Pathophysiology of InflammationPathophysiology of Inflammation
Miklós MolnárMiklós Molnár
Inflammation is a Inflammation is a complexcomplex defense defense reactionreaction in the vascularized connective in the vascularized connective tissue in response to tissue in response to endogenous or endogenous or exogenousexogenous stimuli in order to stimuli in order to destroy, destroy, eliminateeliminate the injurious agents or the injurious agents or microorganisms and initiate a series of microorganisms and initiate a series of events that events that heal and reconstituteheal and reconstitute the the damaged tissuedamaged tissue
Essentials of InflammationEssentials of Inflammation
Subsequent EventsSubsequent Events
Alteration (tissue injury)Alteration (tissue injury)Vascular reactionVascular reactionProliferation (reconstitution)Proliferation (reconstitution)
LocalizationLocalization
The connective tissue and its The connective tissue and its microcirculation including the microcirculation including the surrounding extracellular space.surrounding extracellular space.
PlaPlassmamaproteinsproteins– ProteolProteolytic cascadesytic cascades: :
coagulationcoagulation, kinin, , kinin, fibrinolfibrinolyticytic
Blood cellsBlood cells– NeutroNeutrophphililss, eo, eossinoinophphililss, ,
babassoophphililss, monoc, monocytesytes, , llyymmphphococyytteses, , plateletsplatelets
Cells of the connective tissueCells of the connective tissue– Mast cellsMast cells, fibroblast, fibroblastss, ,
mamaccrorophaphaggss, l, lyymmphphococytesytes Blood veselsBlood vesels
– Endothelium, baEndothelium, basement sement membranemembrane, s, smooth muscle mooth muscle cellscells
ParticipantsParticipants
ParticipantsParticipants
Extracellular matrixExtracellular matrix– FibroneFibronecctin, laminin, tin, laminin, ccollagollageen, n,
enactin, tenascin, proteoglikenactin, tenascin, proteoglikansans etcetc..
SpecifiSpecificc medi mediatorsators– Early Early medimediaatortorss positive, positive,
amplificationamplification
– LateLate medi mediaatortorss negative, negative, restiturestitutiotio
Restitution
Restitution
Proliferation(granuloma)
Restitution
ChronicInflammation
Acute Inflammation
Injury
or
or
Types of Inflammatory Types of Inflammatory reactionsreactions
TypeType AAccututee ChronicChronic
InflammationInflammation Inflammation Inflammation
Duration max. 1 week > 1 week
Characteristics exudation (edema) connective tissue emigration of leuko- proliferation
cytes lymphocytes and macrophages accumulation
InflammationInflammation
Local reactionsLocal reactions Systemic reactionsSystemic reactions
Classical (cardinal)
signs
Acute phase reaction, Acute phase reaction, fever, leukocytosis fever, leukocytosis etc.etc.
Celsus described the four famous signs of Celsus described the four famous signs of inflammation calor, rubor, tumor, and dolorinflammation calor, rubor, tumor, and dolor((A.D. 30)A.D. 30)
Systemic Effects of InflammationSystemic Effects of Inflammation
Acute-phase reactionAcute-phase reaction TNFTNF, IL-1 & IL-6, IL-1 & IL-6 feverfever leukocytosisleukocytosis Iron deficiency, anemiaIron deficiency, anemia proteolysisproteolysis activation of lymphocytesactivation of lymphocytes
Initiation ofInitiation ofAcute PhaseAcute PhaseReactionReaction
MACROPHAGES
TNFα
NEURO-PEPTIDES
ENDOTOXINEXOTOXIN
-INTERFERONIMMUNCOMPLEX
URATE SILICATECRISTALS
IL-1IL-6
Acute Phase proteinsAcute Phase proteins CeruloplasminCeruloplasmin
– Scavenges oxygen radicals generated by leukocytesScavenges oxygen radicals generated by leukocytes
Protease inhibitorsProtease inhibitors– αα11-protease inhibitor, -protease inhibitor, αα11-antichymotrypsin and -antichymotrypsin and αα22-macroglobulin-macroglobulin
C-reactive protein (CRP)C-reactive protein (CRP)– binds to bacteria and produce capsular swelling, precipitation and binds to bacteria and produce capsular swelling, precipitation and
agglutination; binding also fixes complement, thus causing the agglutination; binding also fixes complement, thus causing the production of C3b (an opsonin) and chemotactic factorsproduction of C3b (an opsonin) and chemotactic factors
FibrinogenFibrinogen– may serve as opsonin by clumping bacteria together; breakdown may serve as opsonin by clumping bacteria together; breakdown
products of fibrinogen has anti-inflammatory activityproducts of fibrinogen has anti-inflammatory activity
TransferrinTransferrin– decreases, thus limiting the amount of iron available to meet bacterial decreases, thus limiting the amount of iron available to meet bacterial
growth requirementgrowth requirement
INFECTION, TOXINS, IMMUNCOMPLEXES, NEOPLASIAINFECTION, TOXINS, IMMUNCOMPLEXES, NEOPLASIA
IL-1/TNF IL-6IL-1/TNF IL-6
HypothalamusHypothalamus
Prostaglandins (EProstaglandins (E22))
Vasomotor center ?Vasomotor center ?
Sympathetic nervesSympathetic nerves
Skin vasoconstrictionSkin vasoconstriction
↓ ↓ Heat dissipationHeat dissipation
FEVERFEVER
PPAATTHHOOMMEECCHHAANNIISSMM
OOFF
FFEEVVEERR
Local Effect of Acute Local Effect of Acute InflammationInflammation
Blood flow increasesBlood flow increases (alteration of vascular caliber)(alteration of vascular caliber)
Increased vascular permeabilityIncreased vascular permeability (plasma (plasma proteins and leukocytes leave the circulation, retraction of proteins and leukocytes leave the circulation, retraction of endothelial cells, fenestration)endothelial cells, fenestration)
Cellular eventsCellular events (emigration of leukocytes and (emigration of leukocytes and makrophages: makrophages: mmargination, rolling, adhesion, emigration, argination, rolling, adhesion, emigration,
chemotaxis, phagocytosis)chemotaxis, phagocytosis)
Advantages of exudationAdvantages of exudation
Fluid exudationFluid exudation((dilution of toxinsdilution of toxins))
Increased protein contentIncreased protein contentGlobulins Globulins ((antibodiesantibodies))
Fibrin precipitationFibrin precipitation ((Bacterial fixation, wound healingBacterial fixation, wound healing))
Acute-phase proteinsAcute-phase proteins
Mechanisms of Vascular LeakageMechanisms of Vascular Leakage
1. 1. Endothelial contractionEndothelial contraction widening of intercellular junctions (rapid , short-lived action, histamine, bradykinin, leukotrienes etc. effects only the small venules)
2. 2. Junctional retractionJunctional retractioninduced by IL-1, TNFα, IFN, delayed (4-6 hours) effect
3. 3. Leukocyte-dependent leakageLeukocyte-dependent leakage
free radicals and proteolytic enzymes
4. 4. Leakage from regenerating capillariesLeakage from regenerating capillaries
angiogenesis, intercellular junction developmentangiogenesis, intercellular junction development
Leukocyte extravasationLeukocyte extravasation
MMarginarginationation, rolling, rolling and and adh adhesionesion Transmigration across the endothelium Transmigration across the endothelium
(diapedesis)(diapedesis) Migration in interstitial tissues toward a Migration in interstitial tissues toward a
chemotactic stimuluschemotactic stimulus
Adhesion receptorsAdhesion receptors
ImmunoglobulinImmunoglobulinss endotheliendothelialal adh adhesionesion mole moleculescules::
intercellulintercellularar (ICAM-1), vascular cell ~ (VCAM-1) (ICAM-1), vascular cell ~ (VCAM-1) both both interact with integrins found on leukocytesinteract with integrins found on leukocytes
IntegrinIntegrinss (transmembr(transmembraanne-adhesive heterodimeric e-adhesive heterodimeric
glycoproteins, glycoproteins, αα and and ββ chains chains)) 22-in-inttegrinegrinss (LFA-1, MAC-1 (LFA-1, MAC-1 ICAM-1) ICAM-1) 11-in-inttegrin (VLA-4 egrin (VLA-4 VCAM-1) VCAM-1)
SelectinSelectinss– E-selectin (ELAM-1, endothelium)E-selectin (ELAM-1, endothelium)– P-selectin (GMP140, P-selectin (GMP140, plateletsplatelets))– L-selectin (LAM-1, L-selectin (LAM-1, leukocytes)leukocytes)
Cell Surface Adhesion ReceptorsCell Surface Adhesion Receptors
Roles and Mechanism of Adhesion Roles and Mechanism of Adhesion MoleculesMolecules
1.1. Redistribution of adhesion Redistribution of adhesion molecules to the cell surfacemolecules to the cell surface
P-selectin P-selectin (intracitopla(intracitoplassmatimatic granules of c granules of endothelendothelialial cellscells - - Weibel-Palabe granulWeibel-Palabe granuleses
histamin, thrombinhistamin, thrombin, PAF, PAF cell surfacecell surface adhesion and adhesion and rollingrolling of leukocytes of leukocytes
Roles and Mechanism of Adhesion Roles and Mechanism of Adhesion MoleculesMolecules
2.2. Induction of adhesion molecules on Induction of adhesion molecules on
endotheliumendothelium (IL-1, TNF) (IL-1, TNF) E-selectin, E-selectin, and and ICAM-1, VCAM-1ICAM-1, VCAM-1
3.3. Increased avidity of bindingIncreased avidity of binding LFA-1 LFA-1 on leukocytes dose not adhere to its ligand ICAM-on leukocytes dose not adhere to its ligand ICAM-1 on endothelium at resting condition. However, after 1 on endothelium at resting condition. However, after certain stimuli LFA-1 is converted from a state of low- to certain stimuli LFA-1 is converted from a state of low- to high-affinity binding toward ICAM-1high-affinity binding toward ICAM-1Strong bindingStrong binding Transmigration across endotheliumTransmigration across endothelium
Migration of LeukocytesMigration of Leukocytes
Selectins Integrins
Chemotaxis and Leukocyte ActivationChemotaxis and Leukocyte Activation
EExogxogenous substancesenous substances– babacctterial productserial products (N-formyl-methionin(N-formyl-methioninee containing containing
peptides, lipids)peptides, lipids)
EEndogndogenous substancesenous substances Compounds of cCompounds of complementomplement system system ( C5a, C3a) ( C5a, C3a)
Products of the Products of the LipoxygenaseLipoxygenase pathway pathway (LTB(LTB44))
CCyytokinetokiness (IL-8) (IL-8) receptor bindings PLC-Ca2+ actin-myosin active locomotion and activation of PLA2 AA, degranulation (lysosomal enzymes), modulation of
adhesion molecules
ChemotaxisChemotaxis
PhagocytosisPhagocytosis 1. 1.
Recognition and attachmentRecognition and attachment – opsoninopsonins mediateds mediated (Fc- (Fc-fragment of fragment of IgG, C3b) IgG, C3b)
((via via FcFcR receptorR receptorss))– nonopsoninonopsonic phagocytosisc phagocytosis recognition of recognition of LPS LPS
PhagocytosisPhagocytosis 2. 2. EngulfmentEngulfment
Binding to Binding to FcFcR R pseudopodspseudopods fusion of the fusion of the phagocytic vacules and the lysosomal granulesphagocytic vacules and the lysosomal granules
Killing or DegradationKilling or Degradation Oxygen dependent:
NADPH oxidNADPH oxidasease superoxide ion superoxide ion H H22OO22 MPO HMPO H
22OO22 + Cl + Cl-- HOCl HOClNO synthaseNO synthase NO NO peroxinitrite (CONO peroxinitrite (CONO
22-- ) )
Oxygen independent:
llysozymeysozyme, la, lacctofetoferrrin, MBPrin, MBP –major basic protein- –major basic protein-, , defendefenssininss, , acidacid h hyydroldrolasease
PhagocytosisPhagocytosis
Defects in Leukocyte FunctiomDefects in Leukocyte FunctiomGeneticGenetic
Leukocyte adhesion deficiency 1Leukocyte adhesion deficiency 1
Leukocyte adhesion deficiency 2Leukocyte adhesion deficiency 2
Neutrophil specific granule Neutrophil specific granule
deficiencydeficiency
Chronic granulomatosus diseaseChronic granulomatosus disease– X-linkedX-linked
– Autosomal recessiveAutosomal recessive
Myeloperoxidase deficiencyMyeloperoxidase deficiency
ChChéédiak-Higashi syndromediak-Higashi syndrome
ββ chain of CD11/ CD18 integrins chain of CD11/ CD18 integrins
Selectin receptors Selectin receptors (Sialyated oligosacharide)(Sialyated oligosacharide)
Absence of neutrophil specific Absence of neutrophil specific
granules, defective chemotaxisgranules, defective chemotaxis
Decreased oxidative burstDecreased oxidative burst– NADPH oxidase (membrane component)NADPH oxidase (membrane component)
– NADPH oxidase (cytoplasmic component)NADPH oxidase (cytoplasmic component)
Absent MPO-HAbsent MPO-H22OO22 system system
Multiple defectMultiple defect
DiseaseDisease DefectDefect
Defects in Leukocyte FunctiomDefects in Leukocyte FunctiomAcquiredAcquired
Thermal injury, diabetes, Thermal injury, diabetes, malignancy, sepsis, malignancy, sepsis, immunodeficienciesimmunodeficiencies
Hemodialysis, diabetesHemodialysis, diabetes Leukemia, anemia, sepsis, Leukemia, anemia, sepsis,
diabetes, neonates, diabetes, neonates, malnutritionmalnutrition
ChemotaxisChemotaxis
AdhesionAdhesion Phagocytosis and Phagocytosis and
microbicidal activitymicrobicidal activity
DiseaseDisease DefectDefect
Plasma Proteases Plasma Proteases
Kinin systemKinin systemFibrinolytic systemFibrinolytic systemComplement systemComplement system
The Kinin systemThe Kinin system
Bradykinin1. Inducing arteriolar dilatation
2. Increasing the permeability of venules
3. Causing pain
Kallinkrein1. Activation of plasminogen
2. Activation of C1q in the complement system
3. Found in plasma , tissues and secretions
The Fibrinolytic SystemThe Fibrinolytic System
Plasmin1. Produce vasodilatation by generating FDP
2. Can digest fibrin, removes fibrin deposit3. Can activate complement system by cleaving C3
Plasminogen Activating Factors
prourokinase urokinase
Kallikrein
Other Plasminogen ActivatorsOther Plasminogen Activators
Bacterial substances (eg. streptokinase)Bacterial substances (eg. streptokinase)Cell-derived activators (eg. trypsin)Cell-derived activators (eg. trypsin)Macrophage plasminogen activatorMacrophage plasminogen activatorHageman factorHageman factor
Note:
Plasmin was formerly known as fibrinolysin, this old name is still used for this system
The Complement SystemThe Complement System
Consist of 20 interactive plasma and cell Consist of 20 interactive plasma and cell membrane proteinsmembrane proteins
Activated complement:Activated complement:– Mediating vascular responses (histamine release)Mediating vascular responses (histamine release)– Requiting phagocytic leukocytes (chemotaxis)Requiting phagocytic leukocytes (chemotaxis)– Opsonizing target of phagocytic cellsOpsonizing target of phagocytic cells– Directly damaging target cells or tissueDirectly damaging target cells or tissue
Activation:Activation:– Classic pathwayClassic pathway– Alternative pathwayAlternative pathway
Classic PathwayClassic PathwayThis pathway is activated by antibody-coated targets or
antigen-antibody complexes
C1 inhibitor
Hageman Factor
Alternative PathwayAlternative PathwayActivated by: 1. LPS; 2. plasmin; 3. a factor from cobra venom;
4. aggregated IgM or IgG; 5. complexes of antigen with IgA
C3b inhibitor
The Role of Hageman FactorThe Role of Hageman Factor
C1 inhibitor
Chemical Mediators of Chemical Mediators of InflammationInflammation
VasodilatationVasodilatation Prostaglandins, histaminProstaglandins, histaminVascular permeabilityVascular permeability Vasoactiv amins Vasoactiv amins
CC3a3a and C and C5a5a
BradykininBradykinin Leukotrien CLeukotrien C44, D, D44, E, E44, PAF, PAF Chemotaxis Chemotaxis CC5a5a, Leukotrien B, Leukotrien B4 4 , lipids, bacterial products, lipids, bacterial products
Chemical Mediators of Chemical Mediators of InflammationInflammation
FeverFever IL-1; TNF, Prosztaglandin EIL-1; TNF, Prosztaglandin E22
PainPain Prosztaglandins, BradykininProsztaglandins, Bradykinin
Tissue injuryTissue injury Lysosomal enzymes (neutrophils, macrophages)Lysosomal enzymes (neutrophils, macrophages)oxygen metabolitesoxygen metabolites
Cyclo-oxygenase Hypothesis - 1990’sCyclo-oxygenase Hypothesis - 1990’smembrane phospholipidsmembrane phospholipids
arachidonic acidarachidonic acid
glucocorticoidsglucocorticoids(-)(-)
COX-1COX-1constitutiveconstitutive
COX-2COX-2inducibleinducible
selectiveCOX-2
inhibitors
selectiveCOX-2
inhibitors
ClassicalNSAIDSClassicalNSAIDS
INDUCTION:mitogens
endotoxinscytokines
(-)(-)
(-)(-)
StomachStomach KidneyKidney EndotheliumEndothelium PlateletsPlatelets
PGEPGE22/PGI/PGI22
gastricgastriccytoprotectioncytoprotection
PGEPGE22/PGI/PGI22
renal blood renal blood flowflow
PGIPGI22 TXATXA22
Inflammatory SitesInflammatory Sites
PGEPGE22
inflammatoryinflammatorymediatorsmediators
haemostasishaemostasis
Physiological EffectsPhysiological EffectsPhysiological EffectsPhysiological Effects InflammationInflammationInflammationInflammation
(-)(-)(-)(-)
Phospholipase APhospholipase A22
Hierarchies of cytokinesHierarchies of cytokines
TNF
IL-1
IL-6, IL-8, VEGF, GM-CSF
Stimulus
Effect of anti-TNFEffect of anti-TNF Treatment Treatment
Decreased synthesis of IL-1, IL-6 Decreased synthesis of IL-1, IL-6
Inhibition of the migration of leukocytesInhibition of the migration of leukocytes
Decreased number of endothelial adhesion Decreased number of endothelial adhesion moleculesmolecules (VCAM-1, ICAM-1, E-selectin)(VCAM-1, ICAM-1, E-selectin)
Decreased endothelial chemotactic chemokins (IL-8) Decreased endothelial chemotactic chemokins (IL-8)
Decreased T-cell infiltration (T CD4 sup+, CD45 Decreased T-cell infiltration (T CD4 sup+, CD45 RO sup+)RO sup+)
Chronic InflammationChronic Inflammation
Inflammation of prolonged duration (weeks, Inflammation of prolonged duration (weeks, months) in which active inflammation, tissue months) in which active inflammation, tissue destruction and attempts to healing are destruction and attempts to healing are proceeding simultaneouslyproceeding simultaneously– infiltration with mononuclear cellsinfiltration with mononuclear cells– tissue destructiontissue destruction– attempt to repair by connective tissue (fibrosis)attempt to repair by connective tissue (fibrosis)– angiogenesisangiogenesis
Causes of Chronic InflammationCauses of Chronic Inflammation
Persistent infectionPersistent infectionProlonged exposure to toxic agentsProlonged exposure to toxic agentsImmune reactions against own tissue Immune reactions against own tissue
autoimmune disease (SLE, RA)autoimmune disease (SLE, RA)