local
Largely

confined

Systemic
to

Widespread;

sepsis

the site of infection

which is one form of

although it can have

systemic

systemic

inflammatory

manifestations

(e.g.,

fever in bacterial/viral

response

Tissue injury

(SIRS)

pharyngitis)

Mediators of inflammation
-

Soluble factors that are produced by


various cells or derived from plasma
proteins
that are generated or
activated
in
response
to
the
inflammatory stimulus
They initiate and amplify the
inflammatory response and determine
its pattern, severity, and clinical and
pathological manifestations.

and

and

self-

severe

progressive

Prominent

Less

systemic signs
Type of host

Innate

Adaptive

defense

immunity

immunity

and

Termination

of

inflammation

initiation of tissue repair


-

Often

limited
Local

syndrome

Usually mild

and

Inflammation is terminated when the


offending agent is eliminated.
The
reaction
resolves
because
mediators are broken down and
dissipated, and leukocytes have short
life spans in tissues.
In
addition,
anti-inflammatory
mechanisms are activated to control
the response and prevent excessive
damage
Once inflammation has eliminated the
offending agents, it sets into motion the
process of tissue repair where the
injured tissue is replaced through
regeneration of surviving cells and
filling
of
residual
effects
with
connective tissue (scarring)

Cardinal Signs of Inflammation


Acute vs. chronic inflammation
1. Rubor (redness)
2. Tumor (swelling)
hallmarks of
Feature
Acute
Chronic
3. Calor (warmth/heat)
acute
Onset
Fast:
Slow: days
inflammation
minutes or
4. Dolor (pain)
hours
Main
Exudation of More
tissue 5. Functio laesa (loss of function)
characteristics

fluid

and

destruction,

Cellular

Mainly

Causes of Inflammation
proliferation of
Infection and microbial toxins
blood vessels,
- Bacterial, viral, fungal, parasitic
and deposition
- Inflammatory
responses
vary
of connective
depending on the type of pathogen and
tissue
the characteristics of the host
Monocytes or

infiltrate

neutrophils

macrophages

(polymorpho

and

-nuclear

lymphocytes

plasma
proteins
(edema) and
emigration
of leukocytes

leukocytes or
PMN)

Tissue necrosis
-

Includes:

Ischemia (reduced blood flow;


the cause of MI)
Trauma
Physical and chemical injury
(e.g., thermal injury, as in
burns or frostbite, irradiation,
exposure to environmental
chemicals

Foreign bodies
- Splinters, dirt, sutures
- They cause traumatic injury or carry
microbes
- Endogenous substances (in large
amounts):
Urate crystals (gout)
Cholesterol
crystals
(atherosclerosis)
Lipids
(obesity-associated
metabolic syndrome)
Immune reactions
-

The normally protective immune


system damages the individuals own
tissues.
May be directed against self antigens
(autoimmune diseases) or may be
inappropriate
reactions
against
environmental substances (allergies),
or against microbes
The inflammation is induced by
cytokines produced by T lymphocytes
and other cells of the immune syste,

Recognition of Microbes and Damaged Cells


(the first step in all inflammatory reactions)

Cellular receptors for microbes


-

Cells express receptors in the:


Plasma
membrane
(for
extracellular microbes)
Endosomes
(for
ingested
microbes)
Cytosol (intracellular microbes)
These cellular receptors enable the
cells to sense the presence of foreign
invaders in any cellular compartment.
Toll-like receptors (TLRs) are
the best defined of these
receptors.
The receptors are expressed on many
cell types, including:

Epithelial cells (through which


microbes enter
from
the
external environment)
Dendritic cells
Macrophages
Other leukocytes (which may
encounter microbes in various
tissues)
Engagement of these receptors triggers
the production of molecules involved in
inflammation,
including
adhesion
molecules
on
endothelial
cells,
cytokines, and other mediators.

Sensors of cell damage


- Cytosolic receptors that recognize a
diverse set of molecules that are
liberated/altered as a consequence of
cell damage.
- These molecules include:
Uric acid (a product of DNA
breakdown)
ATP (released from damaged
mitochondria)
Reduced
intracellular
K+
concentrations (reflecting loss
of ions because of plasma
membrane injury)
DNA (when released into the
cytoplasm and not sequestered
in nuclei as it normally should)
- These receptors activate a multiprotein
cytosolic
complex
called
the
inflammasome

induces
the

production of IL-1 recruits


leukocytes
and
thus
induces
inflammation.
Gain-of-function mutations cause of
rare
diseases
known
as
autoinflammatory
syndromes
characterized
by
spontaneous
inflammation
(treatment:
IL-1
antagonists)
Inflammasome
has
also
been
implicated in inflammatory reactions
to:

Urate crystals (gout)


Lipids (in metabolic syndrome)
Cholesterol
crystals
(in
atherosclerosis)
Amyloid deposits in the brain
(Alzheimers disease)

Other cellular receptors involved in


inflammation
-

Many leukocytes express receptors for


the Fc tails of antibodies and for
complement proteins these receptors
recognize
microbes
coated
with
antibodies and complement (coating
process opsonization) and promote
ingestion and destruction of the
microbes as well as inflammation.

The
vascular
reactions
of
acute
inflammation consist of changes in the:
1. Flow of blood
2. Permeability of vessels
Both are designed to maximize
the movement of plasma
proteins and leukocytes out of
the circulation and into the site
of infection/injury.

Exudation the escape of fluid, proteins,

Circulating proteins
-

Complement system reacts against


microbes and produces mediators of
inflammation
Mannose-binding
lectin

circulating protein that recognizes


microbial
sugars
and
promotes
ingestion of the microbes and the
activation of the complement system.
Collectins bind to and combat

and blood vessels from the vascular system


into the interstitial tissue or body cavities.

Exudate
- an extravascular fluid that has a high
protein concentration and contains
cellular debris
- its presence implies that there is an
increase in the permeability of small
blood vessels triggered by some sort of
tissue
injury
and
an
ongoing
inflammatory reaction

Transudate

microbes
ACUTE INFLAMMATION

3 major components:
1. Dilation of small vessels leading to an
increase in blood flow
2. Increased
permeability
of
the
microvasculature enabling
plasma
proteins and leukocytes to leave the
circulation, and
3. Emigration of the leukocytes from the
microcirculation, their accumulation in
the focus of injury, and their activation
to eliminate the offending agent

Reactions

of

Inflammation

Blood

Vessels

in

Acute

In contrast to exudate, a fluid with low


protein concentration (most of which is
albumin), little or no cellular material,
and low specific gravity
It is essentially an ultrafiltrate of blood
plasma that is produced as a result of
osmotic or hydrostatic imbalance across
the vessel wall without an increase in
vascular permeability.

Edema
- Denotes an excess of fluid in interstitial
tissue or serous cavities
- It can either be an exudate or a
transudate.

Pus
- A purulent exudate an inflammatory
exudate rich in leukocytes (mostly
neutrophils), the debris of dead cells,
and in many cases, microbes.

Changes in Vascular Flow and Caliber


-

Contraction of endothelial cells


resulting
in
increased
interendothelial spaces is the
most common mechanism of
vascular leakage.
Endothelial injury resulting in
endothelial cell necrosis and
detachment.
Increased transport of fluids
and
proteins,
called
transcytosis,
through
the
endothelial cell.

Begin early after injury and consist of


the following:
Vasodilation induced by
the action of several mediators
(notably
histamine),
on
vascular smooth muscle; one of
the earliest manifestation of
acute
inflammation;
first
involves the arterioles and then
leads to opening of new
capillary beds in the area
which increases blood flow,
which is the cause of heat and
redness (erythema) at the site
of inflammation.
Increased permeability of
the microvasculature
Engorgement of small vessels
with slowly moving red cells, a
condition termed stasis seen
as vascular congestion
localized
redness
of
involved tissue.
Blood

and
the

leukocytes,

principally

neutrophils,

accumulate

along

vascular

endothelium

the

endothelial cells are also


activated
by
mediators
produced at the sites of
infection and tissue damage,
and express increased levels of
adhesion molecules.

Increased

vascular

(vascular leakage)
-

permeability

Mechanisms
responsible
for
the
increased permeability of postcapillary
venules:

Responses of Lymphatic Vessels and


Lymph Nodes
- In inflammation, lymph flow is
increased and helps drain edema fluid
that accumulates because of increased
vascular permeability.
- In addition, leukocytes and cell debris,
as well as microbes, may find their way
into lymph.
- Lymphatic vessels proliferate during
inflammation to handle the increased
load.
- 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
macrophages this change is termed
as
reactive,
or
inflammatory
lymphadenitis.

Leukocyte Recruitment to Sites of Inflammation


The changes in blood flow and vascular
permeability are quickly followed by an
influx of leukocytes into the tissue.
The most important leukocytes in typical
inflammatory reactions are the ones
capable
of
phagocytosis,
namely
neutrophils and macrophages.
The journey of leukocytes from the vessel
lumen to the tissue is a multistep process
that is mediated and controlled by
adhesion molecules and cytokines called
chemokines. This process can be divided
into sequential steps:
1. In the lumen: margination, rolling, and
adhesion to endothelium.

2. Migration across the endothelium and


vessel wall
3. Migration in the tissues toward a
chemotactic stimulus

Leukocyte adhesion to endothelium

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