basics of inflammation

1. MEDIATORSMEDIATORS
OFOF
INFLAMMATIONINFLAMMATION

2. INTRODUCTIONINTRODUCTION
 Any messenger that acts on blood vessels ,Any messenger that acts on blood vessels ,
inflammatory cells or other cells to contribute to aninflammatory cells or other cells to contribute to an
inflammatory response.inflammatory response.
 Active mediators are produced in response to variousActive mediators are produced in response to various
stimuli such as microbial products , coagulation &stimuli such as microbial products , coagulation &
complement systems.complement systems.
 One mediator can stimulate the release of otherOne mediator can stimulate the release of other
mediators.mediators.
 Mediators vary in range of cellular targets.Mediators vary in range of cellular targets.
 Once activated & released from cell, most mediatorsOnce activated & released from cell, most mediators
are short lived.are short lived.

3.  Mediators are generated either from cell or from plasma proteins.Mediators are generated either from cell or from plasma proteins.
 Cell derived mediators are sequestered in intracellular granulesCell derived mediators are sequestered in intracellular granules
& rapidly secreted by exocytosis or synthesized de novo in& rapidly secreted by exocytosis or synthesized de novo in
response to stimulus.response to stimulus.
 Plasma derived mediators produced mainly in liver & presentPlasma derived mediators produced mainly in liver & present
in circulation as inactive precursors which are activated byin circulation as inactive precursors which are activated by
series of proteolytic cleavages.series of proteolytic cleavages.

4. CELL DERIVED MEDIATORSCELL DERIVED MEDIATORS HISTAMINEHISTAMINE
 MAST CELLSMAST CELLS
 Richest source of histamineRichest source of histamine
 Located in connective tissue adjacent toLocated in connective tissue adjacent to
blood vesselsblood vessels
 Degranulation through receptors forDegranulation through receptors for
IgE- , IgG , Anaphylatoxins C5a ,IgE- , IgG , Anaphylatoxins C5a ,
physical injury & cytokines.physical injury & cytokines.
 Rapidly released mediators ofRapidly released mediators of
inflammationinflammation
 Histamine causes dialatation of arteriolesHistamine causes dialatation of arterioles
& increases permeability of venules.& increases permeability of venules.
 Effects are mediated via binding to H1Effects are mediated via binding to H1
receptors on EC.receptors on EC.

5. ARACHIDONIC ACID METABOLITESARACHIDONIC ACID METABOLITES
 20 – carbon polyunsaturated fatty acids.20 – carbon polyunsaturated fatty acids.
 Derived from linoleic acid.Derived from linoleic acid.
 Esterified in membrane phospholipid ; releasedEsterified in membrane phospholipid ; released
through action of cellular phospholipase A2.through action of cellular phospholipase A2.
 2 major pathways :2 major pathways :
 COX pathway : has constitutively expressed COX-1COX pathway : has constitutively expressed COX-1
and inducible enzyme COX-2 ; Stimulate the releaseand inducible enzyme COX-2 ; Stimulate the release
of Prostaglandins : produced by mast cells ,of Prostaglandins : produced by mast cells ,
macrophages , endothelial cells etc.macrophages , endothelial cells etc.
 Lipoxygenase pathway : stimulate release ofLipoxygenase pathway : stimulate release of
leukotrienes by leukocytes.leukotrienes by leukocytes.

7. PROSTAGLANDINSPROSTAGLANDINS
 PGI2 ( prostacyclins)PGI2 ( prostacyclins)
 VasodialatorVasodialator
 Inhibitor of platelet aggregationInhibitor of platelet aggregation
 Markedly potentiates permeability increasing & chemotacticMarkedly potentiates permeability increasing & chemotactic
effects.effects.
 PGD2 & PGE2PGD2 & PGE2
 Major prostaglandins produced by mast cells.Major prostaglandins produced by mast cells.
 Causes vasodialatation & increases permeability of postCauses vasodialatation & increases permeability of post
capillary venules ; thus potentiating edema formation.capillary venules ; thus potentiating edema formation.
 PGD2 acts as chemoattractant for neutrophils.PGD2 acts as chemoattractant for neutrophils.
 PGE2 is hyperalgesic & produces hypersensitivity to painfulPGE2 is hyperalgesic & produces hypersensitivity to painful
stimulistimuli
 PGF2PGF2αα : stimulates contraction of uterine & bronchial smooth: stimulates contraction of uterine & bronchial smooth
muscles & small arterioles.muscles & small arterioles.

8. LEUKOTRIENESLEUKOTRIENES
 LTB4LTB4
 Potent chemotactic agent.Potent chemotactic agent.
 Activator of neutrophils.Activator of neutrophils.
 Causes aggregation & adhesion of cells to venularCauses aggregation & adhesion of cells to venular
endothelium.endothelium.
 Generation of reactive oxygen species.Generation of reactive oxygen species.
 Release of lysosomal enzymes.Release of lysosomal enzymes.
 LTC4 , LTD4 & LTE4LTC4 , LTD4 & LTE4
 Intense vasoconstrictionIntense vasoconstriction
 bronchospasmbronchospasm
 Increased vascular permeabilityIncreased vascular permeability

9.  LIPOXINSLIPOXINS
 Inhibitors of inflammation.Inhibitors of inflammation.
 Principle action is to inhibit leukocyte recruitment &Principle action is to inhibit leukocyte recruitment &
cellular components of inflammation.cellular components of inflammation.
 Inhibit neutrophil chemotaxis & adhesion toInhibit neutrophil chemotaxis & adhesion to
endothelium.endothelium.
 Lipoxins are endogenous negative regulators ofLipoxins are endogenous negative regulators of
leukotrienes & thus play a role in mediators ofleukotrienes & thus play a role in mediators of
inflammation.inflammation.

10. REACTIVE OXYGEN SPECIESREACTIVE OXYGEN SPECIES
 Released extracellularlyReleased extracellularly
from leukocytes afterfrom leukocytes after
exposure to microbes ,exposure to microbes ,
chemokines & immunechemokines & immune
complexes or following acomplexes or following a
phagocytic challenge.phagocytic challenge.
 NADPH oxidase system:NADPH oxidase system:
 Superoxide anion ,Superoxide anion ,
H2O2 & hydroxylH2O2 & hydroxyl
radical are majorradical are major
species.species.

12.  Implicated in following responses ofImplicated in following responses of
inflammationinflammation
 Endothelial cell damage & increased vascularEndothelial cell damage & increased vascular
permeability.permeability.
 Injury to other cell types ( Parenchymal cells &Injury to other cell types ( Parenchymal cells &
RBCs )RBCs )
 Inactivation of anti-protease such asInactivation of anti-protease such as αα-antitrypsin.-antitrypsin.
 Leads to unopposed protease activity with increasedLeads to unopposed protease activity with increased
destruction of extracellular matrix.destruction of extracellular matrix.

13. NITRIC OXIDENITRIC OXIDE
 Released from endothelial cells to causeReleased from endothelial cells to cause
vasodialatation ; Endothelium derived relaxing factor.vasodialatation ; Endothelium derived relaxing factor.
 Also produced by macrophages & neurons.Also produced by macrophages & neurons.
 Sythesized from L-argenine by enzyme nitric oxideSythesized from L-argenine by enzyme nitric oxide
synthase (NOS)synthase (NOS)
 eNOS & nNOS constitutively expressed at low levels & caneNOS & nNOS constitutively expressed at low levels & can
be activated by an increase in cytoplasmic calcium.be activated by an increase in cytoplasmic calcium.
 iNOS induced when macrophages & other cells are activatediNOS induced when macrophages & other cells are activated
by cytokines.by cytokines.
 Has dual actions in inflammationHas dual actions in inflammation
 Promotes vasodialatation.Promotes vasodialatation.
 Inhibition of cellular components of inflammatory responses.Inhibition of cellular components of inflammatory responses.
 Reduces platelet aggregation & adhesion ; inhibitsReduces platelet aggregation & adhesion ; inhibits
leukocyte recruitmentleukocyte recruitment

15. CYTOKINESCYTOKINES
 TNF & IL1TNF & IL1
 2 major cytokines that mediate inflammation.2 major cytokines that mediate inflammation.
 Produced mainly by activated macrophages.Produced mainly by activated macrophages.
 Induce the expression of endothelial adhesionInduce the expression of endothelial adhesion
molecules & synthesis of chemical mediators.molecules & synthesis of chemical mediators.
 Responsible for production of enzymes associatedResponsible for production of enzymes associated
with matrix remodelling.with matrix remodelling.
 Increase in surface thrombogenicity of endotheliumIncrease in surface thrombogenicity of endothelium
 Act on thermoregulatory centre in hypothalamus ;Act on thermoregulatory centre in hypothalamus ;
induce the production of PGE & results in fever.induce the production of PGE & results in fever.
 IL6 acts on liver to increase the production ofIL6 acts on liver to increase the production of
complement components & coagulation factors.complement components & coagulation factors.

17. CHEMOKINESCHEMOKINES
 Classified into four major groups :Classified into four major groups :
 C-X-C chemokines (IL-8)C-X-C chemokines (IL-8)
 Activation & chemotaxis of neutrophilsActivation & chemotaxis of neutrophils
 C-C chemokines (C-C chemokines (ββ chemokines )chemokines )
 Includes monocyte chemoattractant protein (MCP-1) ,Includes monocyte chemoattractant protein (MCP-1) ,
eotaxin , macrophage inflammatory protein – 1eotaxin , macrophage inflammatory protein – 1α ,α ,
RANTES.RANTES.
 Attract monocytes , eosinophils , basophils &Attract monocytes , eosinophils , basophils &
lymphocytes but not neutrophils.lymphocytes but not neutrophils.
 C chemokines (C chemokines (γγ chemokines )chemokines )
 Specific for lymphocytes.Specific for lymphocytes.
 CX3C chemokinesCX3C chemokines
 Cell surface bound proteinCell surface bound protein
 Soluble formSoluble form

18. PLASMA PROTEIN DERIVED MEDIATORSPLASMA PROTEIN DERIVED MEDIATORS
 3 inter-related systems are activated within this3 inter-related systems are activated within this
categorycategory
 KININ YSTEMKININ YSTEM
 Highly vasoactiveHighly vasoactive
 COMPLEMENT SYSTEMCOMPLEMENT SYSTEM
 VasoactiveVasoactive
 ChemotacticChemotactic
 CLOTTING SYSTEMCLOTTING SYSTEM
 VasoactiveVasoactive
 Cleaves C3Cleaves C3

19. COMPLEMENT SYSTEMCOMPLEMENT SYSTEM
 Plasma proteins - act against microbial agentsPlasma proteins - act against microbial agents
 Products of activated complementProducts of activated complement
 Vascular permeabilityVascular permeability
 ChemotaxisChemotaxis
 OpsonizationOpsonization
 LysisLysis

20. COMPLEMENT SYSTEMCOMPLEMENT SYSTEM
Few reminders
 Classical pathwayClassical pathway
 Alternate pathwayAlternate pathway
 Common pathwayCommon pathway
 Important inflammatory mediatorsImportant inflammatory mediators
 C3a and C5a (anaphylatoxins)C3a and C5a (anaphylatoxins)
–Cause release of histamine from mast cellsCause release of histamine from mast cells
–Lysosomal enzyme release in inflammatory cellsLysosomal enzyme release in inflammatory cells
 C5aC5a
–Activates lipoxygenase pathwayActivates lipoxygenase pathway
–Chemotactic many inflammatory cellsChemotactic many inflammatory cells
–Increases adhesion of leukocytesIncreases adhesion of leukocytes

22. COMPLEMENT SYSTEMCOMPLEMENT SYSTEM
 Opsonization : A process in which opsoninOpsonization : A process in which opsonin
molecule binds on one side to particulate matter &molecule binds on one side to particulate matter &
binds with receptors on phagocytic molecules onbinds with receptors on phagocytic molecules on
other side.other side.
 C3b & IgG are opsonins facilitating the phagocyticC3b & IgG are opsonins facilitating the phagocytic
process.process.
 C5b-9 membrane attack complexC5b-9 membrane attack complex
 Lyses cellsLyses cells
 Stimulates arachidonic acid metabolismStimulates arachidonic acid metabolism
 Produces reactive oxygen metabolitesProduces reactive oxygen metabolites

23. KININ SYSTEMKININ SYSTEM
 Kinins are vasoactive peptides derived from Kininogen byKinins are vasoactive peptides derived from Kininogen by
action of Kallikreinsaction of Kallikreins
 Activated by Hageman factor (XIIa)Activated by Hageman factor (XIIa)
 BRADYKININBRADYKININ
 Potent vasodilatorPotent vasodilator
 Increased vascular permeabilityIncreased vascular permeability
 Contraction of smooth muscleContraction of smooth muscle
 Produce painProduce pain
 Kallikrein itself is a potent activator of Hageman factorKallikrein itself is a potent activator of Hageman factor
allowing for autocatalytic amplification of initial stimulus.allowing for autocatalytic amplification of initial stimulus.

25. COAGULATION SYSTEMCOAGULATION SYSTEM
Clotting system
 Plasma proteinsPlasma proteins
 Can be activated by Hageman factorCan be activated by Hageman factor
 Thrombin converts fibrinogen to fibrinThrombin converts fibrinogen to fibrin
 Fibrinopeptides are formedFibrinopeptides are formed
–↑↑vascular permeabilityvascular permeability
–Chemotactic for leucocytesChemotactic for leucocytes
 Plasmin is important in lysing fibrin clots,Plasmin is important in lysing fibrin clots,
 Activates Hageman factor (XII) bradykinin⇨Activates Hageman factor (XII) bradykinin⇨
 Cleaves C3 C3a⇨Cleaves C3 C3a⇨
 "fibrin-split products" formed from fibrin breakdown"fibrin-split products" formed from fibrin breakdown
–↑↑ vascular permeabilityvascular permeability

26. HAGEMAN FACTORHAGEMAN FACTOR
Dependent Factors
 Factor XII of intrinsic coagulation cascadeFactor XII of intrinsic coagulation cascade
 Involved in :Involved in :
 KININ SYSTEM : produces vasoactive kininsKININ SYSTEM : produces vasoactive kinins
 CLOTTING SYSTEM : induces thrombin formationCLOTTING SYSTEM : induces thrombin formation
 FIBRINOLYTIC SYSTEM : produces plasmin &FIBRINOLYTIC SYSTEM : produces plasmin &
degrades fibrin to produce fibrinopeptides.degrades fibrin to produce fibrinopeptides.
 COMPLEMENT SYSTEM : To produce anaphylatoxinsCOMPLEMENT SYSTEM : To produce anaphylatoxins
& other mediators& other mediators

27. THANK YOU…. !!