Gen Pat Hi Nfl Am

8/9/2019 Gen Pat Hi Nfl Am

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InflammationInflammation&&RepairRepair

Ma. Minda Luz M. Manuguid, M.D.Ma. Minda Luz M. Manuguid, M.D.


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General ConsiderationsGeneral Considerations

InflammationInflammation a complex, stereotypical response ofa complex, stereotypical response ofvascularized living tissuesvascularized living tissues toto any form of injuryany form of injury; a reaction; a reactionof blood vessels, leading to theof blood vessels, leading to the accumulation of fluid &accumulation of fluid &

leukocytesleukocytes in extravascular /in extravascular / interstitialinterstitial tissues; atissues; a protectiveprotectivemechanism, itsmechanism, its primary purposeprimary purpose is tois to destroy / wall off /destroy / wall off /neutralize the source /cause of injuryneutralize the source /cause of injury ;;

-- denoted by the suffixdenoted by the suffix itisitis

RepairRepair the reconstitution of injured tissues by eitherthe reconstitution of injured tissues by eitherregeneration/resolution or replacement by connectiveregeneration/resolution or replacement by connectivetissue / scarringtissue / scarring


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Inflammation may beInflammation may be AcuteAcute ororChronicChronic Extravasated fluid may be aExtravasated fluid may be aTransudateTransudate oror

ananExudateExudate Although Inflammation & Repair areAlthough Inflammation & Repair are

primarily protective, they may at timesprimarily protective, they may at timescause tissue injurycause tissue injury

Inflammation develops as a series ofInflammation develops as a series ofconcomitantly occurring vascular & cellularconcomitantly occurring vascular & cellular

events mediated by chemicalsevents mediated by chemicals The onset of Inflammation always precedesThe onset of Inflammation always precedes

the start of the repair process; & Repair isthe start of the repair process; & Repair isalways completed after Inflammation hasalways completed after Inflammation hasresolved;resolved;


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AcuteAcutevsvsChronicChronicInflammationInflammationAcuteAcute ChronicChronic

oonsetnset

abruptabrupt gradualgradual ddurationuration

short (up to a few days)short (up to a few days) long (may reachlong (may reachyears)years)

predominant cellspredominant cells

neutrophils/ PMNsneutrophils/ PMNs mononuclears mononuclears

main characteristicsmain characteristics exudation of fluid &exudation of fluid & proliferation of proliferation of

bloodbloodproteinsproteins vessels &vessels &

connectiveconnective WBC emigrationWBC emigration tissuetissue


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TransudateTransudatevsvsExudateExudate

specific gravityspecific gravity::

1.020

protein / colloid contentprotein / colloid content:: lowlow highhigh

pathophysiologypathophysiology:: hemodynamic:hemodynamic:

inflammatoryinflammatory::imbalance ofimbalance of leaky vesselsleaky vessels

Starlings forcesStarlings forces


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Cells in InflammationCells in Inflammation

LeukocytesLeukocytes

NeutrophilsNeutrophilsL

ymph

ocytesL

ymph

ocytesEosinophilsEosinophilsBasophilsBasophilsMonocytesMonocytes

PlateletsPlatelets


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Eosinophil BasophilMonocyte

PMNs

Platelets


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Lymphocytes


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Connective tissue cellsConnective tissue cells

MMaasstt cceellllss

FibroblastsFibroblasts

MacrophagesMacrophages

Plasma cellsPlasma cells


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Acute InflammationAcute Inflammation Vascular EventsVascular Events Changes inCaliber & FlowChanges inCaliber & Flow::VasoconstrictionVasoconstrictionimmediate, transient (few seconds),immediate, transient (few seconds),

inconstant; involves arteriolesinconstant; involves arterioles

VasodilatationVasodilatationinvolves arterioles & capillaries; durationinvolves arterioles & capillaries; durationvaries, depends on stimulusvaries, depends on stimulus-- increases blood flow to the affected areaincreases blood flow to the affected area

Increased permeabilityIncreased permeability: : Leaky endotheliumLeaky endothelium : :--endothelial cell contractionendothelial cell contraction

-- endothelial retractionendothelial retraction-- endothelial necrosis & detachmentendothelial necrosis & detachment-- leukocyteleukocyte--mediated endothelial injurymediated endothelial injury-- regenerating capillariesregenerating capillaries


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MarginationMarginationfrom the central column of flowing blood,from the central column of flowing blood,neutrophils go toward the side of the vessel nearest the injuryneutrophils go toward the side of the vessel nearest the injury

RollingRolling,, AdhesionAdhesion, &, & PavementingPavementing neutrophils tumble / roll along to the sides of the vessel & attachneutrophils tumble / roll along to the sides of the vessel & attach/ adhere there, becoming so crowded that they seem to form a/ adhere there, becoming so crowded that they seem to form a

pavementpavement

EmigrationEmigration/ Diapedesis/ Diapedesis transmigration oftransmigration ofleukocytes into the extracellular space by inserting pseudopodialeukocytes into the extracellular space by inserting pseudopodiabetween endothelial cellsbetween endothelial cells

Cellular EventsCellular Events


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MarginationMargination &&EmigrationEmigration


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ChemotaxisChemotaxisunidirectional movement of leukocytesunidirectional movement of leukocytestowards an area of chemical attractiontowards an area of chemical attraction

Chemotactic factorsChemotactic factors:: C5aC5afor neutrophilsfor neutrophilsKallikreinKallikrein Leukotriene B4Leukotriene B4 LTB4LTB4 TGFTGF--betabetafor fibroblasts & macrophagesfor fibroblasts & macrophages Bacterial NBacterial N--formyl peptidesformyl peptidesfor PMNsfor PMNs Eosinophil chemotactic factorEosinophil chemotactic factorECFECF

ChemotaxisChemotaxis


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PhagocytosisPhagocytosisengulfment of particulate materialengulfment of particulate material-- recognitionrecognition && attachmentattachment--OpsonizationOpsonizationcoating of a particle to be engulfed;coating of a particle to be engulfed;

opsoninsopsonins:: C3b; IgGC3b; IgG-- engulfmentengulfment-- killing / degradationkilling / degradation::degranulationdegranulation myeloperoxidasemyeloperoxidase (MPO)(MPO)et al.et al.

respiratory burstrespiratory burst increasedincreasedO2O2u

ptake

upta

ke

Release ofLeukocyte productsRelease ofLeukocyte products: lysosomal enzymes,: lysosomal enzymes,free radicals, prostaglandins & leukotrienesfree radicals, prostaglandins & leukotrienes

PhagocytosisPhagocytosis


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PhagocytosisPhagocytosis


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Chemical Mediators of InflammationChemical Mediators of Inflammation

Vasoactive AminesVasoactive Amines:: HistamineHistamine vasodilator;vasodilator; vascular permeability vascular permeability SerotoninSerotoninvasoconstrictorvasoconstrictor

Plasma ProteasesPlasma Proteases Complement proteinsComplement proteins::C3bC3b;;C5aC5a;;C5b6789C5b6789KininsKinins Clotting factorsClotting factors:: Hageman factorHageman factor;;ThrombinThrombin


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ArachidonicAcid MetabolitesArachidonicAcid Metabolites//EicosanoidsEicosanoids ProstaglandinsProstaglandins::PGD2; PGE2; PGF2a;PGD2; PGE2; PGF2a;

PGI2 (Prostacyclin)PGI2 (Prostacyclin) LeukotrienesLeukotrienes::LTC4;LTD4;LTE4;LTB4LTC4;LTD4;LTE4;LTB4

CytokinesCytokines PhospholipidPhospholipid--derived plateletderived platelet--

aggregating factoraggregating factor OxygenOxygen--derived Free radicals :derived Free radicals :

Superoxide;Superoxide; H2O2; Nitricoxide (NO)H2O2; Nitricoxide (NO)

Lysosomal enzymesLysosomal enzymes Others :Others :Neuropeptides;Growth factorsNeuropeptides;Growth factors


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Plasma ProteasesPlasma Proteases ::ComplementCHONsComplementCHONs

22 pathways of activationpathways of activation :: Classical PathwayClassical Pathway produces anaphylatoxinsproduces anaphylatoxins C3aC3a,,C4aC4a,, C5aC5a&&leads to the formation of theleads to the formation of the C5b6789C5b6789complexcomplexA

naphylatoxins

A

naphylatoxins

causecause smooth muscle contraction,smooth muscle contraction,IgEIgE--mediated basophil & mast cell degranulation, &mediated basophil & mast cell degranulation, & vascular permeability.vascular permeability.

C5b,6,7,8,9C5b,6,7,8,9 -- membrane attackcomplexmembrane attackcomplex--lyses bacterial plasma membraneslyses bacterial plasma membranes

Alternative PathwayAlternative Pathway triggered by bacterialtriggered by bacterialendotoxinendotoxin producesproduces C3aC3a&&C5aC5abut notbut not C4aC4a

C5aC5ais also chemotactic for neutrophilsis also chemotactic for neutrophilsC3bC3bis an opsoninis an opsonin


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Plasma Proteases:Plasma Proteases:KininsKinins

PreKallikreinPreKallikrein

HMWkininogenHMWkininogen--

Hageman factorHageman factor--converts Preconverts Pre--KtoKallikrein & Plasminogen toKtoKallikrein & Plasminogen toPlasmin (clot lysis)Plasmin (clot lysis)

KallikreinKallikrein--cancleave C5toC5acancleave C5toC5a

BradykininBradykinin-- potent vasodilator; causes smoothpotent vasodilator; causes smoothmuscle contraction; mediates Painmuscle contraction; mediates Pain


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EicosanoidsEicosanoids

Cyclooxygenase pathwayCyclooxygenase pathway inhibited byAspirin &inhibited by Aspirin &IndomethacinIndomethacin

Prostaglandins :Prostaglandins :

PGD2, PGE2, PGF2aPGD2, PGE2, PGF2a vasodilatorsvasodilators

PGI2 (Prostacyclin)PGI2 (Prostacyclin) vasodilator; antivasodilator; anti--platelet aggregationplatelet aggregation

Thromboxane (TXA2)Thromboxane (TXA2) vasoconstrictor ; PAFvasoconstrictor ; PAF

Lipooxygenase pathwayLipooxygenase pathway

Leukotrienes :Leukotrienes :LTC4, LTD4, LTE4LTC4, LTD4, LTE4 slowslow--reacting substances ofreacting substances of

anaphylaxisanaphylaxis

LTB4LTB4 chemotactic for neutrophilschemotactic for neutrophils


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CytokinesCytokines

Lymphokines secreted by lymphocytesMonokines secreted by monocytes Interferonshave antiviral properties

- alpha & beta (type 1) interferons

- gamma (type 2) interferons also promoteformation of giant cells in granulomatous inflammation;synergize with endotoxin to induce NO synthase in thedevelopment of systemic anaphylaxis

Interleukinsmostly Colony Stimulating Factors

(CSFs) have a growth effect on leukocytes; secreted bymacrophages and lymphocytes. Cytokines have overlapping, redundant effects, so generally,

a deficiency of one does not ruin the entire system.


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PhospholipidPhospholipid--derived Plateletderived Platelet--

aggregatingaggregating factorfactor PAFPAF secreted bysecreted bybasophils, neutrophils, monocytes, endothelial cellsbasophils, neutrophils, monocytes, endothelial cellsAcetylglycerol ether phosphocholineAcetylglycerol ether phosphocholine

--platelet aggregation & releaseplatelet aggregation & release

-- vasoconstriction & bronchoconstrictionvasoconstriction & bronchoconstriction-- leukocyte adhesion, chemotaxis, degranulationleukocyte adhesion, chemotaxis, degranulation

& oxidative burst& oxidative burst

-- boosts the synthesis of other mediatorsboosts the synthesis of other mediators

NitricOxideNitricOxide soluble free radical gassoluble free radical gasproduced by endothelial cells, macrophages, &produced by endothelial cells, macrophages, &specific neurons using nitric oxide synthasespecific neurons using nitric oxide synthase


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OxygenOxygen--derived Free radicals:derived Free radicals:

--SuperoxideSuperoxide H2O2, OH;H2O2, OH;+NO+NOtoxicderivativestoxicderivatives

actions: endothelial cell damageactions: endothelial cell damage

inactivation of antiproteasesinactivation of antiproteases

activation of metalloproteinasesactivation of metalloproteinases

injury to other cell typesinjury to other cell types

Lysosomal EnzymesLysosomal Enzymes: lactoferrin, lysozyme,: lactoferrin, lysozyme,alkaline phosphatase, NADPH oxidase;alkaline phosphatase, NADPH oxidase;

MPO, acidhydrolases, elastase, proteinase,MPO, acidhydrolases, elastase, proteinase,collagenases, acid proteasescollagenases, acid proteases

Others:Others:NeuropeptidesNeuropeptides,, GrowthfactorsGrowthfactors,,


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Cardinal Signs of InflammationCardinal Signs of Inflammation

(Celsus)(Celsus) RuborRuborrednessredness due to hyperemia &due to hyperemia &

vasodilatationvasodilatation

CalorCalorwarmth/heatwarmth/heat due to increasedd

ue to increasedperipheral blood flowperipheral blood flow

TumorTumor swellingswelling due to fluid extravasationdue to fluid extravasation& consequent edema& consequent edema

DolorDolor painpain du

e todu

e to bradykininbradykinin & stretching& stretchingfrom edemafrom edema

FunctiolaesaFunctiolaesalossof functionlossof functionfromfromreflexional disuse due to pain, necrosis, or healingreflexional disuse due to pain, necrosis, or healing


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Acute InflammationAcute Inflammation


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Possible Outcomes ofAcute InflammationPossible Outcomes ofAcute Inflammation

CompleteComplete ResolutionResolution

AbscessAbscess formationformation SinusSinus //FistulaFistula

Healing by scarring/fibrosisHealing by scarring/fibrosis

Progression toProgression toChronicChronicinflammationinflammation when the injurious stimulus iswhen the injurious stimulus isnot removed or neutralizednot removed or neutralized


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MorphologicPatternsMorphologicPatterns

of Inflammationof Inflammation Catarrhal/MucousCatarrhal/Mucous SerousSerous SuppurativeSuppurative UlcerativeUlcerative FibrinousFibrinous HemorrhagicHemorrhagic GangrenousGangrenous


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ChronicInflammationChronicInflammationSettings:Settings:

persistent infections by certain organismspersistent infections by certain organisms

prolonged exposu

re to potentially toxic agents:prolonged exposu

re to potentially toxic agents:nondegradable inanimate material, e.g. Silica;nondegradable inanimate material, e.g. Silica;

plasma lipid components, e.g. atheroscleroticplasma lipid components, e.g. atherosclerotic

plaquesplaques

autoimmune reactionsautoimmune reactions

uncorrected/untreated acute inflammationuncorrected/untreated acute inflammation


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ChronicInflammationChronicInflammationFeatures:Features:

mononuclear infiltratesmononuclear infiltrates

tissue destructiontissue destruction

attempts at repair by connective tissueattempts at repair by connective tissue

lymphatic involvement:lymphatic involvement:

lymphadenopathylymphadenopathyenlargement of lymph nodesenlargement of lymph nodes

lymphadenitislymphadenitisinflammation (w/ pain, swelling) ofinflammation (w/ pain, swelling) oflymph nodeslymph nodes

lymphangitislymphangitisinflammation (w/ redness & pain) ofinflammation (w/ redness & pain) oflymphatic vesselslymphatic vessels


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ChronicInflammationChronicInflammation


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Granulomatous InflammationGranulomatous Inflammationspecial type of chronic inflammation characterized byspecial type of chronic inflammation characterized by

formation offormation of

GranulomasGranulomasorganoid collections of epithelioidorganoid collections of epithelioidmacrophages, multinucleated giant cells, rimmed bymacrophages, multinucleated giant cells, rimmed by

fibroblasts, lymphocytes, & plasma cellsfibroblasts, lymphocytes, & plasma cells


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MultinucleatedGiantcellsMultinucleatedGiantcells

Types :Types :

LanghansLanghanscharacteristic ofcharacteristic ofTBTBgranulomasgranulomas,,

its >50its >50nuclei are arranged in anuclei are arranged in a V V oror U U formation at the periphery of the cellformation at the periphery of the cell

Foreign bodyForeign bodytypical oftypical offoreign bodyforeign bodygranulomasgranulomas but also found in other conditions, itsbut also found in other conditions, its

nuclei are scatteredwithin the entire cytoplasmnuclei are scatteredwithin the entire cytoplasm

ToutonToutonassociatedwith certain tumorsassociatedwith certain tumors


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RepairRepairResolutionResolutiona return to the prea return to the pre--injury state ofinjury state of

the tissues; requires that cells are capable of mitosis,the tissues; requires that cells are capable of mitosis,

framework is intact, & tissue necrosis is minimalframework is intact, & tissue necrosis is minimal

OrganizationOrganizationhealing thru granulation tissuehealing thru granulation tissueformationformation

FibrosisFibrosisreplacement ofdestroyed tissues byreplacement ofdestroyed tissues by

fibrous connective tissue/scar ; occurs when cellsfibrous connective tissue/scar ; occurs when cellshave no mitotic ability/ framework is destroyed/have no mitotic ability/ framework is destroyed/extensive tissue necrosisextensive tissue necrosis


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Wound HealingWound Healing process of repair that follows injury to skin &process of repair that follows injury to skin &

subcutaneous tissuessubcutaneous tissues

affected by intrinsic factors (in the wound itself,affected by intrinsic factors (in the wound itself,including host conditions) & by extrinsic factorsincluding host conditions) & by extrinsic factors

may result in recovery ofup to 90% of the tensilemay result in recovery ofup to 90% of the tensilestrength ofunbroken skinstrength ofunbroken skin

requires adequate nutritional factors (proteins,requires adequate nutritional factors (proteins,vitamin C) for granulation tissue production &vitamin C) for granulation tissue production &collagen formationcollagen formation

may be bymay be by PrimaryPrimary ororSecondarySecondaryintentionintention


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Wound HealingWound Healing


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Primary unionPrimary unionvsvsSecondary unionSecondary union

small tissue defectsmall tissue defect large tissue defectlarge tissue defectclean incisionclean incision

opposable wound sidesopposable wound sides nonnon--opposableopposable

wound edgeswound edges

rapidhealingrapidhealing longercourselongercourse

minimal scarminimal scar substantial scarsubstantial scar&contraction&contraction


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Line of closure fills with clotted bloodLine of closure fills with clotted blood

Dehydration at surface creates scabDehydration at surface creates scab

24 hrs : neutrophilic infiltrates, mitoses of basal epithelium24 hrs : neutrophilic infiltrates, mitoses of basal epithelium

11--2 days : epithelial basal cells grow along cut dermis2 days : epithelial basal cells grow along cut dermis

3 days : neutrophils gone, macrophages enter, granulation tissue3 days : neutrophils gone, macrophages enter, granulation tissueformsforms

5 days : space fills with granulation tissue, epithelial cells bridge line5 days : space fills with granulation tissue, epithelial cells bridge lineof closure, epidermis at preof closure, epidermis at pre--incision thicknessincision thickness


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Granulation tissueGranulation tissueComponentsComponents

New.growing bloodvesselsNew.growing bloodvessels

Proliferating fibroblastsProliferating fibroblasts

New

matrix synthesis : early: proteoglycans; later: collagensNew

matrix synthesis : early: proteoglycans; later: collagens Inflammatory cellsInflammatory cells

Initiation & maintenanceInitiation & maintenance: polypeptide growth: polypeptide growth

fac

torsfac

torsPurposePurpose: replace lost tissue volume; template: replace lost tissue volume; templatefor scar productionfor scar production


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Maturation of healed woundsMaturation of healed woundsRemodeling & strengthening connective tissueRemodeling & strengthening connective tissue

Skin wound strength: 10% at 1 week; 70Skin wound strength: 10% at 1 week; 70--90% of native90% of native

skin strength at 3 mosskin strength at 3 mos

Wound strengtheningWound strengthening: collagen degradatrion; collagen: collagen degradatrion; collagen

synthesis; switch from type III to type I collagensynthesis; switch from type III to type I collagen

Extracellular crossExtracellular cross--linking of collagenlinking of collagen

Wound contractionWound contraction: to: to 55--10%10%of original defectof original defect ::by 6 wksby 6 wks::cellcell--mediated contraction of extracellularmediated contraction of extracellularmatrix; myofibroblasts; epithelial cellsmatrix; myofibroblasts; epithelial cells


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PathologicAspectsPathologicAspects

of Inflammation & Repairof Inflammation & RepairDisordersDisorders :: Leukocyte adhesionLeukocyte adhesion integrin deficiencyintegrin deficiency ChemotaxisChemotaxis Chediak Hegashi syndromeChediak Hegashi syndrome Bacterial killingBacterial killing Chronicgranulomatous diseaseChronicgranulomatous disease Granulation tissue formationGranulation tissue formation exuberant granulationexuberant granulation tissuetissue //

proud fleshproud flesh Scar formationScar formation keloidkeloid abnormally large,abnormally large,

disorganized collagen fibers;disorganized collagen fibers; desmoiddesmoid aggressiveaggressivefibromatosisfibromatosis

Wound maturationWound maturation presence ofpresence offoreign bodyforeign body persistent inflammation ;persistent inflammation ; vitCdef;vitCdef;

MultipleMultiple SteroidsSteroids


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Pathways of Reparative ResponsesPathways of Reparative Responses

Inflammatory reaction to injuryInflammatory reaction to injury

Stimulus promptly destroyedStimulus promptly destroyed

Minimal cellularnecrosisMinimal cellularnecrosis

Exudate resolvedExudate resolved exudate organizedexudate organized

REGENERATIONREGENERATION SCARRINGSCARRING

e.g.e.g.sunburnsunburn e.g.e.g.fibrinopurulentfibrinopurulent

pericarditispericarditis


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Inflammatory tissue responseInflammatory tissue response

Stimulus not destroyedStimulus not destroyed

Necrosis of CellsNecrosis of Cells

stable or labile cellsstable or labile cells permanent cellspermanent cells

connective tissue frameworkconnective tissue framework

intactintact destroyeddestroyed

regene

ration

regene

ration sc

arringsc

arring sc

arringsc

arring

e.g.e.g. lobarlobar --bacterialbacterial -- myocardialmyocardial

PneumoniaPneumonia abscessabscess infarctinfarct


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Outcomes of InflammatoryProcessesOutcomes of InflammatoryProcesses

Serous effusionSerous effusion ResolutionResolution

Fibrinous effusionFibrinous effusion Resolution /Resolution /

OrganizationOrganization

CellulitisCellulitisResolution unless with necrosisResolution unless with necrosis

AbscessAbscess// InfarctInfarct scarringscarring

UlcerUlcerresolution/organization depending onresolution/organization depending onextentextent


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Thankyou Verymuch !Thankyou Verymuch !

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