Mechanisms of hepatic fibrogenesis in chronic liver of hepatic fibrogenesis in chronic ... HEALTHY INFLAMMATION FIBROGENESIS CIRRHOSIS CONSEQUENCES ... • Robbin

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  • Mechanismsofhepaticfibrogenesis inchronic

    liverdisease

    JPEMS 2014, Physiopathology Module

    Corentin Bessy (Nantes) _ Gabrielle Cepella (Amsterdam) _ Charly Gaisne (Angers) _ Gwladys Guilloineau (Angers) _ Claudia Zob (Cluj-Napoca)

    Directed by Dr. Sophie Conchon

  • HEALTHY INFLAMMATION FIBROGENESIS CIRRHOSIS CONSEQUENCES

    Morphologicalandfunctionalfeatures

    ACUTEINJURY

    MYOFIBROBLASTS

    HEPATICSTELLATECELLS(HSCs)

    Othercellsimplicated

    ACTIVATION

    Injurybecomeschronic

    OVERVIEW

  • Causesoffibrogenesis

    Numerousliverfunctions variouscauses

    Familyassociation,geneticpredisposition

    Primarycauses Viralhepatites :rapid progression Alcoholic liver disease :most

    frequent inWesterncountries Nonalcoholic liver disease

    Secondarycauses Extrahepatic infections Disseminated cancer

  • HEALTHY INFLAMMATION FIBROGENESIS CIRRHOSIS CONSEQUENCES

    ACUTEINJURY

    MYOFIBROBLASTS

    HEPATICSTELLATECELLS(HSCs)

    Morphologicalandfunctional

    features Othercellsimplicated

    ACTIVATION

    Injurybecomeschronic

  • ORIGINOFTHEMYOFIBROBLAST

    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2888531/

  • HEALTHY INFLAMMATION FIBROGENESIS CIRRHOSIS CONSEQUENCES

    ACUTEINJURY

    MYOFIBROBLASTS

    HEPATICSTELLATECELLS(HSCs)

    Morphologicalandfunctional

    features Othercellsimplicated

    ACTIVATION

    Injurybecomeschronic

  • HEPATICSTELLATECELLS(HSCs)Morphologicalfeatures

    Drawingoftheorganisation intheliver.Cambridge.org

  • LIVER, NORMALThe space of Disse contains small amountsof type IV collagen which is highlighted asblue by trichrome staining.

    LIVER,FIBROGENESISThespaceofDisse containslargeamountsoftypeIcollagen

    http://www.pathpedia.com/education/eatlas/histology/liver_and_bile_ducts/Images.aspx?7

  • Functionalfeatures

    Liverfibrosis

    Liverdevelopmentandregeneration

    Immunoregulation

    Angiogenesis

    Retinoidmetabolism

    pathpedia.org

  • ACTIVATION

    HEALTHY INFLAMMATION FIBROGENESIS CIRRHOSIS CONSEQUENCES

    ACUTEINJURY

    MYOFIBROBLASTS

    HEPATICSTELLATECELLS(HSCs)

    Morphologicalandfunctional

    features Othercellsimplicated

    Injurybecomeschronic

  • OTHERCELLSIMPLICATEDNeighboring cells ofHSCs

    HSCsActivatedphenotype

    HSCsQuiescentphenotype

    Normalendothelialcells

    Endothelialcellswithoutfunctions

    Hepatocytes

    Apoptosis

    Increaseoffibrogenesis

    TGF +PDGFECMcomponent

    ECM:Extracellularmatrix

    capillarization

    13

    9

    MatrixMetalloproteinase(MMP)

    restorativemacrophages

    profibrogenicmacrophages

  • Otherimmunecells

    ANTIFIBROGENIC

    PROFIBROGENIC

    RolenotwelldefinedforBcellsandTreg cells

    Th1

    IFN

    Th17

    Th2

    IL17

    IL3

    NKcells ApoptosisofHSCs

  • Molecular mechanism

    Hepatic homeostasis is disturbed FIBROGENESIS

    Leukocyte infiltrationLack of inflammatory cells

    Decrease of NADP oxidase

    Reactive Oxygen Species

    Stellate cells Macrophages Hepatocytes

    Apoptosis of the parenchymal cells

    FIBROGENESIS

    Activation

  • HEALTHY INFLAMMATION FIBROGENESIS CIRRHOSIS CONSEQUENCES

    ACUTEINJURY

    MYOFIBROBLASTS

    HEPATICSTELLATECELLS(HSCs)

    Morphologicalandfunctional

    features Othercellsimplicated

    ACTIVATION

    Injurybecomeschronic

  • HEPATICSTELLATECELLSACTIVATION

    Its responsible ofliver fibrosis We can observeit inchronic hepatic injury

    Itoccurs intwo majorsphases:1. Initiation2. Perpetuation

  • http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2888531/

  • Firstphase:Initiation

    Resultsmostlyfromparacrinestimulationfromneighboringcells

    Alsoduetoexposuretolipidperoxidesandproductsofdamagedhepatocytes

  • Kupffer cellsandendothelialcellsstimulateHepaticstellate cells,byproducingTGF

    Hepatocyte apoptosisfollowinginjuryalsopromotesstellate cellinitiation

    Cytochrome CYP2E1

  • Secondphase:Perpetuation Changement incellbehavior Theneteffectofthesechanges

    istoincreaseaccumulationofextracellularmatrix

    Therearetwo mainprofibrogenetics consequences ofthis changement

    Increasingnumberofextracellularmatrixproducing

    cells

    Increasingmatrixproductionpercell

  • Increasing cell number

    Hepatic stellate cellmitosis,duetomitogensfactors (PDGF)

    Cellsthatmigratetowardscytokinechemoattractants (PDGF,MCP1,andCXCR3)

  • Increasing matrix production Themostpotentstimulus

    formatrixproductionbystellate cellsisTGF(paracrine andautocrinesource)

    Fullyactivatedhepaticstellate cellsshutdownexpressionofMMP

    Acivated stellate cellsproducefunctionalTIMPs(collagenase inhibitor)

    Protein SmoothMuscleActin isincreased

  • HEALTHY INFLAMMATION FIBROGENESIS CIRRHOSIS CONSEQUENCES

    ACUTEINJURY

    MYOFIBROBLASTS

    HEPATICSTELLATECELLS(HSCs)

    Morphologicalandfunctional

    features Othercellsimplicated

    ACTIVATION

    Injurybecomeschronic

  • CONSEQUENCES PortalhypertensionDecreaseofcomplianceintheliverleadstohighervenous

    pressure

    Hepatocarcinoma Chronicdisease:constantcycleofdamageandrepair

    AngiogenesisHSCsproduceangiogenicgrowthfactors

    TwomechanismsofangiogenesisAfterinjury:overexpressionofgrowth

    factorsDuringtissuehypoxia

  • Regression

    Regression ofliver fibrosiscan occur whenunderlying disease istreated

    Increase collagenolytic activity

    http://www.jci.org/articles/view/24282/figure/4

  • Regression(2)

    TIMP1isexpressed during liver disease TIMP1naturally inhibits MMPs MMP1isresponsible for degradation oftype1collagen

    When disease istreated:TIMP1whichresults inMMP

  • Prospectivetherapies

    Currenttreatment Targettheunderlyingdisease

    Sometreatmentstargetingspecificreceptorsinearlyphase

    CB1and2receptorsinfibrogenic cascade PPARagonistshowsreducedinflammation

  • CONCLUSION

    Healing mechanism disease

    HSCs myofibroblasts overproduction of ECM

    Main long run cause: overconsumption of alcohol

    Main long run consequence: portal hypertension

    Influencing cells

    Macrophages Endothelialcells Otherimmunecells

  • REFERENCES

    Mallat,Lotersztajn:cellularmechanisms oftissuefibrosis.5.Novel insightsinto liver fibrosis.(2013)

    Friedman:Mechanisms ofhepatic fibrosis (2010) Pinzani,Rosselli,Zuckermann:Liver cirrhosis (2011) Robbin's pathologic basisofdiseases (chapter 18) DavidABrenner,TatianaKisseleva,DavidScholten,YongHanPaik,KeikoIwaisako,Sayaka

    Inokuchi,BerndSchnabl,Ekihiro Seki,Samuele DeMinicis,Christoph Oesterreicher andKojiro Taura :origin ofmyofibroblasts inliver fibrosis (2012)

    Friedman :Hepatic Stellate Cells:Protean,Multifunctional,andEnigmatic Cells oftheLiver Journal.cambridge.org http://ajcp.ascpjournals.org Bataller,Brenner :Liver fibrosis (2005) http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2888531/

  • Thankyou!