Inflammation an overview

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Inflammation an overview

• Hal Hawkins, Ph.D.,M.D.
• Fundamentals of Inflammation Course, BBSC 6210
• June 25, 2012

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ACUTE INFLAMMATION includes

• Vasodilation and vascular leakage
• Cellular
• recruitment
• activation
• functions
• tissue Injury

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MICROVASCULAR ENDOTHELIAL CELL
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Histamine
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Leakage of venules marked with colloidal
carbon(India ink) after application of histamine
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Triple Response of Lewis
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Vascular reactions account for the classical
cardinal signs of inflammation

• Tumor edema due to plasma leakage
• Rubor dilation of arterioles and engorgement of
  microvasculature
• Calor increased local temperature
• Dolor probably due to stretching and
  prostaglandins

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Time course of acute inflammation
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Neutrophil Recruitment

• MARGINATION
• ADHERENCE
• EMIGRATION AND CHEMOTAXIS

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Julius Cohnheim, 1839-1884
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Experiments of Cohnheim

• The tongue of the frog provides an
  opportunity to see the microcirculation and the
  movements of neutrophils.

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OBSERVATIONS OF COHNHEIM (1882)

• With the slowing of blood flow in the dilated
  venules leukocytes appear in the marginal stream
  and tend to stick to the vessel walls. At first
  the leukocytes stick momentarily and are then
  displaced to be washed away by the blood stream.

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more COHNHEIM

• As they begin to adhere more closely some
  are pushed slowly along by the blood stream,
  becoming flattened and elongated in the direction
  of the flow so that they have the appearance of
  blobs of jelly being pushed along over a sticky
  surface.

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more COHNHEIM

• Gradually some of the cells adhere more
  firmly until even a relatively swift stream of
  plasma and red corpuscles cannot dislodge them.
  
• With an adequate injury some of the
  leukocytes sticking to the wall begin to make
  their way through it by active movements, taking
  2 to 12 minutes to do so.

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Will this link work?http//www.youtube.com/watch
?vWEGGMaRX8f0
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Selectins (responsible for rolling)
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Integrins(essential for firm adhesion and
emigration)
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Integrin activation
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Armond Goldmans discovery of integrins
Armond Goldmans discovery of neutrophil integrins
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And another one in color!

• http//www.youtube.com/watch?v9wxK6oLA5oc

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And a third in diagram form

• http//www.youtube.com/watch?vDMvixApKzKs

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Transient opening of intercellular junctions
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(Neutrophil emigration does not produce vascular
leakage!)
(from Marchesi and Florey)
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Neutrophil Activation

• Receptors (complement, IgG, etc.)
• PAF (platelet activating factor)
• Phospholipase ?
• Inositol triphosphate ? Ca release
• Diacylglycerol ? Protein kinase C

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Platelet-Activating Factor, PAF
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Chemotaxis Migration toward higher concentration
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http//www.youtube.com/watch?vZUUfdP87Ssg
http//www.youtube.com/watch?vZUUfdP87Ssg
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Important chemotactic factors

• Complement fragment C5a
• Bacterial formylated peptides
• Arachidonic acid products,
• e.g. Leukotriene B4
• Cytokines called chemokines, e.g. IL-8

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Relative potencies of chemotactic factors
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Priorities among chemotactic factors
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COMPLEMENTa central mediator of inflammation
and immunity
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Complement components
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Neutrophil Functions

• PHAGOCYTOSIS
• FUSION OF GRANULES
• BACTERIAL KILLING

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Opsonization by complementstimulates phagocytosis
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Phagocytosis
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The Neutrophil Oxidative Burst
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Bacterial Killing

• O2-, superoxide
• H2O2, peroxide
• HOCl, hypochlorous acid ?
• OH, hydroxyl radical
• Acid hydrolases (enzymes)
• Bactericidal proteins, defensins, lactoferrin,
  lysozyme

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Pneumonia
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MEDIATORS of INFLAMMATION

• Plasma proteases, e.g. complement
• Vasoactive amines, e.g. histamine
• Platelet-activating factor PAF
• Arachidonic acid metabolites, e.g. prostaglandin
  E3
• Reactive oxygen and nitrogen species
• Cytokines and chemokines, e.g. IL-8
• Neuropeptides and endothelin

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Prostaglandins and leukotrienes

• Products of arachidonic acid metabolism
• Potent vasodilators/vasoconstrictors
• Cyclo-oxygenase (COX), needed for prostaglandin
  synthesis, is inhibited by aspirin and selective
  COX2 inhibitors including the notorious Vioxx
• Important in fever and pain
• Lipoxygenase leads to leukotrienes,
  proinflammatory lipids active in asthma

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Inflammatory Tissue Injury

• O2-, superoxide
• H2O2, peroxide
• HOCl, hypochlorous acid
• OH, hydroxyl radical
• ONOO-, peroxynitrite
• (all reactive oxygen and nitrogen species)
• Lysosomal neutral hydrolases

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Neutrophil apoptosis

• Follows emigration and phagocytosis
• Minimizes tissue injury

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Regulation of neutrophil apoptosis

• DELAY
• GM-CSF G-CSF
• LPS, IL-1, IL-2
• IFN-gamma
• STIMULATE
• IL-6
• Phagocytosis
• Oxidative burst

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Neutrophil apoptosis is the key to prevention of
tissue injury.

• Cellular contents may not be released
• Clearance by macrophages stimulates activation of
  macrophages to secrete factors favoring wound
  healing

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Whats new?

• Recognition of Pathogen Activated Molecular
  Pathways (PAMPs) including Toll Like Receptors
  (TLRs) and Damage Activated Molecular Pathways
  (DAMPs) (together sometimes called Alarmins).
• TLRs stimulate release of multiple
  pro-inflammatory peptides.
• DAMPs lead to assembly of inflammasomes,
  activation of caspase-1, and production of
  IL-1beta.

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