Chronic Inflammation in detail

1. Chronic
Inflammati
on
Tehseen Anwar
03450743978
13-Arid-1112
Pir Mehr Ali Shah Arid
Agriculture University
By

2. Tehseen Anwar 13-Arid-1112 03450743978
INFLAMMATION
Inflammation is part of the complex biological response
of vascular tissues to harmful stimuli, such as pathogens
damaged cells, or irritants.
CARDINAL SIGNS OF INFLAMMATION
There are five cardinal signs:
1. Calor
2. Rubor
3. Dolar
4. Tumor
5. Funcito leasa
Major types of inflammation on basis of duration are:
1. ACUTE
2. CHRONIC
Acute inflammation is rapid in onset and of short duration,
lasting from a few minutes to as long as a few days, and is
characterized by fluid and plasma protein exudation and a
predominantly neutrophilic leukocyte accumulation.
Chronic inflammationmay be more insidious, is of longer
duration (days to years), and is characterized by influx of
lymphocytes and macrophages with associated vascular
proliferation and fibrosis (scarring).

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CHRONIC INFLMMATION
It is inflammation of prolonged duration(weeks to years) in
which continuing inflammation, tissue injury,and healing, often
by fibrosis, proceed simultaneously.
It is characterized by different set of reactions involved
 Infiltration with mononuclear cells, including
macrophages, lymphocytes, and plasma cells.
 Tissue destruction, largely induced by the products ofthe
inflammatory cells.
 Repair, involving new vessel proliferation (angiogenesis)
and fibrosis.

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CAUSES OF CHRONIC INFLAMMATION
Persistent infections
 Microbes that are difficult to eradicate e.g.
Mycobacterium tuberculosis, Treponema pallidum (the
causative organism of syphilis) and viruses and fungi.
 These all cause persistent infections and evoke T
lymphocyte–mediated immune responsecalled delayed-
type hypersensitivity.
Immune-mediated inflammatory diseases (hypersensitivity
Diseases)
 Diseases that are caused by excessive and inappropriate
activation of the immune system.
 Under certain conditions, immune reactionsdevelop
against the affected person’s own tissues, leading to
autoimmune diseases.
Prolonged exposure to potentially toxic agents
 Exogenous agents include silica which causes silicosis.
 Endogenous causes include atherosclerosis caused by
toxic plasma lipid componentssuchas cholesterol
crystals.
Autoimmunity
 Auto-antigens provoke self-perpetuating immune
responses that cause chronic inflammatory diseases like
RA, MS.
 Responses against common environmental substances
cause chronic allergic diseases, such as bronchial
asthma.

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CHRONIC INFLMMATORY CELLS AND
MEDIATORS
Macrophages
These are dominant cells in chronic inflammation.
Macrophages are normally diffusely scattered in most
connective tissues and are also found in organs
 Kupffer cells – liver
 Sinus Histiocytes - spleen and lymph nodes
 Alveolar Macrophages – Lungs
 Microglia – brain
Together these cells constitute the so-called mononuclear
phagocyte system, also known by the older name of
reticuloendothelial system.
Mononuclear phagocytes arise from a common precursorin the
bone marrow.
From the blood, monocytes migrate into various tissues and
differentiate into macrophages.
 The half-life of blood monocytes is about 1 day.
 The life span of tissue macrophages is several
months or years.
Tissue macrophages are activated by two major pathways:
1. Classical macrophage activation

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2. Alternative macrophage activation
Macrophages are initially activated by the classical pathway,
designed to destroy the offending agents, and this is followed
by alternative activation, which initiates tissue repair.
LYMPHOCYTE
The activation of T and B lymphocytes is part of the adaptive
immune responsein infections and immunologic diseases. Both
classes of lymphocytes migrate into inflammatory sites using
some of the same adhesion molecule pairs and chemokines that

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recruit other leukocytes.In the tissues, B lymphocytes may
develop into plasma cells, which secrete antibodies, and CD4 +
T lymphocytes are activated to secrete cytokines.
There are three subsets of CD4 + helper T cells that
secrete different sets of cytokines and elicit different types
of inflammation:
 TH1 cells producethe cytokine IFN- γ, which activates
macrophages in the classical pathway.
 TH2 cells secrete IL-4, IL-5, and IL-13, which recruit
and activate eosinophils and are responsible for the
alternative pathway of macrophage activation.
 TH17 cells secrete IL-17 and other cytokines that induce
the secretion of chemokines responsible for recruiting
neutrophils and monocytes into the reaction.
Both TH1 and TH17 cells are involved in defense against many
types of bacteria and viruses and in autoimmune diseases. TH2
cells are important in defense against helminthic parasites and
in allergic inflammation.
Macrophages display antigens to T cells and producemembrane
molecules (costimulators) and cytokines (notably IL-12) that
stimulate T-cell responses.

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Other Cells
Eosinophils
Abundant in immune reactions mediated by IgE and in parasitic
infections, recruited by eotaxinderived from leukocytes and
epithelial cells.
Granules contain major basic protein, a highly cationic protein
that is toxic to parasites but also causes lysis of host epithelial
cells.
Mast cells
Mast cells are “armed” with IgE antibody specific for
certainenvironmental antigens. When these antigens are
subsequently encountered, the IgE-coated mast cells are
triggered to release histamines and AA metabolites that elicitthe
early vascular changes of acute inflammation. IgEarmed mast

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cells are central players in allergic reactions, including
anaphylactic shock.
Neutrophils
Induced either by persistent microbes or by mediators produced
by activated macrophages and T lymphocytes.
Neutrophil exudate can persist for many months in
osteomyelitis. Cause chronic damage induced in lungs by
smoking and other irritant stimuli.
GRANULOMATOUS INFLAMMATION
Granulomatous inflammation is a distinctive pattern of
chronicinflammation characterized by aggregates of activated
macrophages with scattered lymphocytes.Granulomas can form
under three settings:
 With persistent T-cell responses to certain
microbes(Such as Mycobacterium tuberculosis, T.
pallidum, or fungi), in which T cell–derived cytokines
are responsible for chronic macrophage activation.
Tuberculosis is the prototypeof a granulomatous disease
caused by infection and should always be excluded as
the cause when granulomas are identified.
 Granulomas may also develop in some immune
mediated inflammatory diseases, notably Crohn
disease,which is one type of inflammatory bowel disease
and animportant cause of granulomatous inflammation
in theUnited States.
 They are also seen in a disease of unknown
etiologycalled sarcoidosis, and they develop in response
to relatively inert foreign bodies (e.g., suture or
splinter),forming so-called foreign bodygranulomas.

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Examples of Diseases with Granulomatous
Inflammation
SYSTEMIC EFFECTS OFINFLAMMATION
The systemic effects of inflammation, collectively called the
acute-phase reaction, or the systemic inflammatory response
syndrome. The cytokines TNF, IL-1, and IL-6 are the most
important mediators of the acute-phase reaction. These
cytokines are produced byleukocytes (and other cell types) in
responseto infection or in immune reactions and are released
systemically.
The acute-phase responseconsists of several clinical and
pathologic changes.
Fever
It is characterized by an elevation of bodytemperature, is one
of the most prominent manifestations of the acute-phase

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response. Fever is produced in responseto substances called
pyrogens that act by stimulating prostaglandin synthesis in the
vascular and perivascular cells of the hypothalamus.
Mechanism
Bacterial products such as lipopolysaccharide (LPS) (called
exogenous pyrogens) stimulate leukocytes to release cytokines
such as IL-1 and TNF (called endogenouspyrogens) which
increase thelevels of cyclooxygenases that convert AA into
prostaglandins. In the hypothalamustheprostaglandins,
especially PGE2, stimulatethe production of neurotransmitters,
which function to reset the temperature set point at a
higherlevel.
NSAIDs (Nonsteroidal anti-inflammatorydrug) including
aspirin, reduce fever by inhibiting cyclooxygenase and thus
blocking prostaglandin synthesis.
Elevated plasma levels of acute-phaseproteins
These plasma proteins are mostly synthesized in the liver. Three
of the best known of these proteins are:
1. C-reactive protein (CRP,
2. fibrinogen
3. serum amyloid A (SAA) protein
Synthesis of these molecules by hepatocytes is stimulated by
cytokines, especially IL-6.

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Function
Manyacute-phaseproteins, such as CRP and SAA, bind to
microbial cell walls, and they may act as opsonins and fix
complement.Fibrinogen bindsto erythrocytes and causes them
to form stacks (rouleaux) that sediment more rapidlyat unit
gravity than individualerythrocytes. This is the basis for
measuring the erythrocyte sedimentation rate (ESR) asa simple
test for the systemic inflammatory response, caused by any
numberof stimuli, including LPS.
Serial measurements of ESR and CRP are used to assess
therapeutic responses in patients with inflammatorydisorders
such as rheumatoid arthritis. Elevated serum levels of CRP are
now used as a marker for increased risk of myocardial
infarction or stroke in patients with atherosclerotic vascular
disease. It is believed that inflammation is involved in
the development of atherosclerosis and increased CRP is a
measure of inflammation.
Leukocytosis
It means production of leukocytes.Cytokines (CSFs)stimulate
production of leukocytes from precursors in the bone marrow.
Leukemoid Reactions
Normal level of leukocyte is 15,000 to 20,000 cells/mL, but in
some extraordinary cases it may reach 40,000 to 100,000
cells/mL. These extreme elevations are referred to as leukemia
reactions because they are similar to those seen in leukemia.
Neutrophilia
Most bacterial infections induce an increase in the blood
neutrophil count, called neutrophilia.

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Lymphocytosis
Viral infections, such as infectious mononucleosis, mumps, and
German measles, are associated with increased numbers of
lymphocytes (lymphocytosis).
Eosinophilia
Bronchial asthma, hay fever, and parasite infestations all
involve an increase in the absolute number of eosinophils,
creating aneosinophilia.
Leukopenia
In typhoid fever and infections caused by some viruses,
rickettsia, and certain Protozoaare usually associated with a
decreased number of circulating white cells (leukopenia).
Because of cytokine-induced sequestration of lymphocytes in
lymph nodes.
In some severe infections, septic shock:fall in blood pressure,
disseminated intravascular coagulation, metabolic
abnormalities; induced by high levels of TNF including IL-12
and IL-1.
OVERVIEW OF TISSUE REPAIR
Cells involved:
 Labilecells: normally continuous turn over (e.g.
epithelial and bone marrow cells) chances of regeneration
are excellent.
 Permanentcells: Not capable of proliferation (e.g. adult
neurons) HEALING BY SCARRING(no regeneration).
 Stablecells: normally little proliferation but remain
capable of more rapid cell division following injury (liver,

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renal tubular epithelium) Chances of regeneration are
GOOD.
Tissue and healing
Granulation tissue: mixture of proliferating capillaries
(angioblasts), fibroblasts, macrophages and plasma cells.
Granulation tissue is formed by the action of different cytokines
and growth factors released by blood platelets and macrophages.
Healing by primary (first) intention: In simple skin incisions
where the edges are in close apposition and actual defect is
minimal, healing occurquickly with small amount of
granulation tissue.
Healing by secondary (second) intention: in other situations
when wound edges are far apart and tissue defect is large and
filed with blood clot and variable amount of debris, here
organization and filling of defect with extensive granulation
take place a long time.