A Key Role for the Endothelium in NOD1 Mediated Vascular Inflammation Comparison to TLR4 Responses 英文参考文献.docVIP
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A Key Role for the Endothelium in NOD1 Mediated Vascular Inflammation Comparison to TLR4 Responses 英文参考文献
AKeyRolefortheEndotheliuminNOD1Mediated
VascularInflammation:ComparisontoTLR4Responses
TimothyGatheral1,DanielM.Reed1,LauraMoreno1,2,PeterJ.Gough3,BartJ.Votta3,ClarkA.Sehon3,
DavidJ.Rickard3,JohnBertin3,EricLim4,5,AndrewG.Nicholson4,5,JaneA.Mitchell1,6
*
1Cardiothoracic Pharmacology, National Heart and Lung Institute, Imperial College, London, United Kingdom, 2Department of Pharmacology, School of Medicine,
3Pattern
Universidad
Complutense
de
Madrid,
Madrid,
Spain,
Recognition Receptor Discovery Performance Unit, Immuno-Inflammation Therapeutic Area,
GlaxoSmithKline, Collegeville, Philadelphia,Pennsylvania, United States of America, 4Royal Brompton and Harefield NHS Foundation Trust, London, United Kingdom,
5NationalHeartandLungInstitute,ImperialCollege,London,UnitedKingdom,6InstituteofCardiovascularMedicineandScience(ICMS),London,UnitedKingdom
Abstract
Understanding the mechanisms by which pathogens induce vascular inflammation and dysfunction may reveal novel
therapeutic targets in sepsis and related conditions. The intracellular receptor NOD1 recognises peptidoglycan which
featuresinthecellwallofGramnegativeandsomeGrampositivebacteria.NOD1engagementgeneratesaninflammatory
responseviaactivationofNFkBandMAPKpathways.WehavepreviouslyshownthatstimulationofNOD1directlyactivates
bloodvesselsandcausesexperimentalshockinvivo.Inthisstudywehaveusedanexvivovessel-organculturemodelto
characterisetherelativecontributionoftheendotheliumintheresponseofbloodvesselstoNOD1agonists.Inadditionwe
presentthenovelfindingthatNOD1directlyactivateshumanbloodvessels.Usinghumanculturedcellsweconfirmthat
endothelialcellsrespondmoreavidlytoNOD1agoniststhanvascularsmoothmusclecells.Accordinglywehavesoughtto
pharmacologically differentiate NOD1 and TLR4 mediated signalling pathways in human endothelial cells, focussing on
TAK1,NFkBandp38MAPK.InadditionweprofilenovelinhibitorsofRIP2andNOD1itself,whichspecificallyinhibitNOD1
ligandinducedinflammatorysignallinginthevasculature.Thispaperisthefirst
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