inflammation mediators

1. 1

2. INFLAMMATORYMEDIATORS
2

3. CONTENTS
 Introduction
 Properties & General principles
 Classification
 Cell derived inflammatory mediators
 Plasma derived inflammatory mediators
 Conclusion
 References
3

4. INTRODUCTION
 Permeability factors
4
Any messenger that acts on blood vessels,
inflammatory cells, or other cells to contribute to an
inflammatory response.

5. PROPERTIES & GENERAL PRINCIPLES
 Mediators are generated either from cells or from
plasma proteins
 Active mediators are produced in response to various
stimuli
 One mediator can stimulate the release of other
mediators
 Mediators vary in their range of cellular targets
 Once activated & released from the cell, most of
these are short lived
5

6. CLASSIFICATION
 Exogenous / Endogenous
6

7.  Cell derived & Plasma derived
7

8. CELL DERIVED INFLAMMATORY
MEDIATORS
8

9. VASOACTIVE AMINES
9

10. HISTAMINE
 Mast cells, basophils & platelets
 Enzyme Histidine decarboxylase (HDC)
 Histamine receptors:- G-Protein coupled receptor
superfamily.
 H1R, H2R, H3R, H4R
 H1 receptors
10

11. Direct
Indirect
11
Release of
histamine
Phosphorylation
of IAP
Increased
vascular
permeability
Release of
histamine
Release of cytokines
& inflammatory
mediators
Increase
inflammatory
response

12.  Increase in salivary histamine levels is correlated with
the severity of periodontitis (Venza et al 2006)
 Gingival fibroblasts mainly express H1R.
 H2R mRNA also expressed but not much significant
(T Minami et al)
12

13. SEROTONIN
 5- Hydroxytryptamine
 Chromaffin cells of GIT, spleen, nervous tissue, mast
cells, platelets
 Action similar to histamine
13

14. LYSOSOMAL ENZYMES
 Granules of neutrophils:
• Specific / secondary
• Azurophil / primary
 Granules of monocytes &
macrophages
14
Acid proteases
Neutral proteases

15.  Antiproteases in serum & tissue fluids
 α1- antitrypsin
 α2- macroglobin
15

16. ARACHIDONIC ACID METABOLITES
 Eicosanoids
 20 carbon polyunsaturated fatty acid,
eicosatetraenoic acid
 Sources: diet, essential fatty acid- linoleic acid
16

17. 17

18. PROSTAGLANDIN
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19. LEUKOTRIENES
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Lipoxins

20. 20

21. PROSTAGLANDINS IN PERIODONTAL DISEASE
 Both gingival and periodontal ligament fibroblasts
secrete prostaglandin E in response to IL-1-β
 PGE2 in periodontal sites demonstrating
inflammation & attachment loss (Offenbacher 1999)
 Induction of Osteoclastic bone resorption
 PGE2 is released from monocytes of patients with
aggressive periodontitis (Offenbacher )
21

22.  PGI – antiproliferative effect
 Cyclosporin A has dose dependent inhibitory effect
on PGI synthesis in gingival tissues.
Nell A et al 1996
22

23. `
23
Lipooxygenase
inhibitorTriclosan

24. 24

25. PLATELET ACTIVATING FACTOR
 Phospholipid derived mediator
 Platelets, basophil, mast cells, neutrophils
macrophages, endothelial cells
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26.  vascular permeability
 Vasoconstriction
 Vasodilatation
 Bronchoconstriction
 Adhesion of leukocytes to endothelium
 Chemotaxis, degranulation
26

27. ACTIVATED OXYGEN SPECIES
 Leukocytes
 NADPH oxidase system
 Chemokines, cytokines, endothelial adhesion
molecules
 Responses in inflammation:
 Endothelial cell damage
 Injury to other cell types
 Inactivation of antiproteases
27

28.  Antioxidants:
 Enzyme Superoxide dismutase
 Enzyme catalase
 Glutathione peroxidase
 Serum Ceruloplasmin
 Serum Transferrin
28

29. NITRIC OXIDE
 Endothelium derived relaxing factor
 Macrophages, endothelial cells, neurons
 Paracrine
 L-Arginine by enzyme nitric oxide synthetase (NOS)
 Endothelial (eNOS)
 Neuronal (nNOS)
 Inducible (iNOS)
29

30. 30

31. CYTOKINES
Cytokines are a diverse group of small protein
molecules with potent biological activity whose main
function is in the regulation of immune responses.
 Lymphokines
 Autocrine
 Paracrine
 Docrine
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32. `
32

33.  Interleukins
 Interferons
 Tumor necrosis factor
 Chemokines
 Transforming growth factor-beta
 Adipokines- leptin & adiponectin
33

34. CLASSIFICATION OF CYTOKINES
 Proinflammatory cytokines:
IL- 1, IL- 6 & TNF
 Chemotactic cytokines:
IL- 8
 Lymphocytes signalling cytokines:
cytokines released by Th1: IL-2, IFN
cytokines released by Th2: IL- 4, IL- 5, IL- 10, IL-13
Jan Lindhe 34

35.  Characteristic of cytokines:
 Cytokines that regulate lymphocytes:
IL-2, IL-4
 Cytokines that activate inflammatory cells:
Interferon γ, TNF β
 Cytokines that stimulate haematopoiesis:
IL- 3, IL- 7
 Colony stimulating factors:
Gm- CSF
Slots 35

36. 36

37. TUMOR NECROSIS FACTOR & INTERLEUKIN 1
37

38. CHEMOKINES
 Chemokines are a family of small (8-10 kD) proteins
that act primarily as chemoattractants for specific
type of leukocytes
 4 major group:
 C-X-C chemokines (α chemokines)
 C-C chemokines (β chemokines)
 C chemokines (γ chemokines)
 CX3C chemokines
38

39.  7 transmembrane G protein-coupled receptor
 Two main functions:
 Stimulate leukocyte recruitment in inflammation
 Control of normal migration of cells through various
tissues
39

40. 40

41. CYTOKINE & PERIODONTAL TISSUE
41

42. CYTOKINE & ALVEOLAR BONE LOSS
42

43. INHIBITORS OF DESTRUCTIVE CYTOKINES
 Anti-inflammatory cytokines:
 IL- 1 receptor antagonist (IL-1ra)
 Transforming growth factor β
 Interferon γ
 Angiogenesis:
 IL-1β , TNF-α
 Fibrogenic cytokines:
 IL-1β, IL-1α 43

44.  Anti-inflammatory activities on bone:
 Blocking cytokine induced activation:
IFN-γ -----> IL-1 & TNF α - induced osteoclast
activation
IL-1ra -----> IL-1 ( α & β ), TNF α
 Blocking osteoclast formation: TGF- β
 Activation of osteoblasts:
FGF, PDGF & Insulin like growth factors I & II
44

45. 46

46. INFLAMMATORYMEDIATORS
47

47. CONTENTS
 Introduction
 Properties & General principles
 Classification
 Cell derived inflammatory mediators
 Plasma derived inflammatory mediators
 Conclusion
 References
48

48. 49

49. COMPLEMENT SYSTEM
 30 proteins, C1 through C9
 Innate & Adaptive immunity
 Increased vascular permeability, chemotaxis &
opsonization
50
Complement refers to a system of factors which occur in
normal serum and activated characteristically by antigen-
antibody interaction & subsequently mediate a number of
biologically significant consequences

50.  Inactive form
 Most abundant component  C3
51

51. 52

52. 53
C3 Convertase

53. 54
C5 Convertase C5b
C5a
C6-C9
MAC

54. 55

55. 56

56.  Central component of inflammation
 Vasoactive substance kinin-like C2a
 Molecules  anaphylatoxins C3a, C5a
 Chemotaxin  C5a
 Opsonin  C3b
57

57.  Cell associated & circulatory regulated proteins
 Inhibit production of active complement fragments
 Normal cells
58

58.  Gingival crevicular fluid:
 In healthy individuals  3%
 In periodontal inflammation: increased
59

59. COAGULATION SYSTEM
60

60. thrombin
fibrin
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Blood clotting

61. 62
Activate mediator system
Inflammation
Coagulation factors
Pro-thrombogenic
Anticogulant mechanism
CLOTTING

62.  Chemokines
 Cytokines
 Endothelial adhesion
molecules
 Prostaglandins
 PAF & NO
63
Protease-activated
Receptor (PAR)
Inflammation

63. KININ SYSTEM
 Vasoactive peptides  kininogen
65

64. 66
Vascular permeability
Sm0oth muscle
Blood vessels
Pain

65. 67

66.  Bradykinin, C3a & C5a - mediators of increased
vascular permeability
 C5a – mediator of chemotaxis
 Thrombin – effect on endothelial cell types
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67.  C3a & C5a generated by several types of reaction:
 Immunological reactions
 Activation of alternate & lectin pathway by microbes
 Agents not directly related to immune responses
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68.  Activated Hegman factor initiates 4 factors involved
in inflammatory response:
 Kinin system
 Clotting system
 Fibrinolytic system
 Compliment system
70

69. 71

70. REFERENCES
 Pathologic Basics of diseases, Robbins & Cotran, 8th
edition
 Clinical periodontology, Carranza, 10th edition
 Clinical periodontology, Carranza, 8th edition
 Clinical periodontology & implant dentistry, Lindhe,
5th edition
 Periodontics, Grant, 6th edition
 Ericag Emmellr,o Dericki . Marshal&l G Regorjy.
Seymour, Cytokines and prostaglandins in immune
homeostasis and tissue destruction in periodontal
disease, PeriodontoIogy 2000. Vol. 14. 1997, 112-143 72

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