5. Chemical Mediators
Def: Any messenger that acts on blood
vessels, leucocytes, or other cells to
contribute to an inflammatory response
v3-CSBRP-May-2012
8. Chemical Mediators
General properties:
• They are generated from:
Cells
Plasma proteins
• Mediators are produced in response to various stimuli
• One mediator can stimulate the release of other
[Guarantees amplification and maintenance of inflammatory response]
• Mediators vary in their range of cellular targets
• Majority are short-lived [Short t ½ and are harmful]
v3-CSBRP-May-2012
10. Cell derived mediators
Vasoactive Amines: Histamine and Serotonin
AA Metabolites: PGs, LTs, and Lipoxins
Platelet-Activating Factor (PAF)
ROS
Nitric Oxide (NO)
Cytokines and Chemokines
Tumor Necrosis Factor and Interleukin-1
Chemokines
Other Cytokines IL6, IL17
Lysosomal Constituents of Leukocytes
Neuropeptides
v3-CSBRP-May-2012
11. Plasma derived mediators
PLASMA PROTEASES
3 interrelated systems are active within this category
1. Kinin system
Highly vasoactive
2. Complement system
Vasoactive
Chemotactic
3. Clotting system
Vasoactive
Cleaves C3
v3-CSBRP-May-2012
12. Cell derived mediators
Vasoactive Amines: Histamine and Serotonin
AA Metabolites: PGs, LTs, and Lipoxins
Platelet-Activating Factor (PAF)
ROS
Nitric Oxide (NO)
Cytokines and Chemokines
Tumor Necrosis Factor and Interleukin-1
Chemokines
Other Cytokines IL6, IL17
Lysosomal Constituents of Leukocytes
Neuropeptides
v3-CSBRP-May-2012
13. Cell derived mediators
Vasoactive Amines: Histamine and Serotonin
• Increase Vascular Permeability
• Histamine and Serotonin
Mediators in the immediate active phase of
increased permeability
– Promotes contraction of smooth muscle
– Stimulates to cells to produce eotaxins
v3-CSBRP-May-2012
14. Cell derived mediators
Vasoactive Amines: Histamine and Serotonin
• Releasing Stimulators
– Direct physical or chemical injury
– Binding of IgE- Ag- complexes
– Fragments of C3a and C5a
– Histamine releasing factors (pmn’s and θ)
– Cytokines (IL-1, IL-8)
– Neuropeptides
v3-CSBRP-May-2012
15. ARACHIDONIC ACID
METABOLITES
• Roles in many biologic and • Via activation of cellular
pathologic processes phospholipases
– Inflammation – By mechanical, chemical
• 20-carbon polyunsaturated and physical stimuli or by
other mediators
fatty acid
– Derived directly from dietary • 2 major pathways
sources or by conversion of – Cyclooxygenase pathway
essential fatty acid linoleic – Lipoxygenase pathway.
acid
• Esterified in membrane
phospholipids
– Must first be released from
phospholipids
v3-CSBRP-May-2012
17. CYCLOOXYGENASE PATHWAY
• 2 cyclooxygenase enzymes
– COX-1
– COX-2
• 3 important products
– Thromboxane A2
– Aggregates platelets and causes vasoconstriction
– Prostacyclin (PGI2)
– Endothelial cells inhibits platelet aggregation and causes
vasodilation
– Prostaglandins PGE2, PGF2 and PGD2
– Variety of actions on vascular tone and permeability
v3-CSBRP-May-2012
18. LIPOXYGENASE PATHWAY
Leukotrienes - LT
• LT B4 is a potent chemotactic agent
• Leukotrienes C4, D4, E4
– Potent vasoconstrictors
– Potent mediators of increased vascular
permeability on venules only
– Up to 1000 times as potent as histamine in
producing increased vascular permeability
v3-CSBRP-May-2012
19. NOTE:
Some anti-inflammatory drugs interfere
with arachidonic acid metabolism
– Corticosteroids interfere with phospholipase
– Aspirin interferes with cyclooxygenase
v3-CSBRP-May-2012
20. PLATELET ACTIVATING
FACTOR - PAF
• Aggregate platelets and cause release
• Bronchoconstriction and Vasoconstriction
• ↑ vascular permeability
• ↑ leukocyte adhesion
• Leukocyte chemotaxis
v3-CSBRP-May-2012
21. CYTOKINES
• Transmitters for cell-to-cell chatting
– Modulate cell function
• Primarily from activated macrophages and
lymphocytes
• IL-1, IL-8, TNF
v3-CSBRP-May-2012
22. IL-I and TNF
“Master Cytokines”
• Origin
– Monocytes
– Macrophages
• Similar in action
• Endothelium
• Acute phase proteins
• Fibroblasts
v3-CSBRP-May-2012
27. Plasma derived mediators
PLASMA PROTEASES
3 interrelated systems are active within this category
1. Kinin system
Highly vasoactive
2. Complement system
Vasoactive
Chemotactic
3. Clotting system
Vasoactive
Cleaves C3
v3-CSBRP-May-2012
29. BRADYKININ
• Released by activated Hageman factor (XIIa)
• Bradykinin
• Release of vasoactive nonapeptide bradykinin
• Generated from the plasma HMWK
• Potent vasodilator
• Increased vascular permeability
• Contraction of smooth muscle PAIN
• Produce pain
• Stimulates release of histamine
• Activates the arachidonic acid cascade
v3-CSBRP-May-2012
30. IMPORTANT NOTE
Activated Hageman factor (factor XIIA)
initiates the clotting, fibrinolytic and kinin
systems
The products of this initiation (kallikrein,
factor XIIA, and plasmin, but particularly,
kallikrein) can, by feedback, activate
Hageman factor, resulting in significant
amplification of the effects of the initial
stimulus
v3-CSBRP-May-2012
31. Complement system
• Plasma proteins - act against microbial
agents
• Products of activated complement
– Vascular permeability
– Chemotaxis
– Opsonization
– Lysis
v3-CSBRP-May-2012