The document summarizes the major chemical mediators involved in the inflammatory response, including their sources, mechanisms of action, and effects. It discusses cell-derived mediators like histamine, prostaglandins, leukotrienes, and cytokines. It also covers plasma protein-derived mediators such as components of the complement, kinin, clotting, and fibrinolytic systems and their roles in inflammation.

1. CHEMICAL MEDIATORS OF
INFLAMMATION
LAKSHMI.V
PG STUDENT
DEPARTMENT OF ORAL PATHOLOGY AND MICROBIOLOGY

2. CONTENTS
Definition
History
Classification
Mechanism of action
Cell derived mediators
Plasma protein derived mediators
Summary
References

3. Definition
“Any substance that acts on blood vessels,
inflammatory cells or other cells to mediate specific
inflammatory response.”

4. Sir Thomas Lewis (1927)

5. CLASSIFICATION OF CHEMICAL MEDIATORS
CELL DERIVED PLASMA DERIVED
• liver
• complement proteins
or kinins
• circulate in inactive form
• proteolytic cleavage
• intracellular granules in cells
• preformed mediators secretory granules
or newly synthesized
• active form
• secreted cellular activation
• synthesized response to stimulus

6. Mechanisms of action
Direct binding specific receptors
Direct enzymatic/toxic activity
Oxidative damage

7. Fate
 Short lived
 Once activated & released,
• Quickly decay e.g. A.A metabolites
• Inactivated by enzymes e.g. Kininase inactivates Bradykinins
• Scavenged e.g. Antioxidants scavenge toxic Oxygen metabolites
• Inhibited e.g. Complement regulatory proteins complement activation

9. CELL DERIVED MEDIATORS
 Vasoactive amines:
• Histamine
• Serotonin
• Neuropeptides
 Arachidonic acid metabolites:
• Prostaglandins
• Leukotrienes
• Lipoxins
 Platelet activating factor
 Reactive oxygen species
 Nitric oxide
 Cytokines & Chemokines

10. VASOACTIVE AMINES
HISTAMINE
Source- Mast cells, Basophils & Platelets
Released-
• Physical injury
• Allergic reactions
• Anaphylotoxins -C3a, C5a
• Histamine releasing proteins
• Neuropeptides -Substance P
• Cytokines-IL1,IL8
Causes-
• arteriolar dilatation, vascular permeability

11. SEROTONIN
• 5-hydroxytryptamine
• Preformed vasoactive mediator
• Neurotransmitter and regulates intestinal motility
• Source- Platelets, Neurons & Enterochromaffin cells
• Induces vasoconstriction during clotting
• Involved in platelet aggregation
• Increases vascular permeability
• Stabilizes our mood, happy

12. NEUROPEPTIDES:
• Small proteins
• Substance P
• Neurokinin A
• Vasoactive intestinal polypeptide (VIP)
• produced in CNS
Action
• Increased vascular permeability
• Transmission of pain stimuli
• Mast cell degranulation

13. ARACHIDONIC ACID METABOLITES
• Eicosanoids –greek word eicosa 20 C unsaturated fatty acid
• Produced from dietry linoleic acid
• Component of cell membrane phospholipid
• Prostaglandin (PG)
• Leukotrienes (LT)
• Lipoxins (LX)
• Inflammation and hemostasis

15. FORMATION OF THROMBOXANE
PLATELET
THROMBOXANE SYNTHATASE
TXA2
Platelet aggregating agent
vasoconstriction

16. FORMATION OF PROSTACYCLIN
Endothelial cell
Prostacyclin synthetase
Vasodilator
Inhibits platelet aggregation
FORMATION OF LEUKOTRIENES
Neutrophil
5-lipoxygenases
Bronchoconstriction
Increased vascular permeability

17. FORMATION OF LIPOXINS
• leukocytes enter tissues
• lipoxygenase-derived AA products leukotrienes
• lipoxins
• inhibit neutrophil chemotaxis and adhesion to endothelium
• endogenous antagonists of leukotrienes.
• sources
 activated Platelets

18. PLATELET ACTIVATING FACTOR
Aggregate platelets and degranulation
Source- membranephospholipidof Neutrophils, basophils, platelets, endothelial cells,
mastcells
Functions-
 Platelet aggregation and release
 Bronchoconstriction & vasoconstriction [high]
 Vasodilation and vascular permeability [low]
 Increases leukocyte adhesion & chemotaxis
 Increases leukocyte degranulation / oxidative burst
 Boosts the synthesis of other mediators –eicasanoids & leukocytes

19. CYTOKINES
• Polypeptide products of many cell types
• Interleukins, TNF, Interferons, Chemokines
• cytokines in acute inflammation-TNF, IL-1, IL-6
• cytokines in chronic inflammation -INTERFERON-Γ (IFN-r),IL-12, IL-17

20. TUMOR NECROSIS FACTOR AND INTERLEUKIN-1
• activated macrophages, mast cells, endothelial cells
• stimulated by
 microbial products
 bacterial endotoxin
 immune complexes
 products of T lymphocytes

21. ROLE
• endothelial activation.
• increased leukocyte binding and recruitment
• enhance the production of additional cytokines (notably chemokines) and eicosanoids.
• IL-1 activates tissue fibroblasts

22. May enter the circulation
Induce systemic reaction
 fever
 lethargy
 hepatic synthesis of various proteins (IL-6)
 metabolic wasting (cachexia)
 neutrophil release into the circulation
 fall in blood pressure

23. CHEMOKINES.
• Family of small structurally related proteins
• synthesized by macrophages and endothelial cells
Functions
 recruit & activative leukocytes to site of inflammation
 control the normal anatomic organization of cells
 mediate activity of lymphocytes
4 major groups(cysteine residues)
 C-X-C chemokines - IL-8
 C-C chemokines - MCP1, Eotaxin, MIP-1 alpha, RANTES.
 C chemokines - Lymphotactin
 CX3C chemokines - Fractalkine

24. REACTIVE OXYGEN SPECIES
• H2O2 ,Superoxide anion(O2-), Hydroxyl radical(HO), Reactive N2 species
• Released from neutrophils & macrophages, chemokines & immune complex –
NADPH oxidase
ACTIONS
• Lysosmes - destroys phagocytosed microbes and necrotic cells
• Low levels -expression of cytokines, chemokines, & adhesion molecules
• High levels -
 Endothelial damage- increased permeability
 Protease activation & antiprotease inactivation
 Direct injury to other cell types (e.g., tumor cells, red cells, parenchymal cells).

25. NITRIC OXIDE
• Short lived, soluble, free radical gas
• Synthesized de novo from L-arginine, molecular Oxygen and NADPH by NOS
3 isoforms • Type I- neuronal NOS (nNOS)
expressed in neurons,
no role in inflammation.
• Type II- inducible NOS (iNOS)
induced in macrophages and endothelial cells
cytokines like IL-1,TNF, and IFN-γ, bacterial endotoxin
role in inflammation
present in hepatocytes, cardiac myocytes & respiratory epithelial cells.
• Type III-endothelial NOS (eNOS)
synthesized primarily in endothelium.

26. Functions of NO
 Microbicidal /cytotoxic in activated macrophages
 Inflammation
• vasodilation
• antagonist in all stages of platelet activation

27. LYSOSOMAL ENZYMES OF LEUKOCYTES
• lysosomal granules of neutrophils and monocytes contain enzymes
• Destroy phagocytosed substances
• Causing tissue damage
Acid proteases -Active in the low-pH
Neutral proteases includes elastase, collagenase- active extracellulary
Neutral proteases cleave the complement proteins C3 & C5
Generate vasoactive mediators C3a and C5a
Generate bradykinin-like peptides from kininogen

28. PLASMA PROTEIN DERIVED MEDIATORS
Plasma
derived
mediators
Complement
system
Kinin systemClotting system
Fibrinolytic
system

29. Complement system
•20 plasma proteins
•Important role in immunity and inflammation
Opsonization
Increased vascular permeability
Chemotaxis
Formation of Membrane attack complex (MAC)

30. Numbered C1-C9 (Inactive)
Activation---Enzymatic cascade
Proteolytic cleavage of C3
Occurs in 3 pathways-
Classical pathway (antigen-antibodies)
Alternate pathway (microbe endotoxins)
Lectin pathway (sugar on microbes)

32. Functions:
• Cell lysis by Membrane Attack Complex (MAC)
• Vascular phenomenon- vascular permeability & vasodilatation
• Leukocyte adhesion, chemotaxis & activation
• Phagocytosis

33. KININ & CLOTTING SYSTEM
• Activated by Hageman Factor (XII)
• Protein synthesized by the liver
• Circulates- inactive form
• Encounters collagen, basement membrane, or activated platelets
• Activated Hageman factor - four systems
KININ CLOTTING FIBRINOLYTIC COMPLIMENT
VASOACTIVE KININS THROMBIN
FIBRINOPEPTIDES
FACTOR X
PLASMIN C3a
C5a

34. KININ SYSTEM
• Bradykinin--Circulating precursor, HMW Kininogen
• Increased vascular permeability
• Arteriolar dilatation
• Bronchial smooth muscle contraction
• Pain
• Short lived --Degraded by kininases- plasma, tissue

35. CLOTTING SYSTEM
Proteolytic cascade
Activation of thrombin –binds receptors on platelets, endothelial cells
Circulating soluble fibrinogen
Fibrin clot Enhanced leukocyte adhesion
Xa -increase v.permeability
leukocyte emigration
Thrombin -- fibrinopeptides- increase v. permeability
chemotactic to leukocytes
coagulation with complement
cleaves

36. FIBRINOLYTIC SYSTEM
• Activated by clotting system
• Plasmin ---cleaves fibrin---lysis of clot
• Participate in vascular event - vascular permeability
• Plasmin---cleaves C3---C3a- vascular permeability
• Plasmin ---activate factor12---amplify clotting response

38. REFERENCES
1. Robins & cotran pathologic basis of disease, 9th edition, elsevier, 2010.
2. Anderson,s pathology- ivan damjanov, james linder, 10th edition,volume-1, elsevier.
3. Essential pathology for dental students, harsh mohan, 4th edition, jay pee, 2012.
4. Textbook of pathology, Vinay kamal, vol 1