PATHOLOGY OF ACUTE AND CHRONIC INFLAMMATION

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PATHOLOGY OF ACUTE AND CHRONIC INFLAMMATION
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Inflammation is the immune response to tissue
injury, infectious or non-infectious. Tissue
injury may be the result of an severe bacterial
infection, infarction, burns or trauma. The
focus of the inflammatory process is a regulatory
event with the purpose of mobilizing various
innate immune effectors and trafficking them to
the appropriate anatomical location where they
can be more effective.
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Acute Inflammatory response
The acute inflammatory response may be localized
or systemic. A localized event happens, for
example, after a tissue injury, caused by trauma,
which serves as a part of entry to many
microorganisms. The local inflammatory site
quickly recruits many innate immune cells such as
neutrophils and macrophages from the local blood
vessels to the site of the injury or infection.
In order to kill the invading bacteria or to
promote tissue repair.
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Acute Inflammatory response
The inflammatory response is the result of
hemodynamic changes of small blood vessels near
the site o the injury or infection and the
arrival of neutrophils and macrophages through
diapedesis. Humoral innate components are
important participants in this process. The
vascular endothelium at the injured site becomes
leaky and the elevated pressure inside blood
vessels results in seepage of the plasma. The
plasma is rich in complement proteins and
contains the proteins of the blood clotting
cascade and plasma system. Through a network of
cytokines and cell receptors all the humoral
innate components and cell effectors become
activated.
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Acute dermatitis and cellulitis.
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Fig. 2.11- Localized Inflammatory Response
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The Kinin cascade produces vasoactive systides
that increase vascular permeabilitys and can
activate the complement cascade. The plasmin
cascade is important in remodeling extracellular
matrix during wound healing and also can activate
complement. Most cells degranulate when they are
activated releasing histamine which causes
increased vascular permeability.
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Activated complement especially the C5A protein
has a potent chemotactic activity attracting
neutrophils, macrophages and lymphocytes to the
inflammatory site. Bacterial products activate
macrophages which also secrete cytokines that
participate in chemotaxis
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MORPHOLOGIC PATTERNS OF ACUTE INFLAMMATION
Acute inflammatory response is a pathologic
process of relatively short duration which may
last from a few minutes to several hours or days.
The severity of the inflammatory response, the
etiology and the type of tissue involved
determine the histopathologic pattern of a given
lesion. Usually acute inflammation is associated
with an exudate composed of serum and/or plasma
and large number of neutrophils. However, there
are some exceptions such as acute viral or
parasitic infections when the cellular infiltrate
is composed respectively by lymphocytes and
eosinophils. The intensity of the inflammatory
response depends on the virulence and number of
pathogens, the severity and extent of tissue
injury and the clinical condition of the host.
These tissue responses originate different types
of inflammatory lesions, which are listed below
in order of severity.
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Vascular response only
Mild inflammatory episode. The patient notices a
localized red area on the skin surface that feels
warm and blanches under pressure (i.e.,
scratching the skin surface). The tissue response
is vasodilatation (vasomotor response).
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Serous inflammation
It is triggered by agents causing mild damage to
blood vessel walls and cytokines associated with
increased vascular permeability. There is
production of exudate which is composed of watery
fluid containing very little protein. Depending
on the inflammatory site the exudate accumulates
serum in tissues (skin blister caused by a mild
burn) or in natural cavities like the pericardial
sac, pleural or peritoneal cavities (eg. Pleural
effusion, ascitis) originated by the secretion of
reactive mesothelial cells.
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Vesicles in both lips containing serous exudate
in a case of herpes.
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Biopsy from the same lesion showing a vesicle in
the epidermis containing serous exudate and
necrotic epithelial cells.
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Fibrinous inflammation
The injury is more severe and the damage to blood
vessel walls is more extensive with increased
vascular permeability. Plasma proteins including
fibrinogen, leak from the blood vessels into
interstitial spaces, and the fibrinogen clots
into fibrin. Histologically the exudate is
composed of a mesh of eosinophilic strands and
very few neutrophils and sometimes as an
amorphous clot.
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Normal heart
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Fibrinous pericarditis.Notice the velvety
appearance of the epicardial surface due to the
fibrinous exudate
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Histology of the same lesion.Band of fibrinous
exudate at the top of the slide.
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Same section at higher magnification.
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Fibrinous exudate
The fibrinous exudate may be degraded by
fibrinolysis and eventually removed by
macrophages restoring the normal tissue structure
(resolution). If the macrophages fail to
completely remove the fibrin the latter is
infiltrated by newly formed blood vessels and
fibroblasts resulting in scar formation
(organization). If the fibrinous exudate is
present for example in the pleural cavity the
process may end with the formation of dense scar
tissue that bridges and obliterates the pleural
cavity (fibrous adhesions).
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Purulent or suppurative inflammation
It is the result of a severe inflammatory insult,
and the resulting exudate is composed mainly by a
large number of neutrophils (purulent exudate).
Many neutrophils die or degenerate in the
inflamed area, releasing their lysosomal granules
and causing tissue necrosis. The gelatinous
mixture of a large number of neutrophils, many of
them degenerated, necrotic tissue debris, and
fibrinous material is called pus. Some
microorganisms such as Staphylococci are
typically pus producers (pathogens).
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Normal lung tissue. Notice the clear alveolar sacs
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Acute bronchopneumonia. The alveolar sacs are
filled with neutrophils.
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Similar lesion at higher magnification.
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Persistent suppuration.Abcess formation.
Persistent injurious stimuli may occasionally
cause a chronic inflammatory response that is
purulent rather than no specific or granulomatous
(persistent suppuration) like actinomycosis. If
the purulent inflammation is associated with a
large amount of exudate and tissue necrosis, a
cavity is formed where the pus is collected
(pyogenic abscess). Abscesses may form in the
parenchyma of major internal organs or soft
tissues. They tend to expand at the periphery by
progressive necrosis and digestion of adjacent
tissues, may drain spontaneously outside the
body, or may burrow through adjacent tissues,
emptying its content into a natural cavity (e.g.,
pleural cavity) or the lumen of a nearby organ
(sinus or fistulous tract).
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Normal lung. The reflexion of the light
indicates a normal pleural surface.
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Acute bronchopneumonia with abcess formation
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Closer view of the same specimen. Notice the
abcess cavity.
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Histology of the same lesion.Abcess cavity at
center lined by necrotic lung tissue.
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Content of the abcess. Purulent exudate.
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Pathogenesis of septicemia.
The treatment of an abscess is by draining its
contents. Otherwise the purulent exudate is
infiltrated by granulation tissue followed by and
scar formation. Abscesses should be aggressively
treated otherwise the patient may develop serious
systemic complications such as bacteriemia,
septicemia, and eventually septic shock. They may
also linger as a chronic inflammatory process.
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Left brain abcess. Bottom of the slide.
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Spleen showing several large pyogenic abcesses.
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Eosinophils. Notice the orange granules and
bilobar nuclei.
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Eosinophilia. Large number of eosinophils in
pleural fluid.
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Necrotizing or gangrenous inflammation
It is the most severe of all inflammatory
responses, and may have a fatal outcome. Gangrene
is the result of massive coagulation necrosis of
tissues caused by bacteria and/or bacterial
toxins. When it happens in a hollow viscus like
the appendix, it is followed by perforation,
acute peritonitis and eventually shock.
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Gangrenous 3rd and 5th toes.
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Tissue section from the previous lesion.Massive
coagulation necrosis of skin and underlying soft
tissues.
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Ulceration
It results from necrosis caused by an acute
inflammatory episode involving the mucosal lining
or surface of an organ. This is followed by the
sloughing of the necrotic tissue and the
formation of a crater. Ulcers may be the result
of bacterial or fungal infection, tissue injury
by chemical or physical agents and ischemia. They
may be deep or shallow, depending on the nature
of the injurious agent and the length of the
inflammatory process. Ulcerations may heal either
by resolution with no sequelae or by leaving
behind a crater lined by fibrous tissue.
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Perforated gastric ulcer close to the
esophagus(see probe).The whitish lining is the
esophageal mucosa.
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Pseudomembranous inflammation
It occurs mainly in the mucosal surface of the
respiratory and alimentary tracts and is caused
by microorganisms such as Clostridium dificile
and Corynebacterium diphtheriae. The
pseudomembrane (not a true tissue membrane) lies
on the mucosal surface of the affected organ (for
example, intestine) and is composed of fibrin
strands, neutrophils, and necrotic epithelial
cells. Pseudomembrane formation generally
reflects the action of bacterial toxins upon
mucosal surfaces.
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Pseudomembranous colitis.The brownish fragments
on the mucosal surface are the pseudomembranes.
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Histology of the previous specimen.The loose
fragment is the pseudomembrane.
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The Systemic Inflammatory Response takes place
when the tissue injury is too severe or when a
large number of microorganisms are present at the
inflammatory site. This innate response requires
the participation of organs and tissues that are
remote from the site of injury. This systemic
response is known as the acute phase response,
which is generalized and remarkably
consistent. Acute phase clinical reactions also
occurs in chronic infections as well as in toxic,
traumatic and immunological disorders.
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Fig. 2.14-Systemic Inflammatory Response
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The acute response increases production of
effectors consumed during inflammation, such as
granulocytes and complement components. The
former is initiated mainly by the inflammatory
cytokines IL1, TN alpha and IL6.
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Fever
Fever is the most prominent and readily measured
systemic reaction of inflammation. The
thermoregulatory center is in the hypothalamus.
Humans are very sensitive to the pyrogenic
activity of bacterial endotoxins. Endotoxins
stimulate the secretion of IL-1, which in turn
acts on the thermoregulatory center through the
induction of local prostaglandin (PGE)
production. Besides endotoxins, fever may be
caused by gram-positive and negative bacteria,
fungi and viruses.
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Leukocytosis
Leukocytosis is a common systemic reaction of
inflammation. Leukocytosis means an increased
number of polymorphonuclear and mononuclear white
blood cells in the peripheral blood. The normal
leukocyte count is between 5,000 and 10,000
cells/mm3. In acute inflammation the count
usually climbs to 15,000 to 20,000 cells/mm3 and
sometimes over 40,000 cells (leukemoid reaction).
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Pathogenesis of leukocytosis
Leukocytosis results initially from the release
of cells from the bone marrow induced by ILl and
TNF. In chronic infection, proliferation of bone
marrow precursors are also induced. Leukocytosis
is usually selective. In bacterial infections
there is usually an increase of neutrophils, in
parasitic infections and allergic conditions
eosinophilia and in viral infections like
infectious mononucleosis or mumps
lymphocytosis. Certain infections, like typhoid
fever or infections caused by certain viruses and
protozoa, are associated with a lower number of
white cells (leukopenia).
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Acute-phase reactant proteins
These proteins are synthesized in the liver.
IL-1, acting in concert with stress hormones like
corticosteroids, stimulates the synthesis of
fibrinogen and C-reactive protein, while there is
a decrease in albumin synthesis. Reactant
proteins are especially useful in monitoring the
progress or detecting new bouts of acute
inflammation during the course of prolonged
chronic conditions such as rheumatoid
arthritis. The SAA protein binds to the
bacterial acting as opsonins. They can also fix
complement. In prolonged chronic inflammatory
processes markedly elevated SAA may cause
systemic amyloidosis.
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Protein catabolism
In certain long-standing chronic conditions
(tuberculosis, brucellosis), IL-1 induces the
catabolism of proteins in the host, associated
with a net loss of nitrogen, loss of body mass,
and muscle wasting. The proteins particularly
involved are those containing phenylalanine,
tyrosine and tryptophan, which are utilized in
the synthesis of antibodies and interleukins.
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Sequestration of plasma iron within Lepatocytes
leading to hypoferremia.
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MORPHOLOGIC PATTERNS OF CHRONIC INFLAMMATION
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Chronic nonspecific inflammation
It is by far the most common. The affected
tissues are infiltrated mainly by lymphocytes and
macrophages. Plasma cells may also be present.
When a chronic inflammatory response follows an
acute episode, part of the preceding neutrophilic
infiltrate may persist among the chronic
inflammatory cells.
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Chronic nonspecific inflammatory exudate. The
dark round cells are lymphocytes.The cells with
clear nuclei are macrophages (see arrow).
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Similar tissue section at higher magnification.
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Chronic pyelonephritis.Sheets of lymphocytes and
macrophages are infiltrating renal tissue
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Chronic persistent suppuration
Persistent injurious stimuli can occasionally
originate inflammatory conditions that are
purulent in nature, such as actinomycosis and
chronic osteomyelitis Suppuration is also seen
when superimposed bouts of acute inflammation
take place at the inflammatory site. Stones
present in the biliary tree (cholelithiasis) may
elicit this type of response.
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Plasmacytic and eosinophilic exudate
In many instances a chronic inflammatory
exudateis is composed mainly by plasma cells as
in chronic osteomyelitis or inflamed nasal
polyps. When a given patient is infected with
parasites, there is an increased number of
eosinophils in the peripheral blood and in the
affected tissues. Tissue eosinophilia is also
seen in acute and chronic hypersensitivity
reactions under the influence of cytokines
secreted by mast cells.
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Plasma cell infiltrate.Notice the eccentric
nuclei, basophilic cytoplasm and binucleated
cells.
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Granulomatous inflammation
A granuloma consists of localized, tight
aggregates of epithelioid cells(activated
macrophages). They develop after prolonged
antigenic stimulation. Epithelioid cells are
large, with a pale, granular eosinophilic
cytoplasm resembling squamous cells. Often
granulomas are surrounded by a collar of
lymphocytes and occasionally plasma cells.
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Morphology of Granulomas.
Very frequently, but not invariably, epithelioid
cells fuse to form giant cells at the periphery
or sometimes at the center of the granuloma.
Giant cells may measure up to 40 to 50 microns
and consist of a large mass of cytoplasm
containing several nuclei arranged either
peripherally (Langhans cell type) which are often
seen in tuberculosis, or scattered at random
throughout the cytoplasm (foreign body giant
cell). The cytoplasm of multinucleated giant
cells may contain foreign body material such as
ferruginous asbestos bodies, cytoplasmic
inclusions like Schaumann and asteroid bodies
(seen in sarcoidosis), and phagocytized bacteria
and fungi.
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There are two types of granulomas
Foreign body granulomas caused by relatively
inert foreign material that cannot be digested,
causing activation of macrophages. Immune
granulomas, which develop in the presence of
indigestible microorganisms (M tuberculosis) by
cell-mediated immune response ( adaptive or
specific immune response).
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Diagram of the pathogenesis of an immune
granuloma.
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Epithelioid cells
Epithelioid cells have only 10 of the phagocytic
activity of non activated histiocytes .
Granulomas may heal by resolution. However, when
they are associated with tissue necrosis, they
heal via granulation tissue and scar formation.
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Normal lung.
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Left lung showing multiple caseous granulomas
(well circumscribed yellow lesions)
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Caseous granuloma showing a core of caseous
necrosis surrounded by epithelioid cells and
giant cells.
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Portion of lung showing multiple
granulomas(discret whitish nodules
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Close-up of the same specimen.
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Upper lobe of left lung showing a cystic lesion
filled with brown exudate( fungal ball).
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Close-up of the same lesion.
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Aspergillus showing 45 degrees, angulated septate
hyphae.
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Suture granulomas.The black material represent
sutures left after surgery surrounded by giant
cells and epithelioid cells.
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Talc granuloma in lung tissue(mass of
homogeneous pink material).The material in
injected endovenously by drug abusers.
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Same tissue section under polarized light.
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The etiologic agents most commonly associated
with granulomas are
Bacteria Fungus Helminthic origin Leprosy Histopla
smosis Schistosomiasis Salmonellosis
Blastomycosis Trichinosis Tuberculosis
Cryptococcosis Brucellosis Metal-induced
(foreign body) Unknown etiology Berylliosis
Sarcoidosis Silicosis Crohn disease
Wegener granulomatosis
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ROLE OF LYMPHATICS AND LYMPH NODES IN INFLAMMATION
Lymph nodes and lymphatics act as filters of the
extravascular fluids. Together with the
mononuclear phagocyte system they represent a
secondary line of defense when the local
inflammatory response fails to control the
injury. During inflammation the lymphatic flow is
increased draining edema fluid from extravascular
spaces. Lymph also may carry the causative
microbial or chemical agents and increased number
of circulating lymphocytes. Lymph channels and
lymph nodes may become secondarily inflamed
(lymphangitis and lymphadenitis).
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ROLE OF LYMPHATICS AND LYMPH NODES IN INFLAMMATION
The regional lymph nodes become enlarged due to
the proliferation and infiltration of macrophages
and lymphocytes in the nodal parenchyma (reactive
lymphadenitis).
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Pathogenesis of bacteriemia and septicemia
When this second line of defense fails due to the
virulence of the infectious agent, bacteria enter
the peripheral circulation. The phagocytic cells
of the liver, spleen and bone marrow become the
next line of defense but in overwhelming
infections bacteria seed distant tissues in the
body such as heart valves, meninges, kidneys and
joints (septicemia). Septicemia is a very serious
complication frequently followed by septic shock
and the patient's death.