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Pathology is the scientific study of disease.
Pathology embraces the functional and structural
changes in disease, from the molecular level to the
effects on the individual.
Pathology is continually subject to change,
revision and expansion as new scientific methods
illuminate our knowledge of disease.
The ultimate goal of pathology is the identification
of the causes of disease, a fundamental objective
leading to successful therapy and to disease
prevention.
4. HISTORY OF PATHOLOGY
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The first opportunity for the scientific study of
disease came from the thorough internal
examination of the body after death.
Autopsies (necropsies or postmortem
examinations) have been performed scientifically
from about 300 BC.
5. WHAT IS DISEASE?
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A disease is a condition in which the presence of
an abnormality of the body causes a loss of normal
health (disease).
The mere presence of an abnormality is
insufficient to imply the presence of disease unless
it is accompanied by ill health, although it may
denote an early stage in the development of a
disease.
The word disease is, therefore, synonymous with
ill health and illness.
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Each separately named disease is characterised by
a distinct set of features (cause, signs and
symptoms, morphological and functional changes,
etc.).
Many diseases share common features and are
thereby grouped together in disease classification
systems.
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Disease is the clinical manifestation, through signs and
symptoms, of an underlying abnormality.
The abnormality may be structural or functional or
both. In many instances the abnormality is obvious and
well characterised (e.g. a tumour); in other instances
poorly defined (e.g. depressive illness).
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Aetiology
The aetiology of a disease is its cause: the initiator of
the subsequent events resulting in the patient's illness.
categories of aetiological agents include:
1.genetic abnormalities
2.infective agents, e.g. bacteria, viruses, fungi, parasites
3.chemicals
4.radiation
5.mechanical trauma.
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Some diseases are due to a combination of causes,
such as genetic factors and infective agents; such
diseases are said to have a multifactorial aetiology.
Sometimes the aetiology of a disease is unknown
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Pathogenesis
is the mechanism through which the etiology (cause) operates
to produce the pathological and clinical manifestations.
Groups of etiological agents often cause disease by acting
through the same common pathway of events.
Examples of pathogeneses of disease include:
A. inflammation: a response to many micro-organisms and other
harmful agents causing tissue injury
B. degeneration: a deterioration of cells or tissues in response to,
or failure of adaptation to, a variety of agents
C. carcinogenesis: the mechanism by which cancer-causing
agents result in the development of tumours
D. immune reactions: undesirable effects of the body's immune
system.
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Structural and functional manifestations
The aetiological agent (cause) acts through a
pathogenetic pathway (mechanism) to produce the
manifestations of disease, giving rise to clinical
signs and symptoms (e.g. weight loss, shortness of
breath) and the abnormal features or lesions (e.g.
carcinoma of the lung) to which the clinical signs
and symptoms can be attributed.
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Common structural abnormalities causing ill health are;
space-occupying lesions (e.g. tumours) destroying,
displacing or compressing adjacent healthy tissues
abnormally sited tissue (e.g. tumours, heterotopias) as a
result of invasion, metastasis or developmental abnormality
loss of healthy tissue from a surface (e.g. ulceration) or
from within a solid organ (e.g. infarction)
obstruction to normal flow within a tube (e.g. asthma,
vascular occlusion)
rupture of a hollow viscus (e.g. aneurysm, intestinal
perforation).
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Examples of functional abnormalities causing ill
health include:
excessive secretion of a cell product (e.g. nasal
mucus in the common cold, hormones having
remote effects)
insufficient secretion of a cell product (e.g. insulin
lack in diabetes mellitus)
impaired nerve conduction
impaired contractility of a muscular structure
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Pathognomonic abnormalities
Pathognomonic features are restricted to a single
disease, or disease category, and without them the
diagnosis is impossible or uncertain..
i.E the presence of Mycobacterium tuberculosis, in
the appropriate context, is pathognomonic of
tuberculosis.
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Complications and sequelae
Diseases may have prolonged, secondary or
distant effects.
Example; the spread of an infective organism from
the original site of infection, where it had provoked
an inflammatory reaction, to another part of the
body, where a similar reaction to it will occur.
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Prognosis
The prognosis forecasts the known or likely course
of the disease and, therefore, the fate of the patient.
When we say that the 5-year survival prospects for
carcinoma of the lung are about 5%, this is the
prognosis of that condition.
19. Growth, differentiation and
morphogenesis
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Growth, differentiation and morphogenesis are the
processes by which a single cell, the fertilised
ovum, develops into a large complex multicellular
organism, with co-ordinated organ systems
containing a variety of cell types, each with
individual specialised functions.
Growth and differentiation continue throughout
adult life, as many cells of the body undergo a
constant cycle of death, replacement and growth in
response to normal (physiological) or abnormal
(pathological) stimuli.
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There are many stages in human embryological
development at which anomalies of growth and/or
differentiation may occur, leading to major or
minor abnormalities of form or function, or even
death of the fetus.
In post-natal and adult life, some alterations in
growth or differentiation may be beneficial, as in
the development of increased muscle mass in the
limbs of workers engaged in heavy manual tasks.
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Types of growth in a tissue
Multiplicative, involving an increase in numbers of
cells. This type of growth is present in all tissues
during embryogenesis.
Auxetic, resulting from increased size of individual
cells, as seen in growing skeletal muscle.
Accretionary, an increase in intercellular tissue
components, as in bone and cartilage.
Combined patterns.
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Differentiation
is the process whereby a cell develops an overt
specialized function or morphology which
distinguishes it from its parent cell.
Thus, differentiation is the process by which genes
are expressed selectively and gene products act to
produce a cell with a specialized function.
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Morphogenesis
Morphogenesis is the highly complex process of
development of structural shape and form of
organs, limbs, facial features, etc.
from primitive cell masses during embryogenesis.
For morphogenesis to occur, primitive cell masses
must undergo co-ordinated growth and
differentiation
26. Cellular Adaptations of Growth and
Differentiation
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Cells respond to increased demand and external
stimulation by hyperplasia or hypertrophy, and
they respond to reduced supply of nutrients and
growth factors by atrophy.
In some situations, cells change from one type to
another, a process called metaplasia.
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HYPERPLASIA
Hyperplasia is an increase in the number of cells in
an organ or tissue, usually resulting in increased
volume of the organ or tissue.
Although hyperplasia and hypertrophy are two
distinct processes, frequently both occur together,
and they may be triggered by the same external
stimulus.
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Hyperplasia takes place if the cellular population is
capable of synthesizing DNA, thus permitting
mitotic division; by contrast, hypertrophy involves
cell enlargement without cell division.
Hyperplasia can be physiologic or pathologic.
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Physiologic Hyperplasia can be divided into: (1)
hormonal hyperplasia,
which increases the functional capacity of a tissue
when needed,
E.g the proliferation of the glandular epithelium of
the female breast at puberty and during pregnancy
and the physiologic hyperplasia that occurs in the
pregnant uterus.
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(2) compensatory hyperplasia, which increases
tissue mass after damage or partial resection.
e.g., after unilateral nephrectomy, when the
remaining kidney undergoes compensatory
hyperplasia).
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Pathologic Hyperplasia
Most forms of pathologic hyperplasia are caused
by excessive hormonal stimulation or growth
factors acting on target cells.
BPH and Endometrial hyperplasia is an example of
abnormal hormone-induced hyperplasia.
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Pathologic hyperplasia, however, constitutes a fertile
soil in which cancerous proliferation may eventually
arise.
Thus, patients with hyperplasia of the endometrium are
at increased risk for developing endometrial cancer
Note; Hyperplasia is also an important response of
connective tissue cells in wound healing, in which
proliferating fibroblasts and blood vessels aid in repair
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HYPERTROPHY
Hypertrophy refers to an increase in the size of cells,
resulting in an increase in the size of the organ.
the hypertrophied organ has no new cells, just larger
cells.
The increased size of the cells is due not to cellular
swelling but to the synthesis of more structural
components.
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cells capable of division may respond to stress by
undergoing both hyperplasia and hypertrophy, whereas
in nondividing cells (e.g., myocardial fibers),
hypertrophy occurs.
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Hypertrophy can be physiologic or pathologic and is
caused by increased functional demand or by specific
hormonal stimulation.
The striated muscle cells in both the heart and the skeletal
muscles are capable of tremendous hypertrophy
The most common stimulus for hypertrophy of muscle is
increased workload.
physiologic growth of the uterus during pregnancy is a
good example of hormone-induced increase in the size
which results from both hypertrophy and hyperplasia
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ATROPHY
Shrinkage in the size of the cell by loss of cell
substance is known as atrophy. It represents a form of
adaptive response and may culminate in cell death.
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Atrophy can be physiologic or pathologic.
Physiologic atrophy is common during early
development. Some embryonic structures, such as the
notochord and thyroglossal duct, undergo atrophy
during fetal development. The uterus decreases in size
shortly after parturition, and this is a form of
physiologic atrophy.
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The common causes of atrophy:
Decreased workload (atrophy of disuse).
Loss of innervation (denervation atrophy).
Diminished blood supply.
Inadequate nutrition
Loss of endocrine stimulation
Aging (senile atrophy).
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METAPLASIA
Metaplasia is a reversible change in which one adult
cell type (epithelial or mesenchymal) is replaced by
another adult cell type.
It may represent an adaptive substitution of cells that
are sensitive to stress by cell types better able to
withstand the adverse environment.
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The most common epithelial metaplasia is columnar to
squamous , as occurs in the respiratory tract in
response to chronic irritation.
Moreover, the influences that predispose to
metaplasia, if persistent, may induce malignant
transformation in metaplastic epithelium
42. Cell injury
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Many agents can injure cells, but they can be
classified into a small number of groups.
Their mechanisms of action are also often very
similar; widely differing agents may act through an
identical final common pathway at the cellular
level.
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Causative agents
A wide range and variety of physical, chemical and
biological agents may be associated with cellular injury
Major causes of cellular injury include:
trauma
thermal injury, hot or cold
poisons
drugs
infectious organisms
ionising radiation.
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Physical agents
Trauma and thermal injury result in cell death by disrupting
cells and denaturing proteins, and also by causing local
vascular thrombosis with consequent tissue ischaemia or
infarction.
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Drugs and poisons
Infectious organisms
The mechanisms of tissue damage produced by infectious
organisms are varied, but with many bacteria it is their
metabolic products or secretions that are harmful.
Thus, the host cells receive a chemical insult which may be
toxic to their metabolism or membrane integrity.
In addition there will often be a host inflammatory
response that may itself prove chemically damaging.
Intracellular agents like viruses often result in the physical
rupture of infected cells
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Mechanisms of cellular injury
Cells may be damaged either reversibly irreversibly in a
variety of ways
The effect on a tissue will depend on:
the duration of the injury
the nature of the injurious agent
the proportion and type of cells affected
the ability of the tissues to regenerate.
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Necrosis
Death of cells or tissues in a living organism, with failure
of membrane integrity, is referred to as necrosis,
irrespective of the cause.
It is a pathological process following cellular injury, and
often involves a solid mass of tissue.
An inflammatory reaction is evoked by the dead tissue.
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Apoptosis
It is an energy-dependent process for deletion of unwanted
individual cells.
It has a role in morphogenesis, and is the mechanism for
continuing control of organ size, maintaining normal size
in the face of cell turnover, or a reduction during atrophy.
Unwanted or defective cells also undergo apoptosis
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Cell renewal
Once adult life is reached, cells can be classified
into three populations according to their potential
for renewal
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Labile cells have a good capacity to regenerate.
Surface epithelial cells are typical of this group;
they are constantly being lost from the surface and
replaced from deeper layers.
Stable cell populations divide at a very slow rate
under physiological conditions, but still retain the
capacity to divide when necessary. Hepatocytes
and renal tubular cells are good examples.
Nerve cells and striated muscle cells are regarded
as permanent because they have no effective
regeneration.
54. OVERVIEW OF INFLAMMATION
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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.
Inflammation accomplishes its protective mission by
diluting, destroying, or otherwise neutralizing harmful
agents (e.g., microbes or toxins).
Thus, inflammation is also intimately interwoven with
repair processes whereby damaged tissue is replaced
by the regeneration of parenchymal cells, and/or by
filling of any residual defect with fibrous scar tissue
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Although inflammation helps clear infections and,
along with repair, makes wound healing possible,
both inflammation and repair have considerable
potential to cause harm.
Thus, inflammatory responses are the basis of life-
threatening anaphylactic reactions to insect bites or
drugs, as well as of certain chronic diseases such
as rheumatoid arthritis and atherosclerosis.
56. Figure 2-1 The components of acute and chronic inflammatory responses: circulating cells and
proteins, vascular wall cells, and the cells and matrix elements of the extravascular connective tissue.
Cells and proteins are not drawn to scale. 2/16/2023
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While the inflammatory response involves a complex set of
highly orchestrated events, the broad outlines of inflammation
are as follows.
An initial inflammatory stimulus triggers the release of
chemical mediators from plasma or connective tissue cells.
Such soluble mediators, acting together or in sequence, amplify
the initial inflammatory response and influence its evolution by
regulating the subsequent vascular and cellular responses.
The inflammatory response is terminated when the injurious
stimulus is removed and the inflammatory mediators have been
dissipated, catabolized, or inhibited.
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Inflammation is divided into two basic patterns.
Acute inflammation is of relatively short duration,
lasting from a few minutes up to a few days, and is
characterized by fluid and plasma protein
exudation and a predominantly neutrophilic
leukocyte accumulation.
Chronic inflammation is of longer duration (days
to years) and is typified by influx of lymphocytes
and macrophages with associated vascular
proliferation and scarring.
basic forms of inflammation can overlap,
59. ACUTE INFLAMMATION
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Acute inflammation is the immediate and early
response to injury designed to deliver leukocytes to
sites of injury.
Once there, leukocytes clear any invading microbes
and begin the process of breaking down necrotic
tissues.
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This process 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)
61. Figure 2-2 The major local manifestations of acute inflammation: (1) vascular dilation (causing erythema and
warmth), (2) extravasation of plasma fluid and proteins (edema), and (3) leukocyte emigration and accumulation
in the site of injury.
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The cascade of events in acute inflammation is
integrated by local release of chemical mediators.
The vascular changes and cell recruitment account for
three of the five classic local signs of acute
inflammation: heat (calor), redness (rubor), and
swelling (tumor).
The two additional cardinal features of acute
inflammation, pain (dolor) and loss of function
(functio laesa), occur as consequences of mediator
elaboration and leukocyte-mediated damage.
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Vascular Changes
A. Changes in Vascular Caliber and Flow
After transient (seconds) vasoconstriction, arteriolar
vasodilation occurs, 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
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Subsequently, the microvasculature becomes more
permeable, resulting in the movement of protein-
rich fluid into the extravascular tissues. This causes
the red blood cells to become effectively more
concentrated, thereby increasing blood viscosity
and slowing the circulation. These changes are
reflected microscopically by numerous dilated
small vessels packed with erythrocytes, a process
called stasis.
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As stasis develops, leukocytes (principally
neutrophils) begin to settle out of the flowing
blood and accumulate along the vascular
endothelial surface, a process called margination.
After adhering to endothelial cells, the leukocytes
squeeze between them and migrate through the
vascular wall into the interstitial tissue.
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B. Increased Vascular Permeability.
In the earliest phase of inflammation, arteriolar vasodilation
and augmented blood flow increase intravascular hydrostatic
pressure and the movement of fluid from capillaries. This fluid,
called a transudate, is essentially an ultrafiltrate of blood
plasma and contains little protein.
However, transudation is soon eclipsed by increasing vascular
permeability that allows the movement of protein-rich fluid and
even cells into the interstitium (called an exudate).
The loss of protein-rich fluid into the perivascular space
reduces the intravascular osmotic pressure and increases the
osmotic pressure of the interstitial fluid.
The net result is outflow of water and ions into the
extravascular tissues; this fluid accumulation is called edema
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Acute inflammation induces leakiness of endothelial
monolayers by a number of pathways;
1.Endothelial cell contraction leads to intercellular gaps in
venules. The most common form of increased vascular
permeability, endothelial cell contraction is a reversible
process elicited by histamine, bradykinin, leukotrienes,
and many other classes of chemical mediators.
is usually short-lived (15 to 30 minutes);
Only those endothelial cells lining small postcapillary
venules undergo contraction; endothelium in capillaries
and arterioles is unaffected-presumably due to fewer
receptors for the relevant chemical mediators.
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Endothelial cell retraction is another reversible
mechanism resulting in increased vascular
permeability. Cytokine mediators (including tumor
necrosis factor [TNF] and interleukin 1 [IL-1])
induce a structural reorganization of the
endothelial cytoskeleton, so that cells retract from
each other and cell junctions are disrupted.
In contrast to the immediate transient response,
endothelial retraction takes 4 to 6 hours to develop
after the initial trigger and persists for 24 hours or
more.
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2. Direct endothelial injury results in vascular leakage by
causing endothelial cell necrosis and detachment.
This effect is usually seen after severe injuries (e.g.,
burns or infections),
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3. Leukocyte-dependent endothelial injury may occur as
a consequence of leukocyte accumulation during the
inflammatory response.
such leukocytes may release toxic oxygen species
and proteolytic enzymes, which then cause endothelial
injury
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4. Leakage from new blood vessels. tissue repair involves
new blood vessel formation (angiogenesis). These
vessel sprouts remain leaky until proliferating
endothelial cells differentiate sufficiently to form
intercellular junctions.
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Cellular Events
The sequence of events in the extravasation of leukocytes from
the vascular lumen to the extravascular space is divided into
(1) margination and rolling,
(2) adhesion and transmigration between endothelial cells, and
(3) migration in interstitial tissues toward a chemotactic stimulus
.
Rolling, adhesion, and transmigration are mediated by the
binding of complementary adhesion molecules on leukocytes
and endothelial surfaces.
74. Figure 2-5 Sequence of events in leukocyte emigration in inflammation. Laminar blood flow and the presence of red blood cells
tend to push leukocytes against the venular wall, increasing their contact with endothelial cells (see the capillary branch at the top
with cells entering the venule flow). The leukocytes (1) roll, (2) arrest and adhere to endothelium, (3) transmigrate through an
intercellular junction and pierce the basement membrane, and (4) migrate toward chemoattractants released from a source of
injury. The roles of selectins, activating agents, and integrins are also indicated.
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Chemotaxis and Activation
After extravasating from the blood, leukocytes migrate
toward sites of injury along a chemical gradient in a
process called chemotaxis.
Both exogenous and endogenous substances can be
chemotactic for leukocytes, including
(1) soluble bacterial products, particularly peptides with N-
formylmethionine termini;
(2) components of the complement system, particularly C5a;
(3) products of the lipoxygenase pathway of arachidonic
acid (AA) metabolism, particularly leukotriene B4 (LTB4)
(4) cytokines, especially those of the chemokine family (e.g.,
IL-8).
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Phagocytosis and Degranulation
Phagocytosis and the elaboration of degradative
enzymes are two major benefits of having recruited
leukocytes at the site of inflammation.
Phagocytosis consists of three distinct but interrelated
steps
(1) recognition and attachment of the particle to the
ingesting leukocyte;
(2) engulfment, with subsequent formation of a
phagocytic vacuole; and
(3) killing and degradation of the ingested material.
78. Figure 2-10 A, Phagocytosis of a particle (e.g., a bacterium) involves (1) attachment and binding of
opsonins (e.g., collectins, or C3b and the Fc portion of immunoglobulin) to receptors on the leukocyte
surface, followed by (2) engulfment and (3) fusion of the phagocytic vacuole with granules
(lysosomes), and degranulation. Note that during phagocytosis, granule contents may be released
extracellularly. B, Summary of oxygen-dependent bactericidal mechanisms within the phagolysosome.
MPO, myeloperoxidase, NADP+ and NADPH, oxidized and reduced forms, respectively, of
nicotinamide adenine dinucleotide phosphate.
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Recognition and attachment of leukocytes to most
microorganisms is facilitated by serum proteins
generically called opsonins; opsonins bind specific
molecules on microbial surfaces and in turn facilitate
binding with specific opsonin receptors on leukocytes.
The most important opsonins are immunoglobulin G
(IgG) molecules (specifically the Fc portion of the
molecule),
Binding of opsonized particles triggers engulfment; in
addition, IgG binding to FcR induces cellular
activation that enhances degradation of ingested
microbes.
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The final step in the phagocytosis of microbes is killing
and degradation. Microbial killing is accomplished largely
by reactive oxygen species.
Phagocytosis stimulates an oxidative burst characterized
by a sudden increase in oxygen consumption, glycogen
catabolism (glycogenolysis), increased glucose oxidation,
and production of reactive oxygen metabolites.
Superoxide is then converted by spontaneous
dismutation into hydrogen peroxide (
+ 2H+ → H2O2).
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However, the lysosomes of neutrophils (called
azurophilic granules) contain the enzyme
myeloperoxidase (MPO), and in the presence of a
halide such as Cl-, myeloperoxidase converts H2O2
to HOCl· (hypochlorous radical).
HOCl· is a powerful oxidant and antimicrobial
agent (NaOCl is the active ingredient in chlorine
bleach) that kills bacteria by halogenation
The dead microorganisms are then degraded by the
action of the lysosomal acid hydrolases.
82. Chemical Mediators of Inflammation
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Vasoactive Amines
A. Histamine is widely distributed in tissues,
particularly in mast cells adjacent to vessels,
although it is also present in circulating basophils
and platelets.
Preformed histamine is stored in mast cell
granules and is released in response to a variety
of stimuli.
histamine causes arteriolar dilation and is the
principal mediator of the immediate phase of
increased vascular permeability
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Plasma Proteases
A. Kinin system activation leads ultimately to the
formation of bradykinin from its circulating
precursor.
Like histamine, bradykinin causes increased vascular
permeability, arteriolar dilation, and bronchial
smooth muscle contraction
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B. clotting system
C. The complement system consists of a cascade of plasma
proteins that play an important role in both immunity and
inflammation.
They function in immunity primarily by ultimately
generating a pore like membrane attack complex (MAC)
that effectively punches holes in the membranes of
invading microbes.
In the process of generating the MAC, a number of
complement fragments are produced, including C3b
opsonins as well as fragments that contribute to the
inflammatory response by increasing vascular permeability
and leukocyte chemotaxis.
86. Figure 2-13 Overview of complement activation pathways. The classic pathway is initiated by C1
binding to antigen-antibody complexes; the alternative pathway is initiated by C3b binding to various
activating surfaces, such as microbial cell walls. The C3b involved in the initiation of the alternative
pathway may be generated in several ways, including spontaneously, by the classic pathway, or by the
alternative pathway itself (see text). Both pathways converge and lead to the formation of inflammatory
complement mediators (C3a and C5a) and the membrane attack complex. Bars over the letter
designations of complement components indicate enzymatically active forms; dashed lines indicate
proteolytic activities of various components. IgG, immunoglobulin G; IgM, immunoglobulin M.
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Arachidonic Acid Metabolites: Prostaglandins,
Leukotrienes, and Lipoxins
Products derived from the metabolism of AA affect a
variety of biologic processes, including
inflammation and hemostasis.
They can be thought of as short-range hormones that
act locally at the site of generation and then rapidly
spontaneously decay, or are enzymatically
destroyed.
88. Figure 2-14 Generation of arachidonic acid metabolites and their roles in inflammation.
Note the enzymatic activities whose inhibition through pharmacologic intervention blocks
major pathways (denoted with a red ×). COX-1, COX-2, cyclooxygenase 1 and 2; HETE,
hydroxyeicosatetraenoic acid; HPETE, hydroperoxyeicosatetraenoic acid.
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Cytokines
Cytokines are polypeptide products of many cell
types (but principally activated lymphocytes and
macrophages) that modulate the function of other
cell types.
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Nitric Oxide and Oxygen-Derived Free Radicals
NO plays multiple roles in inflammation , including
(1) relaxation of vascular smooth muscle
(vasodilation),
(2) antagonism of all stages of platelet activation
(adhesion, aggregation, and degranulation),
(3) reduction of leukocyte recruitment at
inflammatory sites, and
(4) action as a microbicidal agent (with or without
superoxide radicals) in activated macrophages.
92. Figure 2-17 Sources and effects of nitric oxide (NO) in inflammation. Note NO synthesis by endothelial
cells (mostly via endothelial cell [type III] NO synthase [eNOS], left) and by macrophages (mostly via
inducible [type II] NO synthase [iNOS], right). NO causes vasodilation and reduces platelet and leukocyte
adhesion; NO free radicals are also cytotoxic to microbial and mammalian cells. 2/16/2023
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94. Outcomes of Acute Inflammation
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acute inflammation generally has one of three
outcomes
1. Resolution.
2. Scarring or fibrosis ; results after substantial
tissue destruction or when inflammation occurs
in tissues that do not regenerate.
3. Progression to chronic inflammation
95. CHRONIC INFLAMMATION
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Chronic inflammation can be considered to be
inflammation of prolonged duration (weeks to
months to years) in which active inflammation,
tissue injury, and healing proceed simultaneously.
In contrast to acute inflammation, which is
distinguished by vascular changes, edema, and a
largely neutrophilic infiltrate, chronic
inflammation is characterized by the following
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Infiltration with mononuclear ("chronic
inflammatory") cells, including macrophages,
lymphocytes, and plasma cells
Tissue destruction, largely directed by the
inflammatory cells
Repair, involving new vessel proliferation
(angiogenesis) and fibrosis
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Chronic inflammation arises in the following settings:
1. Viral infections. Intracellular infections of any kind typically
require lymphocytes (and macrophages) to identify and
eradicate infected cells.
2. Persistent microbial infections, most characteristically by a
selected set of microorganisms including mycobacteria
(tubercle bacilli), Treponema pallidum (causative organism of
syphilis), and certain fungi. These organisms are of low direct
pathogenicity, but typically they evoke an immune response
called delayed hypersensitivity ,which may culminate in a
granulomatous reaction.
3. Prolonged exposure to potentially toxic agents. Examples
include nondegradable exogenous material 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
4. Autoimmune diseases, in which an individual develops an
immune response to self-antigens and tissues
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Macrophages
Constituting the critical mainstay and heart of chronic
inflammation, macrophages are tissue cells that derive
from circulating blood monocytes after their
emigration from the bloodstream.
Macrophages, normally diffusely scattered in most
connective tissues, may also be found in increased
numbers in organs such as the liver (where they are
called Kupffer cells), spleen and lymph nodes (called
sinus histiocytes), central nervous system (microglial
cells), and lungs (alveolar macrophages).
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In these sites, macrophages act as filters for
particulate matter, microbes, and senescent cells
(the so-called mononuclear phagocyte system), as
well as acting as sentinels to alert the specific
components of the immune system (T and B
lymphocytes) to injurious stimuli
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The half-life of circulating monocytes is about 1
day; under the influence of adhesion molecules and
chemotactic factors, they begin to emigrate at a site
of injury within the first 24 to 48 hours after onset
of acute inflammation, as described previously.
When monocytes reach the extravascular tissue,
they undergo transformation into the larger
macrophages now capable of substantial
phagocytosis
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After activation, macrophages secrete a wide variety of
biologically active products, that, if unchecked, can result
in the tissue injury and fibrosis characteristic of chronic
inflammation.
These products include;
A. Acid and neutral proteases. Recall that the latter were
also implicated as mediators of tissue damage in acute
inflammation.
B. Complement components and coagulation factors.
C. Reactive oxygen species and NO.
D. AA metabolites (eicosanoids).
E. Cytokines, such as IL-1 and TNF, as well as a variety of
growth factors that influence the proliferation of smooth
muscle cells and fibroblasts and the production of
extracellular matrix.
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Lymphocytes, Plasma Cells, Eosinophils, and
Mast Cells.
Other types of cells present in chronic inflammation
are lymphocytes, plasma cells, eosinophils, and
mast cells
105. Figure 2-22 Macrophage-lymphocyte interactions in chronic inflammation.
Activated lymphocytes and macrophages stimulate each other, and both cell
types release inflammatory mediators that affect other cells. IFN-γ, interferon-
γ; IL-1, interleukin 1; TNF, tumor necrosis factor.
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Eosinophils are characteristically found in inflammatory
sites around parasitic infections or as part of immune
reactions mediated by IgE, typically associated with
allergies.
Mast cells are sentinel cells widely distributed in
connective tissues throughout the body and can participate
in both acute and chronic inflammatory responses. Mast
cells are "armed" with IgE to certain antigens.
When these antigens are subsequently encountered, the
prearmed mast cells are triggered to release histamines and
AA metabolites that elicit the early vascular changes of
acute inflammation.
107. Granulomatous Inflammation
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Granulomatous inflammation is a distinctive
pattern of chronic inflammation characterized by
aggregates of activated macrophages that assume
a squamous cell-like (epithelioid) appearance.
Granulomas are encountered in relatively few
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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Granulomas can form in the setting of persistent T-cell responses
to certain microbes (such as Mycobacterium tuberculosis,
Treponema pallidum causing the syphilitic gumma, or fungi),
where T-cell-derived cytokines are responsible for persistent
macrophage activation
Notably, granuloma formation does not always lead to
eradication of the causal agent, which is frequently resistant to
killing or degradation. Nevertheless, the formation of a
granuloma effectively "walls off" the offending agent and is
therefore a useful defense mechanism.
