The specific molecule is likely prostaglandin D2 (PGD2). PGD2 is released by mast cells at sites of injury or infection and acts as a potent vasodilator and increases capillary permeability, leading to edema and plasma extravasation - key components of the inflammatory response. Other prostaglandins like PGE2 may also be involved, but PGD2 is particularly associated with acute inflammation triggered by tissue damage
Similar a The specific molecule is likely prostaglandin D2 (PGD2). PGD2 is released by mast cells at sites of injury or infection and acts as a potent vasodilator and increases capillary permeability, leading to edema and plasma extravasation - key components of the inflammatory response. Other prostaglandins like PGE2 may also be involved, but PGD2 is particularly associated with acute inflammation triggered by tissue damage
Similar a The specific molecule is likely prostaglandin D2 (PGD2). PGD2 is released by mast cells at sites of injury or infection and acts as a potent vasodilator and increases capillary permeability, leading to edema and plasma extravasation - key components of the inflammatory response. Other prostaglandins like PGE2 may also be involved, but PGD2 is particularly associated with acute inflammation triggered by tissue damage (20)
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The specific molecule is likely prostaglandin D2 (PGD2). PGD2 is released by mast cells at sites of injury or infection and acts as a potent vasodilator and increases capillary permeability, leading to edema and plasma extravasation - key components of the inflammatory response. Other prostaglandins like PGE2 may also be involved, but PGD2 is particularly associated with acute inflammation triggered by tissue damage
3. DiapedesisDiapedesis
• It occurs mostly thru post capillary venules
• Chemokines stimulate the PMNs to
emigrate into interstitium
• PMNs leave the vessel thru inter
endothelial gaps
• In the interstitium they travel towards the
site of injury
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4. Adhesion molecules (AM) involved
in diapedesis
• AM present in between the endothelial
cells and in the interstitium facilitate this
process
• These include:
• PECAM-1 or CD31
• Several junctional AMs
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5. DiapedesisDiapedesis
• Must then cross basement membrane
– Collagenases
• PMNs secrete collagenases to dissolve
basement membrane
• Then they reach the site of injury by
Chemotaxis
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6. Summary of DIAPEDESIS
Insertion of pseudopodia
which widens the intercellular gaps
Passage through the gaps
by ameboid movement
Passage through the basement membrane
either by mechanical disruption or possibly by
enzyme (collagenase) effect
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12. Chemotaxis
In the intestitium leucocytes reach the site of
injury by traveling along the concentration
gradient created by the chemokines -
Chemotaxis
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13. Chemotaxis
Def: Chemotaxis is a process by which the
leucocytes travel towards and along the
chemical concentration gradient
Concentration gradient is created by
chemokines
Highest concentration occurs at the center of
injury
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14. This is a diagram showing the effect of chemokine concentration
gradient on chemotaxis direction. The attracted cell moves through
the gradient toward the higher concentration of chemokine.
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Neutrophil
Bacteria
15. Chemotaxis
• Leukocytes follow chemical gradient to the site
of injury
• Chemotactic agents: include
– Soluble bacterial products
– Complement components (C5a)
– Cytokines (chemokine family e.g., IL-8)
– LTB4 (AA metabolite)
• Chemotactic agents bind surface receptors
inducing calcium mobilization and assembly of
cytoskeletal contractile elements
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17. Chemotactic substances will bind to
leukocyte receptors, initiating a stimulus –
receptor interaction that leads to activation
of intracellular contractile proteins
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18. Leukocytes:
–Extend pseudopods with overlying
surface adhesion molecules (integrins)
that bind ECM during chemotaxis
–Leucocytes walk towards the injury
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20. When they reach the site…
• PMNs able to adhere to the intercellular
matrix by binding of integrins to CD44
• By this mechanism they are retained at
the site where they are needed most
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21. Details of Leukocyte Chemotaxis:
Neutrophil adheres via integrin binding
Integrin binds to FN in ECM
Actually recognizes RGD sequence (arg-gly-asp) in FN (not shown in figure)
RGD is also found in other ECM proteins
Integrin is recycled
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23. PHAGOCYTOSISPHAGOCYTOSIS
Ingestion and processing of particulate
material by phagocytic cells
–Particulate matter can be:
• Tissue debris, bacteria, other foreign cells
–Phagocytic cells:
• PMNs
• MØ
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25. PHAGOCYTOSISPHAGOCYTOSIS
The process of phagocytosis involves:
1. Adhesion – Immobilizes the particles
2. Engulfment by extending pseudopodia
3. Fusion - Phagolysosome formation of the lysosomes
with the phagocytic vacuole
4. Degradation / Intracellular microbial killing
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29. PHAGOCYTOSISPHAGOCYTOSIS
The process of phagocytosis:
Adhesion
• Collectins, C3b, Fc portion of Ig
Opsonization:
Coating the particle by OPSONINS
• Complement C3b
• Immunoglobulins IgG
Opsonization facilitates phagocytosis
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33. PHAGOCYTOSISPHAGOCYTOSIS
The process of phagocytosis:
Opsonins:
Like sauce making the bread palatable,
opsonins make particles palatable for
phagocytes
Opsonization facilitates phagocytosis
PMNs and MØ has receptors for C3b & Fc
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35. ActivationActivation
• When the leucocytes gets stimulated by
the cytokines, they get activated
• With activation:
– AM are modulated / potentiated
– Chemotaxis is potentiated
– Elaborate AA metabolites
– Secretion / Degranulation
– Oxidative out burst
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36. Activation
The biologic activities
resulting from
leukocyte activation
include
Chemotaxis
Modulation of AM
Elaboration of AA
Metabolites
Secretion /
Degranulation
Oxidative burst
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37. Defects in Leucocyte Function
Can be genetic / acquired
Results in increased vulnerability to infections
• Defects in leucocyte adheshion
• Defects in phagolysosome function
– Chediak - Higashi syndrome
• Defects in microbicidal activity
– Chronic Granulomatous Disease
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38. Defects in Leucocyte Function
GENETIC
• LAD1 beta chain of CD11/CD18 integrins
• LAD2 fucosyl tranferase required for synthesis of
sialyated oligosccharide (receptor for selectin)
• CGD (decreased oxidative burst)
– X-linked (NADPH oxidase – membrane component)
– Autosomal recessive (NADPH oxidase - cytoplasmic)
– MPO deficiency (absent MPO-H2O2 system)
• Chediak-Higashi syndrome (protein involved in
organelle membrane fusion)
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44. Laboratory Findings in Inflammation
“Left Shift”: an increase in the number of
immature neutrophils
Immature neutrophils: Bands or stabs
Meta or Juvenile
Myleocyte
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45. “Left Shift”
Baso Eos Meta Stabs Segs Lymph Mono
70 20 3321 1
Normal
75 8 11210 3
Left Shift
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47. Laboratory Findings in Inflammation
Erythrocyte Sedimentation Rate
(ESR) will be increased
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48. Erythrocyte Sedimentation Rate (ESR)
0
10
20
30
40
50
60
70
80
90
100
mm
1hr
The distance, in mm,
the RBC fall in 1 hr
is the Sed Rate
0
10
20
30
40
50
60
70
80
90
100
mm
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49. Acute Phase Proteins
During an inflammatory response a
number of interleukins(IL) are produced
IL-6 stimulates the hepatic production of
a number of proteins ,called acute phase
proteins
May-2015-CSBRP
51. Acute Phase Proteins
Acute Phase Proteins are normally found
in the blood at low concentrations, but
following hepatic stimulation by IL-6
their concentration increases
Detection of elevated levels of acute
phase proteins is an indication of an
inflammatory response
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60. Inflammatory Paracrines
• What causes the characteristic sequence of events in acute inflammation? Various
cells at the site of tissue damage or of a specific immune response release regulatory
molecules that act locally as paracrines.
• Macrophages and lymphocytes are important sources of inflammatory paracrines. As
we have discussed, macrophages release IL-1 and TNF-alpha, which have powerful,
widespread effects.
• Also important are mast cells, which are found throughout the body, especially under
epithelia. Mast cells are filled with large vesicles containing histamine and other
inflammatory paracrines (They also release PG D2, several LTs and TNF-alpha,
described below). Factors associated with tissue damage can trigger the exocytosis.
But sometimes it is a specific immune response that triggers the release of the
inflammatory paracrines.
• Also, various arachidonic acid derivatives are important. Both prostaglandins
(notably PG D2) and leukotrienes (LT) can be important, depending on the tissue.
Note the effectiveness of aspirin and various NSAIDs in quieting inflammation.
• Complement peptides, C3a and C5a
• Various other molecules including nitric oxide, certain platelet products, kinins, and
certain other substances we will not discuss (serotonin, etc)
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61. What types of molecules trigger
inflammation?
• Inflammatory paracrines
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62. Name some cells that release the
paracrine molecules.
• Mast cells
• Macrophages
• Almost every cell can release AA
derivatives
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63. What is complement C5a?
When the complement system is activated,
a small peptide C5a is cleaved from the
protein C5. C5a readily diffuses, causing
chemotaxis and inflammation in general
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64. What change caused by inflammatory
paracrines results in edema in the affected
area?
Increased capillary permeability
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65. Suppose tissue damage triggers the release of a
prostaglandin that causes inflammation in the
area. What specific molecule does the tissue
damage activate that starts the synthesis of the
prostaglandin?
Phospholipase A2
Other enzymes, including COX, then
convert the arachidonic acid to the
prostaglandin
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72. Ligands
• In biochemistry and pharmacology, a ligand (Latin ligare = to bind) is a
substance that is able to bind to and form a complex with a biomolecule to
serve a biological purpose.
• In a narrower sense, it is a signal triggering molecule, binding to a site on a
target protein.
• The binding occurs by intermolecular forces, such as ionic bonds, hydrogen
bonds and Van der Waals forces. The docking (association) is usually
reversible (dissociation). Actual irreversible covalent binding between a
ligand and its target molecule is rare in biological systems. In contrast to the
meaning in metalorganic and inorganic chemistry, it is irrelevant whether the
ligand actually binds at a metal site, as it is the case in hemoglobin.
• Ligand binding to a receptor alters the chemical conformation, that is the
three dimensional shape of the receptor protein. The conformational state of
a receptor protein determines the functional state of a receptor. Ligands
include substrates, inhibitors, activators, and neurotransmitters. The
tendency or strength of binding is called affinity.
• Radioligands are radioisotope labeled compounds and used in vivo as
tracers in PET studies and for in vitro .
May-2015-CSBRP
73. This is a diagram showing the effect of chemokine concentration
gradient on chemotaxis direction. The attracted cell moves through
the gradient toward the higher concentration of chemokine.
May-2015-CSBRP
74. WOW!
The movement of leucocytes from out of the blood
vessels into the tissues spaces is known as
DIAPEDESIS
May-2015-CSBRP
75. WOW!
The movement of leucocytes from out of the blood
vessels into the tissues spaces is known as
DIAPEDESIS
May-2015-CSBRP
Notas del editor
After traversing the endothelium PMNs secrete collagenases to dissolve basement membrane
Then they enter the interstitium and reach the site of injury by travelling along the concentration gradient created by the chemokines - Chemotaxis
Towards & along: this is unidirectional movement
This is a diagram showing the effect of chemokine concentration gradient on chemotaxis direction. The attracted cell moves through the gradient toward the higher concentration of chemokine.
CD44 is on the leucocytes which binds with heparin sulfate on the endothelium / fibronectin in the interstitium.
CD44 also can bind to ICAM1 or VCAM present on endothelium (belong to Ig family)
Details of Leukocyte Chemotaxis:
Neutrophil adheres via integrin binding
Integrin binds to FN in ECM
Actually recognizes RGD sequence (arg-gly-asp) in FN (not shown in figure)
RGD is also found in other ECM proteins
Integrin is recycled
Nitric oxide, which is released from endothelial cells and macrophages and produces vasodilatation and cytotoxicity.
Phagocytic cells are either microphages (neutrophils) or macrophages (monocytes from blood or histiocytes from tissues). The process of phagocytosis involves
a.Adhesion of opsonized particles to Fc fragment receptors on the surface of the phagocyte.
b. Engulfment by extending pseudopodia around the particle. Fusion of these pseudopodia will create a heterophagic vacuole formed by internalized plasmalemma.
c. Fusion of the lysosomes with the phagocytic vacuole.
d. Intracellular microbial killing
Phagocytic cells are either microphages (neutrophils) or macrophages (monocytes from blood or histiocytes from tissues). The process of phagocytosis involves
a.Adhesion: attachement of particles to cell surface. This is aided by opsonins. Fc fragment receptors on the surface of the phagocyte.
b. Engulfment by extending pseudopodia around the particle. Fusion of these pseudopodia will create a heterophagic vacuole formed by internalized plasmalemma.
c. Fusion of the lysosomes with the phagocytic vacuole.i.e. phagolysosome formation (pH=4)
d. Degradation / Intracellular microbial killing: results in residual body or extrusion.
Phagocytic cells are either microphages (neutrophils) or macrophages (monocytes from blood or histiocytes from tissues). The process of phagocytosis involves
a.Adhesion: attachement of particles to cell surface. This is aided by opsonins. Fc fragment receptors on the surface of the phagocyte.
b. Engulfment by extending pseudopodia around the particle. Fusion of these pseudopodia will create a heterophagic vacuole formed by internalized plasmalemma.
c. Fusion of the lysosomes with the phagocytic vacuole.i.e. phagolysosome formation (pH=4)
d. Degradation / Intracellular microbial killing: results in residual body or extrusion.
Phagocytic cells are either microphages (neutrophils) or macrophages (monocytes from blood or histiocytes from tissues). The process of phagocytosis involves
a.Adhesion: attachement of particles to cell surface. This is aided by opsonins. Fc fragment receptors on the surface of the phagocyte. Attachemnt immobilizes particles and facilitates engulfment.
b. Engulfment by extending pseudopodia around the particle. Fusion of these pseudopodia will create a heterophagic vacuole formed by internalized plasmalemma.
c. Fusion of the lysosomes with the phagocytic vacuole.i.e. phagolysosome formation (pH=4)
d. Degradation / Intracellular microbial killing: results in residual body or extrusion.
Defects in leucocyte function: Defects inleucocyte function, both fenetic and acquired, lead to increased vulnerability to infections:
--- Defects in leucocyte adheshion
--- Defects in phagolysosome function. One such disorder is Chediak-Higashi syndrome, an AR condition characterized by neutropenia, defective degranulation and delayed microbial killing
--- Defects in microbicidal activity: The importance of exygen dependent bactericidal mechanism is shown by the exstence of a group of congenital disrders with defects in bacterial killing called CGD
Defects in leucocyte function: Defects inleucocyte function, both genetic and acquired, lead to increased vulnerability to infections:
GENETIC
--- LAD1 beta chain of CD11/CD18 integrins
--- LAD2 fucosyl tranferase required for synthesis of sialyated oligosccharide (receptor for selectin)
--- CGD (decreased oxidative burst)
X-linked (NADPH oxidase – membrane component)
Autosomal recessive (NADPH oxidase - cytoplasmic)
MPO deficiency (absent MPO-H2O2 system)
--- Chediak-Higashi syndrome (protein involved in organelle membrane fusion)
Defects in leucocyte function: Defects inleucocyte function, both genetic and acquired, lead to increased vulnerability to infections:
ACQUIRED
-- thermal injury, diabetes, malignancy, sepsis, immunodeficiencies (chemotaxis)
-- Hemodialysis, diabetes mellitus (Adhesion)
-- Leukemia, anemia, sepsis, diabetes, neonates, malnutrition (phagocytosis and microbicidal activity)
Adhesion cascade in leukocyte adhesion deficiency (LAD) syndromes.
<emedicine.medscape.com/article/886248-media>
Introduction to Chemokine Families and the Cells They Affect :
Chemokines (Greek -kinos, movement) are a family of small cytokines, or proteins secreted by cells. Their name is derived from their ability to induce directed chemotaxis in nearby responsive cells; they are chemotactic cytokines. Proteins are classified as chemokines according to shared structural characteristics such as small size (they are all approximately 8-10 kilodaltons in size), and the presence of four cysteine residues in conserved locations that are key to forming their 3-dimensional shape. However, these proteins have historically been known under several other names including the SIS family of cytokines, SIG family of cytokines, SCY family of cytokines, Platelet factor-4 superfamily or intercrines. Some chemokines are considered pro-inflammatory and can be induced during an immune response to promote cells of the immune system to a site of infection, while others are considered homeostatic and are involved in controlling the migration of cells during normal processes of tissue maintenance or development. Chemokines are found in all vertebrates, some viruses and some bacteria, but none have been described for other invertebrates. These proteins exert their biological effects by interacting with G protein-linked transmembrane receptors called chemokine receptors, that are selectively found on the surfaces of their target cells.
In biochemistry and pharmacology, a ligand (Latin ligare = to bind) is a substance that is able to bind to and form a complex with a biomolecule to serve a biological purpose. In a narrower sense, it is a signal triggering molecule, binding to a site on a target protein.
The binding occurs by intermolecular forces, such as ionic bonds, hydrogen bonds and Van der Waals forces. The docking (association) is usually reversible (dissociation). Actual irreversible covalent binding between a ligand and its target molecule is rare in biological systems. In contrast to the meaning in metalorganic and inorganic chemistry, it is irrelevant whether the ligand actually binds at a metal site, as it is the case in hemoglobin.
Ligand binding to a receptor alters the chemical conformation, that is the three dimensional shape of the receptor protein. The conformational state of a receptor protein determines the functional state of a receptor. Ligands include substrates, inhibitors, activators, and neurotransmitters. The tendency or strength of binding is called affinity.
Radioligands are radioisotope labeled compounds and used in vivo as tracers in PET studies and for in vitro .
This is a diagram showing the effect of chemokine concentration gradient on chemotaxis direction. The attracted cell moves through the gradient toward the higher concentration of chemokine.