Inflammation

Addishiwot Tadesse(MD)
Pathologist

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Definition: Inflammation is a local response (reaction) of
living vascularized tissues to endogenous and exogenous
stimuli that cause cell injury.

The term is derived from the Latin ‘inflammare’ meaning

to burn

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Inflammation is fundamentally destined to localize and
eliminate the causative agent and to limit tissue injury.

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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The inflammatory response is closely intertwined with the
process of repair designed to regenerate the damaged tissue
and/or fill the gaps with fibrous tissue (scar).

Inflammation is a physiologic (protective)

response to injury, however inflammation & repair can be
potentially harmful

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Many tissues & cells are involved in inflammation
including the fluid & proteins of plasma, circulating cells,
blood vessels, & cellular & extracellular constituents of
connective tissue.

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Nomenclature
- The nomenclatures of inflammatory lesion are usually
indicated by the suffix 'itis‘

-Thus, inflammation of appendix is called appendicitis and

that of menings as meningitis, etc.

-However, like any rule, it has its own exceptions examples

pneumonia, typhoid fever

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Classification:

Inflammation is classified crudely based on duration of the

lesion and histologic appearances into acute and chronic
inflammation.

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 Inflammation

Acute Chronic

Acute versus chronic inflammation are

distinguished by the duration and the type of
infiltrating inflammatory cells

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Acute inflammation- is of relatively short duration (hours
to days) and is primarily characterized by exudation of fluid
and plasma proteins, as well as a neutrophilic infiltration.

Chronic inflammation is of longer duration (days to

years) and is characterized by mononuclear infiltration,
vascular proliferation and scarring

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The vascular & cellular reactions of both acute & chronic
inflammation are mediated by chemical factors that are
derived from plasma proteins or cells. And are produced in
response to or activated by the inflammatory stimulus.

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ACUTE INFLAMMATION

 Acute inflammation is an immediate and early response to

an injurious agent and it is relatively of short duration,
lasting for minutes, several hours or few days.

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Acute inflammation has three major components
1. Alteration in vascular caliber that lead to an increase in
blood flow
2. Structural changes in the microvasculature that permit
plasma proteins & leukocytes to leave the circulation
3. Emigration of the leukocytes from the microcirculation,
their accumulation in the focus of injury & their
activation to eliminate the offending agent

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 The escape of fluid, proteins & blood cells from vascular
system into the interstitial tissue or body cavities is known
as exudation

 Exudate – is an inflammatory extravascular fluid that has

a high protein concentration, cellular debris &
a specific gravity above 1.020.
-It implies an alteration in the normal permeability of
small blood vessels in the area of injury.

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 Transudate is a fluid with low protein content & a specific
gravity of less than 1.012.
-It results from osmotic or hydrostatic imbalance across the
vessel wall without an increase in vascular permeability

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The five cardinal signs of acute inflammation are

 Redness (rubor) due to dilation of small blood vessels

 Heat (calor) results from increased blood flow
(hyperemia) with accompanying regional vascular dilation
 Swelling (tumor) due to accumulation of fluids in the
extra vascular space as part of the fluid exudates (edema).

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 Loss of function
 Pain (dolor), it partly results from the stretching &
destruction of tissues due to inflammatory edema and in
part from pus under pressure in as abscess cavity. Some
chemicals of acute inflammation, including
bradykinins, prostaglandins and serotonin are known to
induce pain.

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Acute inflammatory reactions are triggered by a variety of
stimuli
 Hypoxia
 Infections
 Trauma
 Physical & chemical agents
 Tissue necrosis
 Foreign bodies
 Immune reactions

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Events of acute inflammation

Acute inflammation is categorized into an early vascular, and a late
cellular responses

1-Vasodilation

Brief arteriolar vasoconstriction followed by vasodilation
accounts for warmth and redness
opens microvascular beds
 is induced by the action of several mediators such as histamine on
vascular smooth muscle

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Vascular leakage
Vascular dilation is quickly followed by increased
permeability of microvasculature resulting in outpouring
of protein rich fluid

As a consequence of increased vascular

permeability, the already dilated blood vessels are now
packed with red cells & slower blood flow condition called
stasis .

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Cellular response

- One of the critical function of inflammation is to deliver

leukocytes to site of injury & to activate the leukocytes to
perform their normal functions in host defense.

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Read details of cellular response ,
phagocytosis engulfement , complement
system and clotting system

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Outcomes of Acute Inflammation

1. Complete resolution

- This is the usual outcome when the injury is limited or

short-lived or when there has been little tissue
destruction & the damaged parenchymal cells can
regenerate

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2. Healing by connective tissue replacement
(fibrosis/organization)
- This occurs after substantial tissue destruction, when the
inflammatory injury involves tissues that are incapable of
regeneration or when there is abundant fibrin exudation

3. Abscess formation – Pyogenic infections may cause intense

neutrophilic infiltration & liquefaction of tissues.

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4. Progression of the tissue response to chronic
inflammation

- Acute to chronic transition occurs when the acute

inflammatory response cannot be resolved due to either
persistence of the injurious agent or some interference with
the normal process of healing.

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Morphologic Patterns of Acute Inflammation

 The severity of the reaction, its specific cause & the

particular tissue & site involved cause variation in
morphologic patterns
Serous inflammation
It is an outpouring of a thin fluid that is derived from
either the blood serum or secretion of mesothelial cells
lining the peritoneal, pleural and pericardial cavities. It
resolves without reactions
Eg – skin blister resulting from burn or viral infection

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Fibrinous inflammation
- More severe injuries result in greater vascular permeability
that ultimately lead to exudation of larger molecules such
as fibrinogens, etc through vascular barrier.

- Fibrinous exudate is a characteristic of inflammation in

serous body cavities such as the pericardium and pleura.

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Course of fibrinous inflammation include
-Resolution by fibrinolysis
- Scar formation between parietal and visceral surfaces
hence, the exudates get organized
Eg -fibrous strands formations that bridge the pericardial
space.

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Suppurative or purulent inflammation
- This type of inflammation is characterized by the
production of large amount of pus .
- pus is a thick creamy liquid, yellowish or blood stained in
color and is composed of
 A large number of living or dead leucocytes (pus cells)
 Necrotic tissue debris
 Living and dead bacteria
 Edema fluid

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There are two types of suppurative inflammation
A) Abscess formation:
 An abscess is a circumscribed accumulation of pus in a
living tissue. It is encapsulated by a so-called pyogenic
membrane, which consists of layers of fibrin, inflammatory
cells and granulation tissues.

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B) Acute diffuse (phlegmonous) inflammation
- It is characterized by diffuse spread of the exudate
through tissue spaces caused by virulent bacteria (eg.
streptococci) without either localization or marked pus
formation. Example: cellulitis

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Catarrhal inflammation

 It is mild and superficial inflammation of the mucous

membrane.
 It is commonly seen in upper respiratory tract following
viral infections where mucous secreting glands are present
in large numbers, eg. Rhinitis.

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Pseudomembranous inflammation
 The basic elements of pseudomembranous inflammation
are extensive confluent necrosis of surface epithelium and
severe acute inflammation of the underlying tissues.

- The fibrinogens in the inflammatory tissue coagulates

within the necrotic epithelium and together with
neutrophilic polymorphs, red cells, bacteria and tissue
debris constituting the false(pseudo) membrane which
forms a white or colored layer over the surface of inflamed
mucosa.
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- Pseudomembranous inflammation is exemplified by
Dipthetric infection of the pharynx or larynx and
Clostridium difficille infection in the large bowel following
certain antibiotic use.

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Ulcers
- An ulcer is a local defect , or excavation, of the surface of
an organ or tissue that is produced by the sloughing
(shedding) of inflammatory necrotic material

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Chronic inflammation

 It can be defined as a prolonged inflammatory process

(weeks and months) where an active inflammation, tissue
destruction and attempts at repair are proceeding
simultaneously.

 It may follow acute inflammation but frequently it begins

insidiously, as smoldering , often asymptomatic response

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Causes of Chronic Inflammation

 Persistent infections
Certain microorganisms associated with intracellular
infection such as tuberculosis, leprosy, certain fungi etc
characteristically cause chronic inflammation.
These organisms are of low toxicity and evoke delayed
hypersensitivity reactions.

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 Prolonged exposure to non degradable but potentially
toxic substances either exogenous such as silica, asbestos
etc or endogenous lipid components in atherosclerosis

 Autoimmunity including rheumatoid arthritis and

systemic lupus erythematosus

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Morphologic features

 Chronic inflammation is characterized by

 Infiltration with mononuclear cells which include
macrophages, lymphocytes, & plasma cells

 Tissue destruction , induced by the persistent offending

agent or by the inflammatory cells

 Attempts at healing by connective tissue replacement of

damaged tissue, accomplished by proliferation of blood
vessels (angiogenesis) & fibrosis

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Mononuclear cell infiltration
 The macrophage is the dominant cellular player in chronic
inflammation

 Macrophages are one component of mononuclear

phagocyte system (sometimes called reticuloendothelial
system) consists of closely related cells of bone marrow
origin, including blood monocytes & tissue macrophages

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- Macrophages are diffusely scattered in the connective tissue
or located in organs such as the liver (Kupffer cells), spleen
& lymph nodes (sinus histocytes) & the lungs (alveolar
macrophages).

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 From blood, monocytes migrate into various tissues &
differentiate into macrophages.

 Circulate as monocytes and reach site of injury within 24 –

48 hrs and transform into macrophages .

 Extravasation of monocytes is governed by the same factors

as in neutrophilic migration.

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 Macrophages may be activated by variety of stimuli
 Cytokines (eg IFN γ) secreted by sensitized T lymphocytes
 Bacterial endotoxins

- Activation results in increased cell size, increased levels of

lysosomal enzymes & greater ability to phagocytose & kill
ingested microbes.

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Other cells in chronic inflammation
 Lymphocytes
- antigen stimulated lymphocytes migrate into
inflammatory sites
- cytokines from activated macrophages mainly IL-12
promote T lymphocyte response.
 Plasma cells
 develop from activated B lymphocytes & produce antibody
directed against persistent antigen in the inflammatory
site.

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 Eosinophils
– are abundant in immune reactions mediated by Ig E & in
parasitic infections.
 Mast cells

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Classification of chronic inflammation based on histologic
features
 Non specific-chronic inflammation, which usually
results from suppurative inflammation. It involves a diffuse
accumulation of macrophages and lymphocytes at site of
injury that is usually productive with new fibrous tissue
formations

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Specific inflammation (Granulomatous
inflammation)
Definition: Granulomatous inflammation is a distinctive
pattern of chronic inflammatory reaction in which the
predominant cell type is an activated macrophages, with a
modified epithelial like epitheloid cells and multinucleated
giant cell.

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 A granuloma in turn is defined as focal area of
granulomatious inflammation with an accumulation of
modified macrophages (epitheloid cells) arranged in small
clusters or nodular collections surrounded by a cuff of
lymphocytes and occasional plasma cells.
 In H&E stained tissue sections, epitheloid cells have a pale
pink granular cytoplasm with indistinct cell boundaries .
The nucleus is oval to elongate & may show folding of the
nuclear membrane

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- Epitheloid cells fuse to form giant cells. They have a large
mass of cytoplasm containing 20 or more nuclei arranged
either peripherally(Langhans-type giant cells) or
haphazardly (foreign body- type giant cells)

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 There are two types of granulomas
Foreign body granuloma are induced by inert foreign
bodies such as sutures. The foreign body is too large o be
phagocytosed by a single macrophage & do not incite any
specific immune response . Epitheliod cells & giant cells
form & encompass the foreign body.

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Immune granuloma are caused by insoluble particles,
typically microbes, that are capable of inducing a cell
mediated immune response
The protype of immune granuloma is tuberculosis.
It is characterized by presence of central caseous necrosis

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Major causes of granulomatious inflammation include

A) Bacterial: Tuberculosis, Leprosy, Syphilis, Cat scratch

disease, Yersiniosis
B) Fungal: Histoplasmosis, Cryptococcosis,
Coccidiodomycosis , Blastomycosis
C) Helminthic: Schistosomiasis
D) Protozoal: Leishmaniasis, Toxoplasmosis
E) Chlamydia: Lymphogranuloma venerum
F) Inorganic material: Berrylosis
G) Idiopathic: Cohn’s disease, Primary biliary cirrhosis
giant cells are formed

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Systemic effects of inflammation
 The systemic changes associated with inflammation ,
especially in patients who have infections, are collectively
called the acute phase response or the systemic
inflammatory response syndrome (SIRS).

 These reactions are response to cytokines whose

production is stimulated by bacterial products

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 Fever
 It is one of the most prominent manifestations of the acute
phase response

- Characterized by an elevation of body temperature usually

by 1 to 4 degree centigrade

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 Bacterial products stimulate leukocytes to release cytokines
such as IL-1 & TNF (endogenous pyrogens) that increase
the enzymes (cyclooxygenase) that convert AA into
prostaglandins .

 In the hypothalamus, the prostaglandins (PGE2) stimulate

the production of neurotransmitters such as cyclic AMP ,
which function to reset the temperature set point at a
higher level

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 Leukocytosis
 Leucocytosis is also a common feature of inflammation
especially in bacterial infections. Its usual count is 15,000to
20,000cell/mm2. But sometimes it may reach extraordinary
high levels of 40,000 to 100,000cells/μl referred as
leukemoid reaction
 The number of immature neutrophils also may rise – “shift
to the left”

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Most bacterial infections induce neutrophillia.
Some viral infections - infectious mononucleosis, mumps,
measles cause lymphocytosis.
Bronchial asthma, hay fever, and parasitic infestation
induce eosinophilia.
Leukopenia is a feature of typhoid fever and some parasitic
infections

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 Acute phase proteins
 These are plasma proteins , mostly synthesized in the liver,
whose plasma concentration may increase as a part of the
response to inflammatory response.

 Most acute phase proteins bind to microbial surface &

serve as opsonin & fix complement

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 Best examples include
 C- reactive protein
protein found in the blood, the levels of which rise in
response to inflammation

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 Fibrinogen – The rise in fibrinogen causes erythrocytes to
form stacks that sediment more rapidly at a gravity than do
individual erythrocytes.

 This is the basis for measuring erythrocyte sedimentation

rate (ESR) as a simple test for the systemic inflammatory
response caused by any number of stimuli.

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 Serum amyloid A potein (SAA) – it causes secondary
amyloidosis in chronic inflammation
- Other manifestation of acute phase response include
increased pulse & blood pressure , anorexia & malaise

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