Chemical mediators of acute inflammation - BPTh, MBBS.ppt

Chemical mediators like IL-1, IL-6, IFN gamma, Leukotrienes secreted during acute inflammation. Pathology ppt.

1. Inflammatory cells and
Chemical mediators
- Dr. URSHLLA KAUL
ASST. PROF
PATHOLOGY DEPT.

2. Types of WBCs

4. Chemotactic
Factors (e.g. c5a)
Vasoactive
Mediators
(e.g. histamine)

5. •Plasma-derived
•Circulating precursors
•Have to be activated
•Cell-derived
•sequestered intracellularly (Preformed)
•synthesized de novo (Newly formed)

6. Chemical mediators of inflammation
(cont.)
•Most mediators bind to receptors on cell surfaces but some
have direct enzymatic or toxic activity
•Mediators are tightly regulated.

7. What are the names of these
Mediators?

8. FUNCTION/ ROLE ??

9. CELL DERIVED MEDIATORS
(PREFORMED)

12. Vasoactive amines
•Histamine
•Derived from Histidine.
•Found in mast cells, basophils and platelets
•Released in response to stimuli
•Promotes arteriolar dilation and venular endothelial
contraction
• results in widening of inter-endothelial cell junctions with increased
vascular permeability
•Bronchoconstriction

13. Vasoactive amines (cont’d)
•Serotonin
•Derived from Tryptophan
•Found in platelets and Enterochromaffin cells
•Vasoactive effects similar to histamine
•Released when platelets aggregate
•Actions: Chemoattractant, phagocytosis, release of pro-
infl cytokines – IL1, IL6

14. PLASMA DERIVED MEDIATORS

15. Fig 2-10
Plasma
Protease
s

16. Fig 2-10
Plasma
Protease
s
1. Factor XII (Hageman Factor)
Activated Factor XII (XIIa)
Kallikrein
Bradykinin
Fibrin
Plasmin
5. Complement
Cascade
2. Kinin Cascade 3. Clotting
Cascade
4. Fibrinolytic
System
Key to all this
1. Factor XII (Hageman Factor)

17. Kinin Cascade
•Leads to formation of Bradykinin
•Bradykinin causes
•Increased vascular permeability
•Arteriolar dilatation
•Smooth muscle contraction
•Bradykinin is short lived (kininases)
•Vascular actions similar to Histamine

18. The Clotting System
•Key to the activation is FACTOR XII
•The end result is FIBRIN

19. Complement system
•Role in immunity (C5-9 complex)
•Membrane Attack Complex (MAC C5-9)
•A MAC attack
•Punches a hole in the membrane
•Role in inflammation (c3a and c5a)
•Vascular effects
•Increase vascular permeability and vasodilation
•Similar to Histamine
•Activates lipoxygenase pathway of arachidonic acid metabolism
(c5a)
•Leukocyte activation, adhesion and chemotaxis (c5a)
•Phagocytosis
•c3b acts as opsonin and promotes phagocytosis by cells bearing receptors for
c3b

20. Fig 2-11

21. Alternate Pathway
C3 C3b
Classic Pathway
C1 C4b
C3 C3a C5
C5b
C6
C7
C8
C9
C5-9
MEMBRANE ATTACK
COMPLEX
Fig 2-11 Summary

22. CELL DERIVED MEDIATORS
(NEWLY SYNTHESIZED)

23. Nitric Oxide
•Derived from L – Arginine  by enzyme NOS (nitric oxide
synthase)
•NO is a soluble free radical gas
•Broad range of functions (many not be related to
inflammatory reactions)
•Effects – Vasodilation, inhibits platelet aggregation. Short-
ranged

24. Platelet-Activating Factor (PAF)
•Another phospholipid-derived mediator released by
phospholipases
•Induces aggregation of platelets
•Causes vasoconstriction and bronchoconstriction
•100 to 1,000 times more potent than histamine in
inducing vasodilation and vascular permeability
•Enhances leukocyte adhesion, chemotaxis, degranulation
and the oxidative burst
•IT DOES EVERYTHING!

25. Chemokines
•Chemoattractants (Attract the WBCs)
•C- type – Lymphotactin: Lymphocyte
•CC type – Eotaxin: Eosinophil, Rantes – T cell, MCP :
Macrophages
•CXC type – IL-8 : Neutrophils
•CX3C type – Fructalkane: T cells and macrophages

27. Arachidonic Acid (AA)
•Where is it located?
•AA is a component of cell membrane phospholipids
•The breakdown of AA into its metabolites produces a
variety of biologic effects
•Metabolites of AA - short-range hormones
•AA metabolites act locally at site of generation
•Rapidly decay or are destroyed
•Again, too dangerous to be left ‘lying around’

28. Arachidonic Acid
•AA is released from the cell membrane by Phospholipases
which have themselves been activated by various stimuli
and/or inflammatory mediators
•AA metabolism occurs via two major pathways named for the
enzymes that initiate the reactions; lipoxygenase and
cyclooxygenase

29. Figure 2-12
Kumar p 37

30. Arachidonic Acid
Pete & Hete
Leukotrienes
Vasoconstriction
Bronchospasm
Increased Vascular
Permeability
Prostaglandins
PG’s
Figure 2-12
Kumar p 37
Summary
Phospholipase A2 Steroids inhibit
Aspirin
NSAID’s
CyclooxygenaseCyclooxygenase

31. Arachidonic Acid
Pete & Hete
Leukotrienes
Vasoconstriction
Bronchospasm
Increased Vascular
Permeability
Prostaglandins
PG’s
Figure 2-12
Kumar p 37
Summary
Phospholipase A2 Steroids inhibit
Aspirin
NSAID’st
CyclooxygenaseCyclooxygenase

32. Arachidonic Acid Pathways
•Lipoxygenase
•HETE
•Chemotaxis
•PETE
•Leukotriene generation
•Leukotrienes
•Vasoconstriciton
•Bronchospasm
•Increased vascular permeability
•Cyclooxygenase
•Prostaglandins
•Vasodilatation
•Increased vascular permeability
•Prostacyclin
•Vasodilatation
•Inhibits platlelet aggregation
•Thromboxane A2
•Vasoconstriction
•Promotes platlelet aggregation

33. Arachidonic Acid Pathways
•Lipoxygenase
•HETE, PETE, Leukotrienes
•Spasm (Vaso, Broncho)
•Cyclooxygenase
•Prostaglandins - EDEMA
•Prostacyclin vs TXA2
•Vasodilatation vs Vasoconstriction
•Platlelet aggregation
Inhibits vs promotes

34. Arachidonic Acid Metabolites
•Participate in every aspect of acute inflammation
•Effective Anti-inflammatory agents act on AA pathways
•Aspirin and Non-Steroidal Anti-inflammatory Drugs (NSAID’s) -
Cyclooxygenase path
•Steroids act, in part, by inhibiting Phospholipase A2

35. Cytokines
•Polypeptides that are secreted by cells – T cells &
macrophages
•IL-1, IL-6, IL-8, TNFα, IL-10
•Act to regulate cell behaviors
•Autocrine, paracrine or endocrine effects
•These “biological response modifiers” are being actively
investigated for therapeutic use in controlling the
inflammatory response.

36. Fig 2-13
p 38
These also do
everything

37. Oxygen-derived free radicals
•Oxygen-derived free radicals responsible for tissue injury
•Direct injury to endothelial cells
•Injury to extracellular matrix via activation of proteases
•Injury to other cell types (e.g., RBC’s, tumor cells)

38. Lysosomal Constituents
•Neutral Proteases - Elastase, Collagenase etc
•Degrade Extracellular Matrix Components
•Lead to destructive, deforming tissue injury