Inflammation

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Inflammation
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• ????
• Leukocyte migration
• Cell-adhesion molecules
• Mediators of inflammation
• The inflammatory process
• Anti-inflammatory agents

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Lymphocyte recirculation routes
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Extravasation Cell-adhesion molecules
(CAMs) (endothelial cells
leukocytes) - selectins - mucins -
integrins - ICAMS Receptors bind to CAMs
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General structures of the four families of
cell-adhesion molecules


Glycosylated proteins
Heterodimeric proteins Expressed by
leukocytes Facilitate adherence (LAD
disease)
Contain Ig/mucin-like domains Expressed on
endothelial cells Bind to
integrin/selectin molecules
Interact with sialylated carbohydrate
moieties of mucin-like molecules.
Responsible for the initial stickiness of
leukocytes to vascular endothelium.
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Steps in neutrophil extravasation
Inflammatory response ? cytokines, inflammatory
mediators Vascular endothelium activated Increased
expression of CAMs
Receptor activation- induced conforma-tional
change in the integrin molecules ? increased
affinity adhesion
Neutrophil activation by chemoattractant stimulus
chemokines, PAF, C5a, C3a, C5b67, bacterial
peptides
The neutrophil tumbles end-over-end along the
endothelium.
The neutrophil migrates through the vessel wall
into the tissues.
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Cell-adhesion molecules and chemokines involved
in the first three steps of neutrophil
extravasation
adhesion
rolling
activation
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Schematic cross-sectional diagram of a lymph node
postcapillary venule with high endothelium (HEV)
As many as 1.4 x 104 lymphocytes
extravasate every second through HEVs into a
single lymph node.
Each of the secondary lymphoid organs, with the
exception of the spleen, contains HEVs.
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Lymphocytes attached to the surface of a
high-endothelial venule
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Naïve T cell tend to home to secondary lymphoid
tissues through their HEV regions
Activation of a naïve cell occurs within
secondary lymphoid tissue.
(Homing receptor)
(Mucin-like CAM)
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Steps in extravasation of a naïve T cell through
a high endothelial venule into a lymph node

• Activation of
• integrin molecules

(a homing receptor)

• G-protein-coupled
• receptors

• Lymphocyte-specific
• chemoattractants

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• Mediators of inflammation
• Chemokines and other mediators released by
  tissue
• mast cells, blood platelets, leukocytes and
  lymphocytes.
• Mediator-producing systems in plasma
• - the kinin system
• - the clotting system
• - the fibrinolytic system
• - the complement system
• Some lipids act as inflammatory mediators
• Some cytokines are important inflammatory
  mediators

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Chemokines - key mediators of inflammation
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• Chemokines
• A superfamily of small polypeptides (90-130 aa
  residues)
• Major regulators of leukocyte traffic
• (adhesion, chemotaxis, activation)
• Involved in inflammation, homeostatic/development
  al
• processes, angiogenesis, wound healing
• Induced in response to infection
• ? Assembly of leukocytes at sites of
  infection
• gt 50 chemokines, possess 4 conserved cysteine
  residues
• (C-C subgroup, C-X-C subgroup)
• gt 15 chemokine receptors (CC receptors, CXC
  receptors)
• The interaction between chemokines and their
  receptors
• is of high affinity (Ka gt 109) and high
  specificity.

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Chemokines signal through receptors coupled with
heterotrimeric large G proteins

• Changes in shape of leukocytes
• Activation of integrins
• Generation of oxygen radicals
• Release of granular contents and proteases

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Patterns of expression of some principal
chemokine receptors on different classes of human
leukocytes
TH1 cells CCR1, -3, -5 TH2 cells CCR3, -4
Chemokine-receptor profiles mediate leukocyte
activity.
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Plasma enzymes act as inflammatory mediators
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Tissue damage induces formation of plasma enzyme
mediators by the kinin system, the clotting
system, and the fibrinolytic system
(a plasma clotting factor)
fibrinogen
C5
C5a C5b
mast cell degranulation mediators release
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• The complement system
• anaphylatoxins (C3a, C4a, C5a)
• ? mast cell degranulation mediators
  (histamine) release
• ? increase vascular permeability
• induce smooth-muscle contraction
• C3a, C5a and C5b67
• ? adhesion, extravasation and migration
• of monocytes and neutrophils
• Influxes of fluid that carry antibody and
• phagocytic cells to the site of antigen entry.

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Lipids act as inflammatory mediators
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The breakdown of membrane phospholipids generates
important mediators of inflammation, including
thromboxane, prostaglandins, leukotrienes, PAF
(macrophages, monocytes, neutrophils and mast
cells)
(platelet- activating factor)
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Cytokines act as inflammatory mediators
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• IL-1, IL-6, TNF-a, IL-12, and many chemokines
• exhibit redundant and pleiotropic effects.
• IL-1, IL-6, TNF-a
• IFN-g attracting activating macrophages
• IL-12 inducing the differentiation of
• the proinflammatory TH1 subset

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IFN-g contributing to chronic inflammation by
attracting and activating macrophages. IL-12
induces the differentiation of the
proinflammatory TH1 subsets.
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The inflammatory process
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• The inflammatory process
• acute inflammatory response (neutrophils,
  1010/day)
• - localized inflammatory response
• (redness, swelling, heat, pain)
• - systemic acute-phase response
• chronic inflammation (antigen persists)
  (macrophages)
• - IFN-g
• - TNF-a
• - fibrosis (scar formation)
• - granuloma formation
• chronic inflammatory diseases

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The major local manifestations of acute
inflammation
extravasation of plasma fluid and proteins
Leukocyte emigration and accumulation in the
site of injury.
vascular dilation (erythema warmth)
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• A localized acute inflammatory response
• redness heat
• vasodilation - an increase in vascular diameter
• an increase in the volume of blood in the area
• a reduction in the flow of blood
• swelling
• an increase in vascular permeability
• leakage of fluid from the blood vessels
• an accumulation of fluid in the tissue (edema)
• extravasation of leukocytes
• activation of the kinin, clotting, fibrinolytic
• and complement (C53a, C4a, C5a) systems

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• Macrophages
• arrive about 5-6 hours after an inflammatory
  response begins
• exhibit increased phagocytosis
• exhibit increased release of mediators,
  cytokines and
• lytic enzymes that contribute to the
  inflammatory response
• (IL-1, IL-6, TNF-a)

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Overview of the cells and mediators involved in a
local acute inflammatory response
(tissue damage)
Tissue repair TGF-b, proliferation of
fibroblasts, deposition of extracellular matrix
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• The inflammatory process
• acute inflammatory response (neutrophils, 1010 x
  10/day)
• - localized inflammatory response
• (redness, swelling, heat, pain)
• - systemic acute-phase response
• chronic inflammation (antigen persists)
  (macrophages)
• - IFN-g
• - TNF-a
• - fibrosis (scar formation)
• - granuloma formation
• chronic inflammatory diseases

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Overview of the organs and mediators involved in
a systemic acute-phase response
(inhibits the growth of pathogens)
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The acute-phase response produces molecules that
bind pathogens but not host cells.

On vertebrate cells, these mannose residues are
covered by other sugar groups, especially by
sialic acid while avoiding complement activation
on host cell surfaces.
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C/EBP is expressed constitutively in liver
hepatocytes and promotes transcription of albumin
and transthyretin genes
During an inflammatory response
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Comparison of the structure and function of C/EBP
and NF-IL6
Both transcription factors are dimeric proteins
containing a leucine-zipper domain and a basic
DNA-binding domain. Both proteins bind to the
same nucleotide sequence in the promoter or
enhancer of the genes encoding various liver
proteins.
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Outcome of acute inflammation
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• The inflammatory process
• acute inflammatory response (neutrophils, 1010 x
  10/day)
• - localized inflammatory response
• (redness, swelling, heat, pain)
• - systemic acute-phase response
• chronic inflammation (antigen persists)
  (macrophages)
• - IFN-g
• - TNF-a
• - fibrosis (scar formation)
• - granuloma formation
• chronic inflammatory diseases

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A prolonged DTH response can lead to formation of
a granuloma
Lytic enzymes released from activated macrophages
in a granuloma can cause extensive tissue damage.
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Roles of IFN-g and TNF-a in chronic inflammation
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Summary of pleiotropic activity of interferon
gamma (IFN-?)
Activated macrophages secrete TNF-a. TNF-a
acts synergistically with IFN-g to initiate a
chronic inflammatory response.
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Biological activities of TNF-?
(endotoxin)
Endotoxin induces macrophages to produce TNF-a,
which then acts to destroy the tumor.
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Transgenic mouse (top) bearing a TNF-a transgene
becomes anorectic and severely wasted
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• The inflammatory process
• acute inflammatory response (neutrophils, 1010 x
  10/day)
• - localized inflammatory response
• (redness, swelling, heat, pain)
• - systemic acute-phase response
• chronic inflammation (antigen persists)
  (macrophages)
• - IFN-g
• - TNF-a
• - fibrosis (scar formation)
• - granuloma formation
• chronic inflammatory diseases

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HEV-like regions sites of lymphocyte
extravasation into the inflamed tissue. IFN-g
and TNF-a may play a role in the induction of
HEV-like regions along the vasculature.
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Leukocyte-adhesion deficiency (LAD) in humans and
cattle - A rare autosomal recessive
disease - omphalitis (a swelling and
reddening around
the stalk of the umbilical cord) -
Patients suffer recurrent and often chronic
bacterial infections (inability of
their leukocytes to undergo adhesion-dependent
migration into sites of inflammation)
- An absence of CD18 (an essential component
of a number of integrins)
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Anti-inflammatory agents
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• Anti-inflammatory agents
• Antibody therapies reduce leukocyte
  extravasation
• - to block the activity of various adhesion
  molecules
• (anti-ICAM-1 anti-LFA-1)
• Corticosteroids are powerful anti-inflammatory
  drugs
• - reduction in the numbers and activity of
  immune-system cells
• - prevents NF-kB activation
• - reduces the phagocytic and killing ability of
  macrophages
• and neutrophils
• - reduces chemotaxis
• - reduces expression of class II MHC molecules
  and
• IL-1 production by macrophages
• - reduces the release of lysosomal enzymes
• NSAIDs combat pain and inflammation

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• Corticosteroids
• lipophilic
• can cross the plasma membrane
• form receptor-hormone complex in the cytosol
• transported to the nucleus
• bind to specific regulatory DNA sequences
• induce increased transcription of the NF-kB
  inhibitor (I-kB)
• binding of I-kB to NF-kB in the cytosol
• prevent the translocation of NF-kB into the
  nucleus
• prevent NF-kB activation of a number of genes
• (genes involved in T cell activation and
  cytokine production)

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Inhibition of cyclooxygenase 1 and 2 by NSAIDs
Cox-2-specific NSAIDs inhibit inflammation and
do not cause damage to the GI tract
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• Inflammation
• redness
• swelling
• heat
• pain
• immune-system cells
• mediators

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Sequence of leukocyte events in inflammation
(shown here for neutrophils)