Paclitaxel Modulates TGFβ Signaling in Scleroderma Skin Grafts in Immunodeficient Mice 英文参考文献.docVIP

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Paclitaxel Modulates TGFβ Signaling in Scleroderma Skin Grafts in Immunodeficient Mice 英文参考文献.doc

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Paclitaxel Modulates TGFβ Signaling in Scleroderma Skin Grafts in Immunodeficient Mice 英文参考文献

o Openaccess,freelyavailableonline PL S MEDICINE PaclitaxelModulatesTGFbSignaling inSclerodermaSkinGrafts inImmunodeficientMice Xialin Liu1[,Shoukang Zhu1[,Tao Wang1,Laura Hummers2,Fredrick M.Wigley2,Pascal J.Goldschmidt-Clermont1, Chunming Dong1* 1DivisionofCardiology,DepartmentofMedicine,DukeUniversityMedicalCenter,Durham,NorthCarolina,UnitedStatesofAmerica,2DivisionofRheumatology,Johns HopkinsUniversity,Baltimore,Maryland,UnitedStatesofAmerica CompetingInterests:Theauthors havedeclaredthatnocompeting interestsexist. ABSTRACT Background AuthorContributions:CDhadthe originalideaforthestudy,and designedandoversawthestudy.XL andSZperformedmostofthe experimentalproceduresanddata analysisandparticipatedinthestudy design.TWperformedsome experiments.LHandFMWrecruited thepatientsandcollectedtheskin biopsies.PJGChelpeddevelopthe conceptofthestudy,andcoordinated andsupervisedtheexperiments.XL, PJGC,andCDcontributedtothe writingofthereport. Systemicsclerosis(SSc)ischaracterizedbyexcessivefibrosisandobliterativevascularlesions. Abnormal TGFb activation is implicated in the pathogenesis of SSc. Aberrant TGFb/Smad signalingcanbecontrolledbystabilizationofmicrotubuleswithpaclitaxel. MethodsandFindings SScandhealthyhumanskinbiopsieswereincubatedinthepresenceorabsenceofpaclitaxel followed by transplantation into severe combined immunodeficient mice. TGFb signaling, fibrosis, and neovessel formation were evaluated by quantitative RT-PCR and immunohis- tochemical staining. Paclitaxel markedly suppressed Smad2 and Smad3 phosphorylation and collagendepositioninSScgrafts.Asaresult,theautonomousmaintenance/reconstitutionof the SSc phenotype was prevented. Remarkably, SSc grafts showed a 2-fold increase in neovesselformationrelativetonormalgrafts,regardlessofpaclitaxeltreatment.Angiogenesis in SSc grafts was associated with a substantial increase in mouse PECAM-1 expression, indicatingthemouseoriginoftheneovascularcells. AcademicEditor:TomHuizinga, LeidenUniversityMedicalCentre,