藥物性肝損傷,炎癥治療的最新進展

報告人：張靖垚導(dǎo)師：劉昌教授藥物性肝損傷，炎癥治療的最新進展報告人：張靖垚藥物性肝損傷，炎癥治療的最新進展223Benzyl

alcohol：苯甲醇，1.苯甲醇是最簡單的芳香醇之一2.健康危害：具有麻醉作用，對眼、上呼吸道、皮膚有刺激作用。攝入引起頭痛、惡心、嘔吐、胃腸道刺激、驚厥、昏迷。3.有抑菌、止癢作用3Benzyl

alcohol：苯甲醇，4BA(270ug/g,IP).4BA(270ug/g,IP).53of3micediedBA(270ug/g,IP).6hours用BA的時間6hours53of3micediedBA(270ug/g6High-mobilitygroupbox1：importantmediatorofinjuryinbothsterileandnonsterileliverinjury,includingAPAPtoxicity.BAtreatmentreducedAPAP-inducedin?ammation.6High-mobilitygroupbox1：im7APAP-inducedliverinjuryisdependent,inpart,onTLR9,RAGE,HMGB-1,andIL-6expression.6-hourPrecognitionreceptors(PRRs)–TLR2,TLR4,TLR9orRAGESeveralstudieshavehighlightedtheroleofdifferentPRRsandin?ammasomeactivationonAPAP-inducedliverinjury.

7APAP-inducedliverinjuryis8Glycyrrhizin（甘草酸）,whichposesanti-HMGB-1propertiesMicede?cientinhepatocyte-speci?cexpressionofHMGB-18Glycyrrhizin（甘草酸）,whichpose9910Together,thesedatasuggestapathwayofTLR9-orRAGE-mediatedinjurythatsignals,orisampli?edby,hepatocyteparenchymalHMGB1releaseandsubsequentincreasesinserumIL-6.10Together,thesedatasuggest11BAprotectsthroughTLR4receptorexpression.BAfailedtoprotectagainstliverinjuryinmicede?cientinTLR4expression,suggestingthatBAsignaled,atleastinpart,throughthisreceptor.CD14hasbeenshowntobeacoreceptorofTLR4Hepatocyte-speci?cKODC-speci?cKOmyeloidcell–speci?cKOGlobalknockout

adipose-speci?cKO11BAprotectsthroughTLR4re121213mitochondrialinjuryplasmalevelsofmtDNA13mitochondrialinjuryplasma14體外實驗APAP(5mM)onprimarymouse(C57BL/6)hepatocytes14體外實驗APAP(5mM)onprimary151.APAP-inducedinjuryispartiallymediatedbyactivationoftheNalp3in?ammasome.2.activationofNalp3canbebedownstreamofTLR9.3.CriticaltoNalp3in?ammasomesignalingiscleavageandactivationofcaspase-1，which,inturn,cleavesthepro-formsofIL-1bandIL-18.151.APAP-inducedinjuryispar16BA’sinhibitioninhepaticin?ammasomesignalingwasTLR4dependent.16BA’sinhibitioninhepatici理論基礎(chǔ)17BAcaninhibitmitochondrialelectrontransportatseveralpointsalongtherespiratorychainChazotteB,VanderkooiG.Multiplesitesofinhibitionofmitochon-drialelectrontransportbylocalanesthetics.BiochimBiophysActa1981;636:153-161.理論基礎(chǔ)17BAcaninhibitmitochond1818191920First,astheauthorsdiscussedthemselves,BAcaninhibitmitochondrialrespirationandistoxicathigherdoses.Second,BAwasmosteffectivewhengivenduringanarrowwindowaroundthetimeofAPAPtreatment,BAonlyprotectswhenpresentduringthemetabolismphaseofAPAP.theestablishedclinicalantidoteN-acetylcysteinen（乙酰半胱氨酸）ismosteffectiveduringthemetabolismphaseandbeyondwithlowerrisk.Third,Mostimportantly,allagreethatonlyafewpg/mlIL-1βareactuallyproducedduringAPAPhepatotoxicity.20First,astheauthorsdiscus212122低溫，紫外線照射，缺氧22低溫，紫外線照射，缺氧23240minafterhemorrhageShockRatHemorrhageShockmodelshock23240minafterhemorrhageSho24

RecombinantCIRP+RAW264.7cells4h100ngml?1PolymyxinB,PMB,

anLPS-bindingantibiotic24RecombinantCIRP+RAW264.725BlockadeofCIRPreducesTNF-αandIL-6production,hepaticinjuryandmortalityafterhemorrhage.25BlockadeofCIRPreduces2626272728ratperitonealmacrophages細胞裂解物conditionedmediumfromratperitonealmacrophagesconditionedmediumofRAW264.7cellsSepsismodel28ratperitonealmacrophages細胞29

rmCIRP+peritonealmacrophages29rmCIRP+peritonealmacropha303031小鼠盲腸31小鼠盲腸32生物膜，防粘連膜ActivatedproteinC：

1.anticoagulantandantiin?ammatoryprotease2.potentantiin?ammatory,cytoprotective,andpro?brinolyticproperties32生物膜，防粘連膜ActivatedproteinC33NairetalLeachetal’sscale33Nairetal34peritonealfluid炎癥因子水平34peritonealfluid炎癥因子水平35peritonealtissues炎癥因子轉(zhuǎn)錄水平35peritonealtissues炎癥因子36一般的APChasthesignalingfunctionhasnormalanticoagulant

butdefectivePAR1signalingfunction無活性的APC36一般的APChasthesignalingha37373838393940thrombin-antithrombin(TAT)complex肝素.Tofurtherdeterminewhethertheinhibitionofcoagulationcascademakesanycontributiontopost-surgicaladhesionbandformationAnalysisofcoagulationandfibrinolyticmarkers40thrombin-antithrombin(TAT)41影響腹膜液中的凝固與纖溶系統(tǒng)41影響腹膜液中的凝固與纖溶系統(tǒng)42Highlights?ThelongnoncodingRNAlncTCF7ishighlyexpressedinlivercancertissuesandCSCs?LncTCF7isimportantforself-renewalofliverCSCs?LncTCF7activatestheWntsignalingpathwaythroughTCF7expression?LncTCF7recruitstheSWI/SNFcomplextoactivatetheTCF7promoter42Highlights4343藥物性肝損傷,炎癥治療的最新進展報告人：張靖垚導(dǎo)師：劉昌教授藥物性肝損傷，炎癥治療的最新進展報告人：張靖垚藥物性肝損傷，炎癥治療的最新進展46247Benzyl

alcohol：苯甲醇，1.苯甲醇是最簡單的芳香醇之一2.健康危害：具有麻醉作用，對眼、上呼吸道、皮膚有刺激作用。攝入引起頭痛、惡心、嘔吐、胃腸道刺激、驚厥、昏迷。3.有抑菌、止癢作用3Benzyl

alcohol：苯甲醇，48BA(270ug/g,IP).4BA(270ug/g,IP).493of3micediedBA(270ug/g,IP).6hours用BA的時間6hours53of3micediedBA(270ug/g50High-mobilitygroupbox1：importantmediatorofinjuryinbothsterileandnonsterileliverinjury,includingAPAPtoxicity.BAtreatmentreducedAPAP-inducedin?ammation.6High-mobilitygroupbox1：im51APAP-inducedliverinjuryisdependent,inpart,onTLR9,RAGE,HMGB-1,andIL-6expression.6-hourPrecognitionreceptors(PRRs)–TLR2,TLR4,TLR9orRAGESeveralstudieshavehighlightedtheroleofdifferentPRRsandin?ammasomeactivationonAPAP-inducedliverinjury.

7APAP-inducedliverinjuryis52Glycyrrhizin（甘草酸）,whichposesanti-HMGB-1propertiesMicede?cientinhepatocyte-speci?cexpressionofHMGB-18Glycyrrhizin（甘草酸）,whichpose53954Together,thesedatasuggestapathwayofTLR9-orRAGE-mediatedinjurythatsignals,orisampli?edby,hepatocyteparenchymalHMGB1releaseandsubsequentincreasesinserumIL-6.10Together,thesedatasuggest55BAprotectsthroughTLR4receptorexpression.BAfailedtoprotectagainstliverinjuryinmicede?cientinTLR4expression,suggestingthatBAsignaled,atleastinpart,throughthisreceptor.CD14hasbeenshowntobeacoreceptorofTLR4Hepatocyte-speci?cKODC-speci?cKOmyeloidcell–speci?cKOGlobalknockout

adipose-speci?cKO11BAprotectsthroughTLR4re561257mitochondrialinjuryplasmalevelsofmtDNA13mitochondrialinjuryplasma58體外實驗APAP(5mM)onprimarymouse(C57BL/6)hepatocytes14體外實驗APAP(5mM)onprimary591.APAP-inducedinjuryispartiallymediatedbyactivationoftheNalp3in?ammasome.2.activationofNalp3canbebedownstreamofTLR9.3.CriticaltoNalp3in?ammasomesignalingiscleavageandactivationofcaspase-1，which,inturn,cleavesthepro-formsofIL-1bandIL-18.151.APAP-inducedinjuryispar60BA’sinhibitioninhepaticin?ammasomesignalingwasTLR4dependent.16BA’sinhibitioninhepatici理論基礎(chǔ)61BAcaninhibitmitochondrialelectrontransportatseveralpointsalongtherespiratorychainChazotteB,VanderkooiG.Multiplesitesofinhibitionofmitochon-drialelectrontransportbylocalanesthetics.BiochimBiophysActa1981;636:153-161.理論基礎(chǔ)17BAcaninhibitmitochond6218631964First,astheauthorsdiscussedthemselves,BAcaninhibitmitochondrialrespirationandistoxicathigherdoses.Second,BAwasmosteffectivewhengivenduringanarrowwindowaroundthetimeofAPAPtreatment,BAonlyprotectswhenpresentduringthemetabolismphaseofAPAP.theestablishedclinicalantidoteN-acetylcysteinen（乙酰半胱氨酸）ismosteffectiveduringthemetabolismphaseandbeyondwithlowerrisk.Third,Mostimportantly,allagreethatonlyafewpg/mlIL-1βareactuallyproducedduringAPAPhepatotoxicity.20First,astheauthorsdiscus652166低溫，紫外線照射，缺氧22低溫，紫外線照射，缺氧67240minafterhemorrhageShockRatHemorrhageShockmodelshock23240minafterhemorrhageSho68

RecombinantCIRP+RAW264.7cells4h100ngml?1PolymyxinB,PMB,

anLPS-bindingantibiotic24RecombinantCIRP+RAW264.769BlockadeofCIRPreducesTNF-αandIL-6production,hepaticinjuryandmortalityafterhemorrhage.25BlockadeofCIRPreduces7026712772ratperitonealmacrophages細胞裂解物conditionedmediumfromratperitonealmacrophagesconditionedmediumofRAW264.7cellsSepsismodel28ratperitonealmacrophages細胞73

rmCIRP+peritonealmacrophages29rmCIRP+peritonealmacropha743075小鼠盲腸31小鼠盲腸76生物膜，防粘連膜ActivatedproteinC：

1.anticoagulantandantiin?ammatoryprotease2.potentantiin?ammatory,cytoprotective,andpro?brinol