Session 10:

Chronic Inflammation

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 Learning tasks
At the end of this session, students are expected to be
able to:
• Define chronic inflammation.
• Identify causes of chronic inflammation.
• Explain morphological features of chronic
inflammation.
• Explain types of chronic inflammation.

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 Definition
• Chronic inflammation is inflammation of
prolonged duration (weeks to years) in which
continuing inflammation, tissue injury and
healing often by fibrosis proceed simultaneously.
 Causes of Chronic Inflammation
i. Chronic inflammation following acute
inflammation.
ii. Recurrent attacks of acute inflammation.
iii. Chronic inflammation starting from agents
known to cause chronic inflammatory response.
iv. Persistent infections by microbes which are
difficult to eradicate.
v. Immune-mediated inflammatory diseases
(hypersensitivity and autoimmune diseases).
vi. Prolonged exposure to potentially toxic agents.
 Morphological features of Chronic
inflammation
• Chronic inflammation is characterized by a different
set of reactions:
1. Infiltration with mononuclear cells, including
macrophages, lymphocytes, and plasma cells.
2. Tissue destruction, largely induced by the
products of the inflammatory cells.
3. Repair (healing by fibrosis), involving new vessel
proliferation (angiogenesis) and fibrosis.
 Chronic inflammatory cells and
mediators
• Chronic inflammation involves complex
interactions between several cells population and
their secreted mediator.
• These chronic inflammatory cells mainly include:
– Macrophages.
– Lymphocytes.
– Plasma cells.
– Mast cells.
– Eosinophils.
 Macrophages
• Dominant cells of chronic inflammation.
• Derived from circulating blood monocytes.
• Diffusely scattered in most connective tissues.
• They are also found in organs such as:
– Liver (Kupffer cells)
– Spleen and lymph nodes (sinus histiocytes)
– CNS (microglial cells)
– Lungs (alveolar macrophages)
– Langerhans’ cells/dendritic histiocytes (skin)
• Forming mononuclear phagocyte system
(reticuloendothelial system).
 Macrophages cont…
• Monocytes arise from precursors in the bone
marrow and circulate in the blood for only about a
day.
• They migrate to a site of injury within 24 to 48
hours after the onset of acute inflammation.
– Under the influence of adhesion molecules and
chemokines.
• When monocytes reach the extravascular tissue,
they undergo transformation into macrophages.
 Macrophages cont…
• Macrophages are larger and have a longer lifespan
and a greater capacity for phagocytosis than do
blood monocytes.
• In all tissues, macrophages:
– Act as filters for particulate matter, microbes, and
senescent .
– Effector cells that eliminate microbes in cellular and
humoral immune responses.
 Macrophages activation
• Tissue macrophages are activated by diverse
stimuli to perform a range of functions.
• There are two (2) major pathways of macrophage
activation:
i. Classical pathway.
ii. Alternative pathway.
 Classical macrophage activation
• Classical macrophage activation is induced by:
i. Microbial products such as endotoxin.
ii. T cell–derived signals, importantly the cytokine
Interferon gamma (IFN-γ).
iii.Foreign substances including crystals and
particulate matter.
Classical macrophage activation cont…
• Activated macrophages secrete cytokines that
stimulate inflammation.
– Those cytokines are interleukin-1 (IL-1), interleukin-
12 (IL-12), interleukin-23 (IL-23) and chemokines.
• These activated macrophages are important in host
defense against ingested microbes and in many
chronic inflammatory reactions.
Classical macrophage activation cont…
• Classically activated macrophages produce:
i. Lysosomal enzymes.
ii. Nitric oxide.
iii. Reactive oxygen species.
– Those above products enhance activated macrophages
the ability to kill ingested organisms.
• Thus classically activated macrophages are
microbicidal.
Alternative macrophage activation
• Alternative macrophage activation is induced by
cytokines such as interleukin-4 (IL-4) and
interleukin-12 (IL-13)
– Those interleukins are produced by T lymphocytes and
other cells, including mast cells and eosinophils.
• Alternative activated macrophages have principal
role is in tissue repair.
– They secrete growth factors that promote angiogenesis,
activate fibroblasts and stimulate collagen synthesis (in
tissue repair).
– They are not actively microbicidal.
 Activity: Brainstorming
• What are the roles of macrophages in host defense
and inflammatory response?

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Roles of macrophages in host defense
and inflammatory response
1. Macrophages ingest and eliminate microbes and
dead tissues.
2. Macrophages secrete chemical mediators of
inflammation.
3. Macrophages initiate the process of tissue repair
and are involved in scar formation and fibrosis (in
alternative activation pathway).
4. Macrophages display antigens to T lymphocytes
and respond to signals from T cells (bidirectional
interactions).
 Macrophages cont…
• After the initiating stimulus is eliminated and the
inflammatory reaction abates, macrophages
eventually die or wander off into lymphatics.
• In chronic inflammatory sites, however,
macrophage accumulation persists, because of
continued recruitment from the blood and local
proliferation.
• Interferon gamma (IFN-γ) can also induce
macrophages to fuse into large, multinucleate
giant cells.
 Lymphocytes
• Lymphocytes are mobilized in the setting of:
– Specific immune stimulus (in infections)
– Non–immune mediated inflammation (due to ischemic
necrosis or trauma).
• These are the major drivers of inflammation in
many autoimmune and other chronic inflammatory
diseases.
• The activation of T and B lymphocytes is part of
the adaptive immune response.
 Lymphocytes cont…
• Lymphocytes migrate into inflammatory sites using
some of the same adhesion molecule pairs and
chemokines that recruit other leukocytes.
• In the tissues:
i. B lymphocytes may develop into plasma
cells, which secrete antibodies.
ii. CD4+ T lymphocytes are activated to
secrete cytokines thus these cells promote
inflammation and influence the nature of the
inflammatory reaction.
 Subsets of CD4+ helper T cells
• There are three (3) subsets of CD4+ helper T cells
that secrete different sets of cytokines and elicit
different types of inflammation:
i. CD4+ helper T cells 1 (TH1).
ii. CD4+ helper T cells 2 (TH2).
iii. CD4+ helper T cells 17 (TH17).
 Subsets of CD4+ helper T cells and
cytokines produced
1. TH1 cells produce the cytokine IFN-γ
– Activates macrophages in the classical pathway.
2. TH2 cells secrete interleukin-4 (IL-4),
interleukin-5 (IL-5) and interleukin-13 (IL-13).
– Recruit and activate eosinophils and are responsible for
the alternative pathway of macrophage activation.
3. TH17 cells secrete interleukin-17 (IL-17) and
other cytokines that induce chemokines.
– Recruiting neutrophils and monocytes into the reaction.
 Subsets of CD4+ helper T cells
cont…
• Both CD4+ helper T cells 1 (TH1) and CD4+ helper
T cells 17 (TH17) cells are involved in defense
against:
– Bacteria.
– Viruses.
– Autoimmune diseases.
• CD4+ helper T cells 2 (TH2)cells are important in
defense against:
– Helminthic parasitic infestations.
– Allergic inflammation.
 Lymphocytes and macrophages
interaction
• Lymphocytes and macrophages interact in a
bidirectional way thus propagating chronic
inflammation.
– Macrophages display antigens to T cells, express
membrane molecules and produce cytokines
(interleukin-12 (IL-12) and others) that stimulate T cell
responses.
– Activated T lymphocytes, in turn, produce cytokines,
which recruit and activate macrophages and thus
promote more antigen presentations and cytokine
secretions.
Lymphocytes and macrophages
interaction

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 Eosinophils
• These are characteristically found in inflammatory
sites in:
i. Parasitic infections.
ii. Allergic reactions.
• Eosinophils is recruited by adhesion molecules
of neutrophils and chemokines e.g. eotaxin.
• Eosinophil granules contain major basic protein
that is toxic to parasites but also causes epithelial
cell necrosis.
 Mast cells
• In atopic persons (those prone to allergic
reactions), mast cells are “armed” with IgE
antibody specific for certain environmental
antigens (allergens).
• When these antigens are subsequently encountered,
the IgE-coated mast cells are triggered to release
histamines and arachidonic acid metabolites that
elicit the early vascular changes of acute
inflammation.
 Neutrophils
• Although the presence of neutrophils is the
hallmark of acute inflammation, many forms of
chronic inflammation may continue to show
extensive neutrophilic infiltrates,
– Due to either persistent microbes or necrotic cells, or
mediators elaborated by macrophages.
• Such inflammatory lesions are sometimes called
“acute on chronic”—for example, in inflammation
of bones (osteomyelitis).
 Tissue destruction and necrosis
• Tissue destruction and necrosis are the central
features of most forms of chronic inflammatory
lesions.
• This is caused by activated macrophages which
release a variety of biologically active substances:
– Enzymes (protease, elastase, collagenase, lipase).
– Reactive oxygen species.
– Cytokines (interleukin-1 [IL-1], interleukin-8 [IL-8],
tumour necrosis factor [TNF]).
– Nitric oxide.
– Angiogenesis and growth factor.
 Proliferative changes
• As a result of necrosis, proliferation of small
blood vessels and fibroblasts is stimulated.
• This resulting in formation of inflammatory
granulation tissue, whose end result is healing by
fibrosis and collagen laying takes place.
 Types of Chronic inflammation
• Chronic inflammation can be classified into the
following two (2) types based on histologic
features:
1. Chronic non specific inflammation.
2. Chronic granulomatous inflammation.
Chronic non-specific inflammation

• It is characterised by non-specific inflammatory

cell infiltration (macrophages and lymphocytes)
such as in chronic osteomyelitis and lung abscess.
• Occurs when the irritant substance produces a
nonspecific chronic inflammatory reaction with
formation of granulation tissue and healing by
fibrosis e.g. chronic osteomyelitis, chronic ulcer.
 Chronic granulomatous
inflammation
• It is a distinctive pattern of chronic inflammation
characterized by aggregates of activated
macrophages with scattered lymphocytes.
• Granulomas are circumscribed, tiny lesion, about
1 mm in diameter.
– Composed predominantly of collection of modified
macrophages (activated macrophages) called
epithelioid cells and rimmed at the periphery by
lymphoid cells (lymphocytes).
– Epithelioid cells resemblance to epithelia in
appearance.
 Granuloma

Lymphocytes

'Epithelioid histiocytes'
(Modified, immobile macrophages)

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 Granuloma formation
• The formation of a granuloma effectively “walls
off” the offending agent and is therefore a useful
defense mechanism.
• However, granuloma formation does not always
lead to eradication of the causal agent, which is
frequently resistant to killing or degradation
• Thus granulomatous inflammation with subsequent
fibrosis may even be the major cause of organ
dysfunction in some diseases such as tuberculosis.
 Granulomas can form under the
following settings:
i. With persistent T-cell responses to certain
microbes as in TB.
ii. Granulomas may develop in some immune-
mediated inflammatory diseases, e.g. Crohn
disease.
iii. They develop in response to relatively inert
foreign bodies (e.g., suture or splinter) forming
foreign body granulomas.
iv. Granulomas are also seen in a disease of
unknown etiology e.g. in sarcoidosis.
 Morphology of granuloma
• In the usual H&E preparations, some of the
activated macrophages in granulomas have pink,
granular cytoplasm with indistinct cell boundaries.
• Aggregates of epithelioid macrophages are
surrounded by a collar of lymphocytes.
• Older granulomas may have a rim of fibroblasts
and connective tissue.
• Besides the presence of epithelioid cells,
granulomas may have multinucleated giant cells,
necrosis and fibrosis.
 Diseases with granulomatous
inflammation
1. Bacterial: Tuberculosis, Syphilis, Leprosy, Cat
scratch disease, Plague.
2. Fungal: Histoplasmosis, Cryptococcosis,
Coccidioidomycosis, Blastomycosis.
3. Helminthic: Schistosomiasis.
4. Protozoal: Leishmaniasis, Toxoplasmosis.
5. Chlamydia: Lymphogranuloma venerum.
6. Inorganic material: Berylliosis, Silicosis.
7. Immunological: Crohn’s disease.
8. Idiopathic: Sarcoidosis.
 Key points
• Chronic inflammation is a prolonged host response to
persistent stimulus.
• It is caused by microbes that resist elimination,
immune responses against self and environmental
antigens, and some toxic substances (e.g., silica).
• It is characterized by persistent inflammation, tissue
injury, attempted repair by scarring.
• Cellular infiltrate consisting of activated
macrophages, lymphocytes, and plasma cells.
• Mediated by cytokines produced by macrophages and
lymphocytes (notably T lymphocytes).
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 Review questions
1. Explain how lymphocytes and macrophages
interaction fueling chronic inflammation.
2. How tissue destruction and necrosis occurs in
chronic inflammatory reaction?
3. List two (2) factors favour proliferative changes in
chronic inflammatory reaction
4. What are the components of granuloma?
5. List three (3) settings which favour granuloma
formation.

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 References
• Bezabeh M.; Tesfaye A.; Ergicho B. et al (2004):
General pathology lecture notes for Health Sciences
students. Ethiopia Public Health Training Initiative.
Pg. 35-38.
• Kumar V.; Abbas A. K.; Aster J. C.;(2013): Robbins
and Contran Pathologic Basis of Disease (9th Ed.)
Elsevier Saunders, China. Pg. 53-57.
• Mohan H.;(2010): Text book of Pathology (6 th Ed.)
Jaypee Brothers Medical Publishers, India . Pg. 141-
144, 147-149.
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