Autophagy Mediates the Delivery of Thrombogenic Tissue Factor to Neutrophil Extracellular Traps in Human Sepsis 英文参考文献.docVIP

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Autophagy Mediates the Delivery of Thrombogenic Tissue Factor to Neutrophil Extracellular Traps in Human Sepsis 英文参考文献.doc

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Autophagy Mediates the Delivery of Thrombogenic Tissue Factor to Neutrophil Extracellular Traps in Human Sepsis 英文参考文献

AutophagyMediatestheDeliveryofThrombogenic TissueFactortoNeutrophilExtracellularTrapsinHuman Sepsis KonstantinosKambas1.,IoannisMitroulis1.,EiriniApostolidou1,AndreasGirod2, AkriviChrysanthopoulou1,IoannisPneumatikos3,PanagiotisSkendros1,IoannisKourtzelis4, MariaKoffa5,IoannisKotsianidis6,KonstantinosRitis1* 1First Department of Internal Medicine, Democritus University of Thrace, University General Hospital of Alexandroupolis, Alexandroupolis, Greece, 2Life Sciences Research Unit-FSTC, University of Luxembourg, Walferdange, Luxembourg, 3Intensive Care Unit, Democritus University of Thrace, University General Hospital of Alexandroupolis,Alexandroupolis,Greece,4SchoolofBiology,AristotleUniversityofThessaloniki,Thessaloniki,Greece,5LaboratoryofCellularandMolecularBiology, Department of Molecular Biology and Genetics, Democritus University of Thrace, Alexandroupolis, Greece, 6Department of Hematology, Medical School, Democritus UniversityofThrace,Alexandroupolis,Greece Abstract Background:Sepsisisassociatedwithsystemicinflammatoryresponsesandinductionofcoagulationsystem.Neutrophil extracellulartraps(NETs)constituteanantimicrobialmechanism,recentlyimplicatedinthrombosisviaplateletentrapment andaggregation. Methodology/PrincipalFindings:Inthisstudy,wedemonstrateforthefirsttimethelocalizationofthrombogenictissue factor(TF)inNETsreleasedbyneutrophilsderivedfrompatientswithgram-negativesepsisandnormalneutrophilstreated witheitherserumfromsepticpatientsorinflammatorymediatorsinvolvedinthepathogenesisofsepsis.LocalizationofTF in acidified autophagosomes was observed during this process, as indicated by positive LC3B and LysoTracker staining. Moreover,phosphatidylinositol3-kinaseinhibitionwith3-MAorinhibitionofendosomalacidificationwithbafilomycinA1 hinderedthereleaseofTF-bearingNETs.TFpresentinNETsinducedthrombingenerationinculturesupernatants,which furtherresultedinproteaseactivatedreceptor-1signaling. Conclusions/Significance:Thisstudydemonstratestheinvolvementofautophagic