pathology lecture

1. Mediators of Inflammation

2. Introduction
• What are mediators?
A mediator is a substance or structure
that mediates ( progresses, propagates or
enhances)inflammatory response.

3. Properties of Mediators of
Inflammation
• Major cell types that produce mediators
are
• Platlets
• Monocytes
• Macrophages
• Mast cells
• Mesechymal cells
&
epithelium

4. • Active mediators are produced in respose to
various stimuli
• One mediators can stimulate the release of
other mediators

5. They are
• short lived
• Quickly decay
• Inactivated by enzymes
Or
Inhibited
A system of check and balance

6. Chemical Mediators
of Inflammation
Cell-Derived
Plasma-Protein-
Derived

7. Chemical Mediators of Inflammation
Cell-Derived Plasma-Protein-Derived
Vasoactive Amines
Eicosanoids
PAF
Cytokines
Chemokines
ROS
NO
Lysosomal Enzymes of Leukocytes
Neuropeptides

8. Chemical Mediators
of Inflammation
Cell-Derived
Plasma-Protein-
Derived
Complement
Coagulation and Kinin
Systems

9. Cell-Derived Mediators

10. Vasoactive Amines
Histamine
&
Serotonin

11. Histamine
• Source:
many cell types, esp. mast cells, circulating
basophils, and platelets
• Actions:
 ARTERIOLAR DILATION
 INCREASED VASCULAR PERMEABILITY
 ENDOTHELIAL ACTIVATION
• Inactivated by:
Histaminase

12. Histamine
• Stimuli of Release:
1. Physical injury
2. Immune reactions
3. C3a and C5a fragments of complement
(anaphylatoxins)
4. Leukocyte-derived histamine-releasing
proteins
5. Neuropeptides (e.g. substance P)
6. Certain Cytokines (e.g. IL-1 and IL-8)

13. Serotonin
(5-HT)
• Source:
Platelets
• Action:
Similar to histamine’s
• Stimulus:
Platelet aggregation

14. Eicosanoids
Eicosanoids
=
Arachidonic Acid (AA) Metabolites
=
Prostaglandins (PG),
Leukotrienes,
and Lipoxins

16. Eicosanoids
• Source:
Leukocytes
Mast cells
Endothelial cells
Platelets

17. Arachidonic Acid
• 20-carbon polyunsaturated fatty acid (4
double bonds)
• Obtained from dietary linoleic acid
• Present in the body in its esterified form
as a component of cell membrane
phospholipids
• Released from phospholipids via
phospholipases

18. AA Metabolism
• Two major enzymatic pathways:
1. Cyclooxygenase  Prostaglandins &
Thromboxanes
2. Lipooxygenase  Leukotrienes and
Lipoxins

19. Platelet Activating Factor
(PAF)

20. Platelet Activating Factor
(PAF)
• Another phospholipid derivative
• Very potent bioactive molecule
• Source: membranes of
Neutrophils, monocytes, basophils,
endothelial cells, & platelets
• Derived by the action of
Phospholipase A2
• Acts via G-protein-coupled receptor

21. PAF
• Actions:
 Platelet activation (aggregation &
degranulation)
 Vasoconstriction
 Bronchoconstriction
 Leukocyte adhesion
 Leukocyte degranulation
 Chemotaxis
 Synthesis of other mediators, esp.
Eicosanoids

22. Cytokines

23. TNF and IL-1
• Source:
Activated macrophages
Mast cells
Endothelial cells
• Stimulation:
Bacterial endotoxins
Immune complexes
Physical injury &
Variety of inflammatory stimuli

25. Chemokines

26. Chemokines
• Small proteins
• They are chemoattractants for specific
type of leukocytes
• Main functions:
1. Leukocyte recruitment & activation in
inflammation
2. Control the normal migration of cells
through various tissues.

27. Types
• C-X-C Chemokines
• C-C Chemokines
• C-Chemokines
• CX3C Chemokines

28. Reactive Oxygen Species

29. Reactive Oxygen Species
• Synthesized via
NADPH oxidase pathway
• Source:
Neutrophils and Macrophages
• Stimuli of release:
Microbes
Immune complexes
Cytokines

30. • Low level of these mediators increase the
expression of chemokines,cytokines and
endothelial leukocyte adhesion molecules
• Amplifying the inflammatory response

31. Nitric Oxide

32. Nitric Oxide
• Short-lived
• SOLUBLE
• Free-radical gas
• Isoforms of NO Synthase (NOS):
1. Type I (nNOS) : neuronal, not significant
in inflammation
2. Type II (iNOS): inducible, in
macrophages and endothelial cells, NO
production in inflammation
3. Type III (eNOS): constitutive,
endothelium

34. NO
• Functions:
1. Vasodilation
2. Antagonism of platelet activation
(adhesion, aggregation, & degranulation)
3. Reduction of leukocyte recruitment
4. Microbicidial (cytotoxic) agent (with or
without ROS) in activated macrophages

35. Lysosomal Enzymes of
Leukocytes
Leukocytes:
Neutrophils & Monocytes
Enzymes:
• Acid proteases
• Neutral proteases (e.g. elastase,
collagenase, & cathepsin)
Their action is checked by:
Serum antiproteases (e.g. α1-antitrypsin)

36. Neuropeptides
• Small proteins
• Secreted by nerve fibers mainly in lung &
GIT
• Initiate inflammatory response
• Substance P :
 Transmits pain signals
 Regulates vessel tone
 Modulates vascular permeability

37.  Vascular effects (C3a & C5a)
 Leukocyte activation, adhesion, chemotaxis
(C5a)
 Phagocytosis (C3b,iC3b)
 MAC ( C9)

38. (High molecular-weight
kininogen)

39. THANKS!
Have a nice day