Inflammation

MB ChB
 Inflammation
• Response of vascularized tissues to infections and damaged
tissues
• Leading to accumulation of fluid and leukocytes in order to
eliminate the offending agents
• Protective host response essential for survival
• Rids the host of initial cause of cell injury and consequences
of such injury – necrotic tissue
• Serves to destroy, dilute or wall off injurious agent and sets
in motion process of repair
• Mediators of inflammation circulate in blood or are in
tissues from which they are recruited
• Process of inflammation delivers these cells and proteins to
damaged or necrotic tissues or microbes
• They are activated and function to get rid of harmful or
unwanted substances
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Properties of inflammatory response
• Components
– Blood vessels
– Leukocytes – inflammatory cells
• Harmful effects
– Tissue damage, self-limiting or permanent
– Autoimmune disease, hypersensitivity reactions
• Local and systemic inflammation
• Mediators
– Vascular and cellular reactions triggered by mediators
• Acute and chronic inflammation
• Termination of inflammation and initiation of tissue repair
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Types of inflammation
• Acute inflammation
– short duration, lasting minutes, hours or days
– exudation of fluid and plasma proteins - oedema
– emigration of leukocytes mainly neutrophils
• Chronic inflammation
– longer duration
– associated with presence of lymphocytes &
macrophages
– proliferation of blood vessels, fibrosis and tissue
necrosis
– Produces more tissue damage
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Cardinal signs of inflammation
• Rubor – redness
• Tumor – swelling
• Calor – heat
• Dolor – pain
• Functio laesa – loss of function

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Acute inflammation
• Immediate and early response to injurious
agents
• Serves to deliver leukocytes and plasma
proteins to sites of infection or tissue injury
• The reaction subsides once the factor causing
the response is eliminated
• One of the reactions of innate immunity

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Causes of inflammation
Inflammatory reactions triggered by:
•Infections and microbial toxins – most common
cause of inflammation
•Tissue necrosis from any cause – molecules
released from necrotic cells elicit inflammation
•Foreign bodies – cause traumatic tissue injury or
carry microorganisms
•Immune reactions – hypersensitivity reactions
– Autoimmune diseases – directed against self Ags
– Inappropriate reactions - allergies
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Steps of acute inflammation
Acute inflammatory response goes through a
series of steps:
• Recognition of microbes or necrotic tissue
• Recruitment of leukocytes and plasma proteins
from circulation
• Activation of leukocytes and plasma cells to
eliminate offending stimulus
• Termination of reaction
• Repair of damaged tissue
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Reactions of blood vessels
• Undergo changes that facilitate movt of plasma proteins and
leukocytes out of circulation
• Escape of fluid, proteins and blood cells into interstitial tissue
is called exudation
• Exudate
• Extracellular fluid with high protein content
• Contains cellular debris
• Has high specific gravity
• Transudate
• Low protein content
• Little or no cellular material
• Low specific gravity
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Vascular changes
• Changes in vascular flow and calibre occur early
• Vasodilatation leads to increased blood flow (heat
and redness)
• Slowing of circulation due to increased permeability
causes exudation of fluid, blood viscosity and stasis
• Peripheral orientation of leukocytes along
endothelium (margination)
– followed by rolling and migration into interstitium
 permeability exudation of protein-rich fluid into
interstitium intravascular osmotic pressure giving
rise to oedema (swelling)
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Cellular events
• Leukocytes migrate to site of injury, then:
– ingest offending agents
– kill bacteria and other microorganisms
– degrade necrotic tissue and foreign antigens
– may prolong inflammation and induce tissue
damage by release of enzymes, chem mediators
• In inflammatory lesion, neutrophils present in
first 6 - 24 hours, monocytes in next 24 – 48
hours

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Chemotaxis
Movt of leukocytes along chemical gradient due
to chemoattractants
• Exogenous agents:
– bacterial products
• Endogenous products:
– components of complement system eg C5a
– products of lipooxygenase pathway – leukotrienes
– cytokines eg IL-8

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Phagocytosis
Three steps in phagocytosis:
• Recognition and attachment of particle
• Opsonisation – particle is coated to phagocytosis
• Engulfment –extension of cytoplasm (pseudopods)
around object
• Killing or degradation –superoxide is generated and
converted to H2O2
• Granules of neutrophils contain enzymes
• O2 independent mechanisms include
– bactericidal permeability increasing protein
– lysozyme, lactoferrin, major basic protein
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Chemical mediators of inflammation
• Substances that initiate and regulate
inflammatory reactions
• Secreted by cells or generated from plasma
proteins
• Bind to specific receptors on target cells
• Can act on one or a few target cells
• Most are short-lived once activated
• Have potential to cause harmful effects

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Vasoactive amines
• Histamine
– derived from mast cells, basophils, platelets in preformed state
– causes dilatation of arterioles and permeability
• Serotonin (5-hydroxytryptamine)
– present in platelets and enterochromaffin cells
– actions similar to histamine
• Stored as preformed molecules in cells
– released after platelets are stimulated
• physical injury (trauma, cold, heat)
• binding of Abs to mast cells
• anaphylatoxins (C3a, C5a)

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Plasma proteases
• Complement system
– after activation causes lysis by membrane attack complex
(MAC). Gives out components:
• C3a, C5a (anaphylatoxins) -permeability and
vasodilation
• C5a –chemotactic agent, C3a –opsonin
• Kinin system
– results in generation of bradykinin
 permeability, causes contraction of smooth muscle,
dilatation of vessels, pain when injected into skin
– triggered by activation of FXII of intrinsic clotting pathway
• Clotting system
– activation results in formation of fibrinopeptides which
permeability
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Arachdonic acid (AA) metabolites
• AA derived from diet or by conversion from linoleic
acid of cell membrane phospholipids
• AA by cycloxygenase pathway produces
prostaglandins (PG):
– thromboxane (TXA2) –vasoconstrictor and PLT
aggregating factor
– prostacyclin (PGI2) –vasodilator, inhibits PLT aggregation
– PGD2, PGE2, PGF2 -cause vasodilation, potentiate
oedema

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• Lipoxygenase pathway generates 5-HETE
giving rise to leukotrines (LTs)
– 5-HETE –chemotactic agent
– LTB4 –chemotactic agent
– LTC4, LTD4, LTE4 –vasoconstriction,
bronchospasm, permeability

• Lipoxins
- inhibitors of inflammation
- inhibit leukocyte recruitment

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Complement system
• Collection of soluble proteins and membrane receptors
that function in defence against microbes and
inflammation
• During activation, several products are elaborated that
take part in inflammation
• Three main functions of complement system
– Inflammation
• C3a and C5a are anaphylatoxins
• Stimulate histamin release from mast cells
• C5a is chemotactic agent for inflammatory cells
– Opsonisation and phagocytosis
• C3b is an opsonin
– Cell lysis –MAC makes cells permeable to water and ions19
Platelet-activating factor (PAF)
• Derived from phospholipids in a number of cells
– causes PLT activation
– vasoconstriction and bronchoconstriction
– increases leukocyte adhesion to endothelium

Cytokines
• substances that modulate function of other cells
- include monokines, lymphokines, colony stim
factors, interleukins, chemokines, growth factors
- IL-1, TNF – fever, sleep, PGI synthesis
- chemokines – activate specific leukocytes and are
chemoattractants
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Nitric oxide (NO)
• Produced by endothelial cells, macrophages,
neurones
• Acts in a paracrine manner through cGMP
• Potent vasodilator
• Causes smooth muscle relaxation
• Reduces PLT aggregation and adhesion

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Morphologic pattern of acute inflammation
• Acute inflammation is characterised by
– Dilatation of small blood vessels
– Accumulation of leukocytes and fluid in
extravascular tissue
• Special morphologic patterns may occur
depending on
– Severity of the reaction
– Specific cause
– Particular tissue and site involved
• May suggest the underlying cause
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Serous inflammation
• Exudation of cell-poor fluid
• Accumulation of thin fluid within spaces
created by cell injury or body cavities – pleural,
peritoneal, pericardial
• Called an effusion
• Fluid not infected by microorganisms
• Fluid derived from plasma or mesothelial cells
that line the cavities
• Blister is accumulation of serous fluid in skin
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Fibrinous inflammation
• Occurs with increased vascular permeability
when large molecules like fibrinogen escape
• Commonly occurs in inflammatory conditions
of body cavities
• Fibrinous exudates may be removed by
fibrinolysis and macrophages
• If not removed may stimulate accumulation of
fibroblasts and form scar tissue
• Fibrous tissue may cause obliteration of cavity
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Suppurative inflammation - abscess
• Formation of a purulent exudate or pus
• Localised collection of pus – abscess
• Abscess consists of dead cells, necrotic debris,
neutrophils and oedema fluid
• In time abscess may be walled off and
replaced by fibrous tissue
• Produced by pyogenic organisms – bacteria
and fungi

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Ulcers
• Local defect or excavation of surface of an organ
or tissue due to sloughing of inflamed necrotic
tissue
• Ulceration follows tissue necrosis and resultant
inflammation
• Ulcers occur along GIT, GUT and skin
• Chronic skin ulcers occur in lower limbs due to
vascular insufficiency
• Peptic ulcers of stomach and duodenum are best
examples
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Outcomes of acute inflammation
• Complete resolution
– When injury is limited or short-lived
– When there is little tissue destruction and the
damaged cells can regenerate
• Healing by connective tissue replacement
(fibrosis)
– When there is massive tissue destruction
– Injury of tissues not capable of regeneration
– Abundant fibrin exudation in tissue or cavities
• Progression to chronic inflammation
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 Chronic inflammation
• Inflammation of long duration
• There is active inflammation, tissue
destruction and attempts at repair at same time
• May follow acute inflammation
• Or may begin insidiously as a slow-grade
smoldering response without an acute phase
• Most disabling chronic inflammatory
conditions eg rheumatoid arthritis start as such
• Causes tissue damage and disability in some
cases

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Causes of chronic inflammation
May arise under the following conditions:
•Persistent infection by organisms that are difficult to
eradicate eg mycobacteria
• Organisms may elicit a delayed type hypersensitivity
reaction
•Persistent exposure to toxic or non-degradable
agents eg silica
•Hypersensitivity diseases - due to excessive and
inappropriate activation of immune system
• Autoimmune diseases
• Allergic diseases
• Inflammatory bowel disease – unregulated immune
responses against microorganisms
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Morphologic features

Chronic inflammation characterised by:

•Infiltration by chronic inflammatory cells –
macrophages, lymphocytes, plasma cells
•Tissue destruction by offending agent or by
inflammatory cells
•Healing by connective tissue replacement of
damaged tissue with fibrosis

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Cells in chronic inflammation
Macrophages –derived from blood monocytes
•Dominant cells in chronic inflammation
•Present in many tissues
•In organs - liver (Kupffer cells), spleen and LNs (sinus
histiocytes), lungs (alveolar macrophages)
•Are activated by different stimuli
•Activated macrophages:
– Eliminate injurious agent
– Cause tissue injury
•Macrophage accumulation persists by continuous
recruitment from circulation or local proliferation
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Lymphocytes
• Interact with macrophages in chronic inflammation
• When activated produce cytokines, some of which
activate macrophages eg IFN-γ
Plasma cells – derived from activated B lymphocytes
• Produce antibodies against specific antigens
Mast cells –present in connective tissue
• Anaphylactic reactions and parasitic infections
• Present in many chronic inflammatory reactions
Eosinophils – produce major basic protein which is
toxic to parasites
• Also cause lysis of epithelial cells
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Granulomatous inflammation
• Characterized by formation of granulomas
• A granuloma consists of macrophages that are
transformed into epithelial-like cells surrounded by a
collar of lymphocytes and occasionally plasma cells
• Epithelioid cells may fuse to form giant cells with
multiple nuclei. Types of giant cells:
- Langhan’s type –nuclei arranged in a horse-shoe.
Seen in tuberculous infections
- Foreign body type – nuclei haphazardly arranged
- Warthin-Finkeldey type –have cytoplasm and nuclear
inclusion bodies. Seen in measles infection

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Types of granulomas
• Foreign body granulomas
– Triggered by inert foreign bodies
– Form around materials – glove powder, sutures
– Foreign material may be identified
• Immune granulomas
– Due to agents that induce persistent-cell mediated
immune response
– Inciting agent difficult to eradicate
– Macrophages activate T cells to produce cytokines
which activate other T cells
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 Granulomatous inflammation
• Distinctive pattern of chronic inflammation seen in a
limited number of conditions
• Mycobacterium tuberculosis granulomas are called
tubercles
• May display central caseous necrosis which if present is
characteristic of tuberculosis
• Other conditions in which granulomas are formed:
– leprosy
– fungal infections
– parasitic infections
– syphilis
– cat-scratch disease – caused by Afipia felis
– sarcoidosis
– Crohn disease
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Systemic effects of inflammation
• Systemic changes associated with acute
inflammation called acute phase response
• Due to reactions to cytokines
– Fever
– Acute phase proteins
• C-reactive protein, fibrinogen, serum amyloid A
– Leukocytosis
– Others
• ↑pulse and blood pressure
• rigors, chills, anorexia, malaise
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