Chronic Inflammation

 Definition:
 Inflammation of prolonged duration in which active inflammation,
tissue injury and the healing proceed simultaneously
 Caused by prolonged and persistent tissue injury
 There is production of granulation tissue which
matures into fibrous tissue.
 These changes are called proliferative changes in
contrast to exudative changes of acute inflammation
Chronic inflammation
Causes:
 Persistent Infections

 Ex. Treponema palladium (causative

organism of syphilis)
 Organism of low toxicity and evoke an
immune reaction = delayed
hypersensitivity
 Prolonged Exposure to toxic Agents,

 Exogenous (Silicosis)
 Endogenous (Atherosclerosis)

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Chronic inflammation
Causes:
 Autoimmunity

 Ex. Autoimmune diseases

 Particulate matter

 Hypersensitivity reactions

 Unknown agents.

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Chronic Inflammation
 Morphologic Features:
 Foci of acute exudative inflammation sometimes with active
suppuration
 Infiltration with mononuclear cells (macrophages, lymphocytes
& plasma cells)
 indicates persistent reaction to injury
 Tissue destruction (Necrosis)
 Done by way of Inflammatory cells
 Repair involving angiogenesis and fibrosis (Dense fibrous
tissue)
 Attempt to replace lost tissue
Cells of Chronic Inflammation
 Mononuclear Phagocyte system
 Form part of cells of the mononuclear phagocyte
system Scattered throughout the body
 Circulating blood monocytes →Tissue macrophages
 Cells of the system include: Kuppfer cells which line
hepatic sinusoids, Alveolar Macrophages (lung),
Sinus Histiocytes (spleen), Microglia (CNS), adrenal
cortex and lymphatic sinuses of lymph nodes
 Cells in the medulla of the lymph nodes and red pulp
of the spleen

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Maturation of Mononuclear
Phagocytes
Macrophages…..
 Cells on the surface of serous cavities e.g. the
omentum
 Histiocytes in connective tissue, osteoclasts in bone
and microglial cells of the CNS
 The monocytes of blood and their precusors in the
bone marrow

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Morphology of macrophages
 They are motile cells and can assume various
shapes
 Have an oval indented nucleus, abundant
cytoplasm rich in lysosomes and surface microvilli
 They can be recognised by the presence of
phagocytic vacuoles
 They are larger than monocytes
 In the resting state closely resemble lymphocytes

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Morphology of macrophages…
 Monocytes are immature macrophages which on
stimulation transform to macrophages
 In chronic inflammation macrophages assume the
special features of epitheloid cells or of giant cells
 Giant cells have two or more nuclei and can fuse
together to form very large giant cells with
sometimes over 100 nuclei. Such cells transform
into foreign body cells and langahans cells
 Osteoclasts are formed by coalescence of
monocytes whose function is bone resorption.

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Macrophage functions
 Phagocytosis and destruction of macro-organisms
and other harmful unwanted material
 Scavenging role
 Removal of dead or effete cells
 Can ingest large amounts of insoluble material
retaining it for months or years e.g. abnormal lipids
or dust particles

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Macrophage functions….
 Secretion of factors that stimulate fibrosis
 Production of some components of the compliment
 Participation in immune responses
 Production of endogenous pyrogen and colony
stimulating factor which promotes proliferation and
maturation of polymorphs and monocyte
precursors.

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Mechanisms of macrophage accumulation during
Chronic Inflammation
 Continued recruitment of monocytes from the
circulation
 Most important source for macrophages
 Local proliferation of macrophages from the blood
stream
 Immobilization of macrophages within the site of
inflammation
 Cytokines and oxidized lipids can cause
immobilization
Effects of Macrophage Activation
Other Cells of Chronic Inflammation

 Infiltration with mast cells, lymphocytes and plasma cells

 Lymphocytes
 Mobilization in both antibody – mediated and
 Mast Cells
 Widely distributed in connective tissues and participate in both acute
and persistent inflammatory reactions
 Binds the Fc portion of the IgE antibody
 Plasma Cells
 Produce antibody directed either against persistent antigen in the
inflammatory site or against altered tissue components
 Eosinophils
 parasitic infections
 Mediated by IgE
 Eotaxin – a chemokine that has the ability to prime eosinophils for
chemotaxis
Granulomatous inflammation

 This is the pattern of inflammation occurring

in chronic inflammation
 It’s a pattern of chronic inflammatory reaction
in which the predominant cells are
aggregations of macrophages having an
enlarged, squamous cell-like appearance
(called Epitheloid macrophages)
GRANULOMA

 This is a Nodular collection of Epitheloid

macrophages surrounded by a rim of
LYMPHOCYTES
 It’s a focal area of Granulomatous inflammation
 In an Heamatoxyline &Eosin stain can see:
 Epitheloid cells have pale granular cytoplasm with indistinct
boundaries
 Giant cells = Epitheloid cells that fuse (Langhan’s)
 Can be found in the periphery or sometimes in the center of the
granuloma
 Have large mass of cytoplasm
 Have 20 or more small nuclei arranged in the periphery or
haphazardly
Granulomatous inflammation

 Types of Granulomatous Inflammation

 1. Immune granulomas
 Caused by insoluble particles that are capable of
inducing a cell-mediated immune response
 Macrophages are transformed into Epitheloid cells and
multinucleate giant cells
 Examples:
 Bacteria
 Tuberculosis *** (high incidence due to drug resistant
stains)
 Leprosy
 Parasites
 Schistosomiasis (3 types)
 Fungi
 Histoplasmosis
 Blastomycosis
Granulomatous inflammation
2.Foreign Body Granulomas
Don’t incite either an inflammatory or immune
response.
Epitheloid cells and giant cells are apposed to the
surface and encompass the foreign body.
The foreign body is usually found in the center of the
granuloma.
Examples:
Metal/Dust
Berylliosis
Silicosis
Foreign body
Splinter
Suture
Granulomatous inflammation

 3. Sarcoidosis
 Bad systemic disease, probably autoimmune disease
 Etiologic agent is unknown
LYMPHATICS IN INFLAMMATION

 Secondary line of defense

 Lymph flow is increased in inflammation and
helps drain the edema fluid
 Lymphangitis
 Lymphadenitis
Third line of defense

 When organisms gain access to the vascular

circulation- Bacteremia
 Next line of defense
 Phagocytic cells of the liver, spleen, and bone marrow
 Heart valves, meninges, kidneys, and joints are
favored sites of implantation for blood-borne
organisms
Systemic Effects of Inflammation
 Infections→ reactions to cytokines
↓
 Acute phase response or the systemic
inflammatory response syndrome (SIRS)
 Acute phase response consists of
Acute phase response

 Fever-elevation of body temperature by 1° to

4°C
 Pyrogens stimulate prostaglandin synthesis in
the vascular and perivascular cells of the
hypothalamus
 exogenous pyrogens (LPS)
 endogenous pyrogens (TNF, IL-1)
 1.Fever
 PGE2 via neurotransmitters such as cyclic AMP
↓
 Reset the temperature set-point at a higher level
↓
 Fever
↓
 Fever induce heat shock proteins that enhance lymphocyte
responses to microbial antigens
2.Acute-phase proteins

 Acute phase proteis includes

 C-reactive protein (CRP)
 Fibrinogen
 Serum amyloid A protein (SAA)

 They are synthesised by hepatocytes

 Synthesis is by upregulated by cytokines
 IL-6 (for CRP and fibrinogen)
 IL-1 or TNF (for SAA)
2.Acute-phase proteins

 CRP and SAA act as opsonins helps in clearing

Necroticcell nuclei
Microbial cell walls

Unlimited production of SAA - secondary

amyloidosis in chronic inflammation
3.Leukocytosis

 Common feature of inflammatory reactions

 Bacterial infection
 Usually 15,000 or 20,000 cells/μl,
 40,000 to 100,000 cells/μl- Leukemoid
reactions
3.Leukocytosis contd…

 A) Accelerated release of cells from the bone

marrow post - mitotic reserve pool
↓
(shift to the left) by cytokines
 B) Colony stimulating factors cause increase
production of WBC
3.Leukocytosis contd…

 Most bacterial infections induce

Neutrophilia
 Viral infections-Lymphocytosis
 Typhoid fever , Rickettsiae-Leukopenia
 Bronchial asthma, hay fever, and parasitic
infestations- Eosinophilia
Other features of APR

 Other features of acute phase reactants include

 Effects of cytokines on brain cells
 Increased pulse and blood pressure
 Decreased sweating,
 Rigors (shivering)
 Chills (search for warmth)
 Anorexia
 Somnolence
 Malaise
Effects of chronic inflammation
 It can be a protective process
 Forms a barrier to bacteria and their toxins
 Provides numerous small vessels from which
exudation and emigration of leukocytes can
continue
 Sometimes a destructive process like in delayed
hypersensitivity reactions or in autoimmune
disorders

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Effects of chronic inflammation….
 May conceivably help to suppress a causal micro-
organism not yet identified e.g. in sarcoidosis,
Crohns disease and rheumatoid arthritis.
 The fibrous tissue may induce serious effects by
constricting orifices.
 May lead to loss of parenchymal cells in certain
organs leading to shrinkage, irregular scarring and
distortion.
 The fibrous tissue may wall off chronic infections
of strengthen weakened structures

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Sepsis

 Sepsis ;- severe bacterial infection

 Septic shock – Triad
1. Liver failure – no Gluconeogenesis (Hypoglycemia)
2. Loss of perfusion pressure & heart failure –
hemodynamic shock
3. Disseminated Intravascular Coagulation (DIC) –
Multiple Thrombi in circulation & Fibrin split
products
 Multi Organ Failure
 Mainly Lung (ARDS), Liver also Kidney & Bowel
Consequences of impaired inflammation
Defective inflammation Excess Inflammation
 ↑ susceptibility to  Allergies

infection  Important in
 Delay in wound healing  Cancer
 Tissue damage  Atherosclerosis
 IHD
 Alzheimer's
 Fibrosis as a sequel of
chronic infections,
metabolic conditions