This document discusses inflammatory mediators, which are messengers that contribute to the inflammatory response by acting on blood vessels, immune cells, or other cells. Inflammatory mediators can be classified as either cell-derived or plasma-derived. Cell-derived mediators include histamine, serotonin, lysosomal enzymes, eicosanoids such as prostaglandins and leukotrienes, platelet-activating factor, reactive oxygen species, nitric oxide, and cytokines. Plasma-derived mediators include components of the complement, coagulation, kinin, and fibrinolytic systems. Many of these mediators stimulate the release of other mediators and have effects like increasing vascular permeability and chemotaxis. Cytokines and

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
18

19. LEUKOTRIENES
19
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
25

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
31

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
61
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
68

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
69

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

71. 73