Inflammation and cellular responses

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• Inflammation and cellular responses
• Prof Orla Sheils

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Inflammation

• Is a protective response
• The bodys response to injury
• Interwoven with the repair process

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Inflammation

• Types
• Acute (sec, mins, hrs)
• Chronic (days, weeks, months, yrs)

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Causes of inflammation

• Bacterial
• Viral
• Protozoal
• Metazoal
• Fungal
• Immunological
• Tumours
• Chemicals, toxins etc
• Radiation

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Acute inflammation
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Inflammation

• The Cardinal Signs of Acute Inflammation
• RUBOR
• CALOR
• TUMOR
• FUNCTIO LAESA

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Cardinal signs of inflammation
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Cardinal signs of inflammation
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Cardinal signs of inflammation
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Cardinal signs of inflammation
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Cardinal signs of inflammation
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Cardinal signs of inflammation
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Inflammation

• The basis of the five cardinal signs
• Increased blood flow due to vascular dilatation
  gives redness and heat.
• Increased vascular permeability gives oedema
  causing tissue swelling.
• Certain chemical mediators stimulate sensory
  nerve endings giving pain. Nerves also stimulated
  by stretching from oedema.
• Pain and swelling result in loss of function.

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Components of acute and chronic inflammation
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Cell of the acute inflammatory response

• Polymorphonuclear leukocyte

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The process of inflammation
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The phases of inflammation

• FIRST THERE IS VASCULAR DILATATION followed by
  exudation of protein-rich oedema fluid which
  floods the area, dilutes toxins, allows
  immunoglobulins to opsonise bacteria and provides
  substrate (fibrinogen) for fibrin scaffold.
• SECOND THERE IS ACTIVE EMIGRATION OF POLYMORPHS
  through vessel wall and along the chemotactic
  gradient to the site of injury

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The phases of inflammation

• THE VASCULAR PHASE OF INFLAMMATION
• Fluid escapes from vessels because of endothelial
  cell (EC)
• retraction, opening up gap-junctions.
• The vessels which are normally involved are the
  post-capillary
• venules where the EC have high affinity receptors
  for histamine.
• Severe EC injury leads to leakiness of all
  vessels
• capillaries, venules and arterioles - giving
  acute local oedema,
• e.g. blister formation after a burn.

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Local vascular manifestations of acute
inflammation
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Leukocyte migration in inflammation
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Molecules modulating endothelial-neutrophil
interactions
LFA-1 and MAC-1 (activated integrins)
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Acute inflammation tissue effects
Pavementation and diapedesis
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Acute inflammation tissue effects
Inflammatory cells in protein exudate
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Acute inflammation tissue effects
Blood vessel involved in the acute inflammatory
process
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Acute inflammation tissue effects
Bronchopneumonia
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Acute inflammation tissue effects
Abscess collection of acute inflammatory cells
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Acute inflammation tissue effects
Multiple splenic abscesses
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Chemical mediators of inflammation

• Vasoactive amines
• Histamine
• Serotonin (5-HT)
• Neuropeptides
• Substance P
• Plasma proteases and the complement system
• Action of Hageman factor
• Arachidonic acid metabolites
• Prostaglandins
• Leukotrienes
• Lipoxins
• Cytokines
• IL-1, TNF etc.
• Chemokines (CXC and CC)
• Nitric oxide and oxygen-derived free radicals

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Chemical mediators of inflammation

• PREFORMED
• Histamine, Serotonin
• NEWLY SYNTHESISED
• Prostaglandins
• Leucotrienes
• Platelet activating factor
• Cytokines
• Nitric oxide
• LOCAL AND SYSTEMIC

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Chemical mediators of inflammation (local and
systemic)
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Plasma proteases



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The complement system
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Arachidonic acid metabolites
HETE hydroxyeicosatetraenoic acid HPETE
hydroperoxyeicosatetraenoic acid
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Cytokines (IL-1 and TNF)
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Nitric oxide (NO)
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Effects of mediators of inflammation
Vasodilation Prostaglandins, NO Increased
vascular permeability Histamine, serotonin, C3a,
C5a, bradykinin, Leukotrienes C4, D4, E4,
platelet activating factor Chemotaxis, leukocyte
activation C5a, leukotriene B4, bacterial
products, chemokines (IL-8) Fever IL-1, IL-6,
TNF, prostaglandins Pain Prostaglandins,
bradykinin Tissue damage Neutrophil and
macrophage lysosomal enzymes, oxygen
metabolites NO
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Phagocytosis
Phagocytosis of bacteria by polymorphs
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• PHAGOCYTOSIS
• Recognition and attachment
• Foreign objects coated with opsonins IgG and C3b
  which attach to
• receptors on polymorph surface.
• Engulfment
• Cell membrane fuses around an object at the some
  time lysosomes
• empty into the vacuole, often before vacuole has
  time to seal - this gives
• rise to 'regurgitation during feeding' and
  enzymatic damage to surrounding
• tissue.
• Killing or degradation
• H2O2, hypohalous acid (HOC1) produced by
  myeloperoxidase and
• superoxides kill bacteria. Lysozyme digests them.

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Chronic inflammation
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Cells of the chronic inflammatory response

• Lymphocytes
• Monocytes/ macrophages
• Plasma cells

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Maturation of circulating monocytes to
macrophages
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Macrophage-lymphocyte interactions in chronic
inflammation
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Cellular interactions in chronic inflammation
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Chronic inflammation tissue effects
Knee joint in rheumatoid arthritis
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Chronic inflammation tissue effects
Chronic cervicitis
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Chronic inflammation tissue effects
Lung abscess
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Granulomatous inflammationa special form of
chronic inflammation
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Granuloma

• Definition
• A collection of macrophages, lymphocytes,
  mononuclear cells and fibroblasts with or without
  giant cell formation and constitutes a special
  form of chronic inflammation

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Granulomatous inflammation Bacterial TB,
Leprosy, Syphillis, cat-scratch
disease Parasitic Schistosomiasis Fungal Histo
plasma, blastomycosis, cryptococcus Inorganics,
metals, dusts Silicosis, berrylliosis Foreign
body Unknown Sarcoidosis
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Granulomatous inflammation tissue effects
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Granulomatous inflammation tissue effects
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Granulomatous inflammation tissue effects
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Granulomatous inflammation tissue effects
Epithelioid cells
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Granulomatous inflammation tissue effects
Talc granulomas in the lung
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Healing and repair
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Wound healing critical steps
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The cell cycle
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Cyclins, cyclin dependent kinases and cyclin
dependent kinase inhibitors
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Cell-cell interactions in repair
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Cell surface receptors in healing and repair
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The major components of the extracellular matrix
(ECM) required for healing and repair
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Extracellular matrix re-modelling occurs by the
action of Matrix metalloproteinases
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Matrix metalloproteinase regulation
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Critical steps in angiogenesis
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Major growth factors in wound healing
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Wound healing critical steps
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Granulation tissue
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Granulation tissue
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Scar tissue
Skin
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Scar tissue
Lung
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Outcome of healing and repair
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When healing goes wrong
Keloid scar