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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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