Inflammation IV –

Chronic

Kusum Kapila
September 2006
 Inflammation
A dynamic continuum of change

Resolution with scarring*

Resolution

Inciting Acute Chronic-active Chronic

Stimulus Inflammation Inflammation Inflammation

Resolution with
Abscess
scarring*
*The longer the stimulus persists, the

greater the scarring will be.

 SUBACUTE INFLAMMATION:
Transition period
separating acute and
chronic inflammation.
-hyperaemia
-edema is regressing
-evidence of repair such as
fibroplasia and
angiogenesis is lacking.
Occasional viral
infections may result in
primary lymphocytic
accumulation often
referred to as subacute
Mixed inflammtory
infiltrate
 CHRONIC-ACTIVE INFLAMMATION:

Definition: Chronic inflammation accompanied by

acute exacerbations in
which the tissues exhibit all of the usual
characteristics of chronicity, with superimposed
features of acute inflam.
Time: Long period with exacerbations
Vascular Involvement: Same as with acute
Inflammatory cells: Neutrophils and chronic
inflammatory cells
Lymphatics: May be inflamed
Clinical Signs: Variable
Repeated episodes of inflam overlap
Host fails to contain the acute condition
Common causes of chronic inflammation:

1- Persistent acute inflammation

a- Persistence of the agent
b- Interference with normal healing
2- Persistent infections by organisms resistant
to phagocytosis and intracellular killing
-tuberculosis,
-leprosy,
-brucellosis,
-viral
 Survival of Phagocytosed
Microorganisms
Most bacteria are killed following phagocytosis.
some survive - either due to a disorder of the
host’s defense system – or due to their own
specialized protective mechanisms.
Organisms survive within phagolysosome
- eg. Coxiella burnetti, some
Mycobacterium
Some escape phagolysosome and grow in
cytoplasm
- Eg. Listeria, Rickettsiae
Some don’t allow lysosome to fuse with
phagosome
- Eg. Toxoplasma gondii
- Mycobacterium tuberculosis
Inflammation

Defects in Phagocytosis
Congenital:
1. Chediak-Higashi Syndrome (autosomal recessive)
Defective intracellular transport protein, inability to lyse
bacteria
2. Job Syndrome (Hyper IgE)
3. Chronic granulomatous disease (x-linked)
Neutrophils incapable of producing H2O2 during
phagocytosis - No oxidative burst
- Results in recurrent infections.
4. Myeloperoxidase deficiency
Inflammation

Defects in Phagocytosis
Acquired:
• Iatrogenic immunosuppression (most
common)
• Overwhelming infections
• Severe trauma or burn
• Diabetes mellitus
• Chronic debilitating disease
 Common causes of chronic inflammation:

3- Prolonged exposure to potentially toxic

agents:
Endogenous -necrotic bone, uric acid crystals
Exogenous- silica,asbestos,prosthesis,suture
material
4- Autoimmune diseases:
Organ specific -Hashimoto’s
Non –organ specific- Rheumatoid arthritis ,
Systemic lupus erythematosus (SLE)
5-Unknown aetiology- ulcerative colitis
6-Primary Granulomatous diseases-sarcoidosis
 PATHOGENESIS – CHRONIC
INFL
Persistent release of chemical mediators
induce
- Tissue destruction
-Persistent increase in blood flow
-increased vascular permeability
-Recruitment of inflammatory cells
macrophages, lymphocytes, plasma cells
- Proliferation
-Parenchymal cells (epithelial)
-Supportive cells (fibroblasts,
capillary endothelial cells)
 Chronic Inflammation

Definition: Inflammation of prolonged

duration (weeks to months to years), in
which active inflammation, tissue injury and
healing occur at the same time.
Characteristics
1. Mononuclear inflammatory cells
2. Tissue destruction
3. Repair
a. Fibroblasts
b. Endothelial cell proliferation
(angiogenesis)
 CHRONIC INFLAMMATION:
Inflammation which persists over a period
of time.
Chronic Mononuclear
infiltration
macrophages,
lymphocytes,
plasma cells
Tissue Destruction
Attempts of healing –
fibrosis and
angiogenesis
Acute (often present as
well)
[chronic-active]
-Vascular changes
-Edema, haemorrhage
-Neutrophilic infiltrate
Macrophage-prime cell in chr infl
prominent role due the large repertoire of products it can
produce when activated Tox. O2
Proteases
Key macrophage events Collagenases
Chemotx factors
1. Recruitment from circulation Coag factors
AA metabolites
2. Local Proliferation NO
PDGF FGF
3. Immobilization TGF-β

4. Differentiation (microglia, kupffer,

alveolar macrophage, osteoclasts).
Mononuclear Infiltration

Macrophages
A component of mononuclear phagocyte system
(MPS) including:

Blood monocytes

Tissue macrophages
a- liver (Kupffer’s cells)
b- spleen (sinus histiocytes)
c- lymph nodes (sinus histiocytes)
d- lungs (alveolar macrophages)
e- skin (melanophage)
f- brain (microglia)
g- bone (osteoclast)
h- specialised macrophage- epithelioid cell
 Chronic inflammation -
macrophage accumulation
persists
1.Continued recruitment of
monocytes from circulation
2.Production of adhesion
molecules and chemotactic
factors
-C5a, IL-8, PDGF, TGF-ß,
chemokines
3. Local proliferation and
Immobilization of
macrophages at the site
4. Recruitment of other
lymphocytes
5.Destruction of target cells
 Macrophage-lymphocytes
interaction in chronic
inflammation
Lymphocytes
activate macrophages
- IFN
Lymphocytes and
macropahges
constantly stimulate
one another unless
stimulus is removed
Note that the
activated
macrophage
releases
products that are
similar to those
released by
PMNs
 Macrophage- chr infl
Biologically active substances produced by
Macrophages cause:
Tissue Injury:
-Toxic oxygen metabolites
-Proteases
-Neutrophilic chemotactic factors
-Coagulation factors
-Arachidonic acid metabolites
-Nitric oxide
Fibrosis:
-Growth factors (PDGF, FGF, TGFß)
-Fibrogenic cytokines
-Angiogenesis factors
 Chronic inflammation
Other types of cells
present
1. B & T lymphocytes
(antibody and cell
mediated immunity)
2. Plasma cells
(produce antibodies)
3. Eosinophils
(contain major basic
protein –MBP, toxic to
parasites)
 Macrophage – Tissue
destruction
Macrophages can
produce tissue
destruction when
inappropriately
activated.
-Explains why tissue
destruction is one of
the hallmarks of chronic
inflammation.
-also reason for seeing
acute/active response
in chronic inflammation
 CHRONIC INFLAMMATION:
Inflammation which persists over a period
of time.

Lymphatics –
involvement variable - +/-
proliferation and activation
Clinical Signs: Primary dependent
upon duration of the illness and
inflammatory lesions
NOTE: Many changes represented in
chronic inflammation are also seen in
areas of REPAIR.
 Macroscopic
appearance of chronic
inflammation
Chronic ulcer
Chronic abscess cavity

Thickened wall –hollow viscus

Granulomatous inflammation

fibrosis
Chronic Peptic Ulcer
healing by fibrosis
 Macroscopic appearance of
chronic inflammation – chr abscess
 Macroscopic appearance of
chronic inflammation – hollow
viscera
 Chronic inflammation -
interstitial
Certain etiologic agents
such as viruses are
more likely to lead to
chronic inflammation,
the inflammatory
infiltrates of chronic
inflammation are more
likely to be interstitial
(within tissues) rather
than exudative (above
surfaces or in spaces)
like acute inflammation.
 Granulomatous Inflammation

Definition: Granulomatous response

characterized by the presence of
lymphocytes,macrophages, and plasma cells
.Modified macrophages appear "epithelioid,"
and may be"multinucleated "
Distinctive pattern of chronic inflammation
TIME: always chronic
Etiology: 1.some non-digestible organism or
particle which serves as a chronic
inflammatory stimulus, 2.delayed-type
hypersensitivity is often required.
 Granuloma:
Focal area (often small 0.5 -2mm) of
granulomatous inflammation, which is
organised and comprises of epithelioid
macrophages
Usually surrounded by a collar of lymphocytes
and occasionally plasma cells
presence of fibrous connective tissue
Presnce of Langhan’s or foreign body giant
cells
 Granuloma

Epithelioid cells
- more cytoplasm
- look like epithelial cell
- specialized for
secretion
of cytokines
- Fewer receptors
- Less phagocytic
activity
Multinucleated Giant
cells
- Coalescence of
macrophages
 granulomas
There are two types of
granulomas:
1- Foreign body
granulomas
Talc powder, Suture
strings, etc
2- Immune granulomas
Tuberculosis, Syphilis,
Sarcoidosis, Brucellosis
Cell Mediated
Immunity
accelerates
development
of granulomatous
inflam and intensifies
 Inflammation
Granulomatous Inflammation

Fibroblasts

Lymphocytes

Macrophages, Epithelioid
Cells, and Giant Cells

Caseous Necrosis
Non-caseating Granuloma
Caseating Granuloma
Secondary Tuberculosis
 Granulomatous Inflammation
Inflammatory Cells

Epithelioid cells
(epithelioid
macrophages)
Multinucleated
Giant cells
T- lymphocytes
■Neutrophils
- Pyogranulomatous
inflammation
■Eosinophils
- Eosinophilic
granulomatous
inflammation
 Granulomatous
Inflammation
Etiology - Continued
Bacteria
- Mycobacterium
sp
- Actinomyces
bovis
Fungi
- Blastomyces
dermatitidis
- Coccidiodes
immitis
- Aspergillus
fumigatus
Parasites
 Granulomatous Inflammation
Fungi
Histoplasmosis Bacteria
Blastomycosis Tuberculosis
Metal/Dust Leprosy
Berylliosis
Silicosis Parasites
Foreign body Schistosomiasis
Splinter
Suture
Graft material
Sarcoidosis
 Spectrum of Inflammatory Responses
to Infection

Inflammatory cell reaction depends on the host

immune response to the organism

Lymphocytes Viruses
Granulomas Mycobacteria, fungal organisms,
brucella
Granulomas with necrosis M. Tuberculosis,
Histoplasmosis
Eosinophils + Granulomas Helminthes
Granulomas + Suppuration Plague, tularemia, listeria,
yersinia infection

*Granulomas do not form in patients with cell-mediated

immune deficiency.
 Multinucleate Giant cells
Normal tissues
-osteoclasts (bone)
-trophoblasts
(placenta)
-megakaryocytes
(bone marrow)
Giant cells in
Inflammation
-foreign body
-Langhan’s
-touton
Giant cells in Tumour
-Reed Sternberg cell
-tumour giant cells
Giant cells in Inflammation

Touton – at
Langhan’s sites of
lipid
breakdown

Foreign body
 Foreign body giant cells

Suture material Cholesterol

Silica Hair
Characteristics of acute and chronic
inflammation

ACUTE CHRONIC

Vascular changes
Vasodilation and Minimal
Increased permeability

Cellular infiltrates Polymorphs Mononuclear

No replication Replication

Stromal changes
Minimal - Cellular proliferation
separation Fibrosis
due to edema
 exception
Typhoid is an
example of acute
inflammation which
induces leucopenia
with relative
lymphocytosis