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3. Inflammation

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Inflammation
KANG`OMBE C KAKENGE
Inflammation
• Protective host response to rid body of stimuli;
damaged or necrotic tissues and foreign antigen
• Occurs in vascularized tissue against stimuli
leading to accumulation of fluid and leukocytes
• Protective – rids body of injurious stimulus
• Serves to destroy, dilute or wall off injurious
agent and sets in motion process of repair
• During repair injured tissue is replaced by
regeneration of cells or fibrous tissue, or both
• May be harmful in some situations - eg
hypersensitivity reaction
• Terminated when offending agent is eliminated 2
Types of inflammation
• Acute – short duration, lasting minutes, hours
or days
- characterized by exudation of fluid and plasma
proteins
- emigration of leukocytes mainly neutrophils
• Chronic – longer duration
- associated with presence of lymphocytes &
macrophages
- proliferation of blood vessels, fibrosis and
tissue necrosis
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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
• Three major components:
- alteration in vascular calibre blood flow
- structural changes in microvasculature – plasma
proteins and leukocytes leave circulation
- emigration of leukocytes to focus of injury
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Stimuli for acute inflammation
Acute inflammatory reactions may be 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
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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
• Transient vasoconstriction then vasodilatation
blood flow (heat and redness)
• Slowing of circulation due to permeability
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
oedema (swelling)
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Cellular events
• Movement of leukocytes to site of injury which
then:
- ingest offending agents
- kill bacteria and other microorganisms
- degrade necrotic tissue and foreign antigens
- may prolong inflamm and induce tissue
damage by release of enzymes, chem mediators
• In an 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
• Chemical compounds that modify or amplify
inflammatory process
• Originate from plasma or from cells
• 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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1. Vasoactive amines (histamine and
serotonin)
• 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
• Amines are released after platelets are stimulated upon
contact with collagen, thrombin, ADP and Ab-Ag
complexes
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2. Plasma proteases
• Complement system
- after activation causes lysis by membrane attack complex. 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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3. 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
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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4. Platelet-activating factor (PAF)
• Derived from phospholipids in a number of cells
- causes PLT activation
- vasoconstriction and bronchoconstriction
- increases leukocyte adhesion to endothelium
5. 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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6. 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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Outcomes of acute inflammation
• Complete resolution
• Abscess formation – infection by pyogenic
organisms
• Healing by connective tissue replacement
(fibrosis)
• 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
such as 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
• They elicit a delayed type hypersensitivity reaction
• Persistent exposure to toxic or non-degradable
agents eg silica
• Immune mediated inflammatory diseases
• Autoimmune diseases
• Allergic diseases
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Histologic 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
• Also found in organs - liver (Kupffer cells),
spleen+LNs (sinus histiocytes), lungs (alveolar
macrophages)
• Are activated by different stimuli
• Activated macrophages:
– Eliminate injurious agent
– Causes 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 causes 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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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 may be
formed:
- leprosy
- fungal infections
- parasitic infections
- syphilis
- cat-scratch disease – caused by Afipia felis organisms
- sarcoidosis
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- Crohn disease
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 proteins, fibrinogen, serum amyloid A
• Leukocytosis
• Others
– ↑pulse, BP, rigors, chills, anorexia, malaise
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