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Depressant

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    Depressant

ChinaMedicalAbstract{Surgery).2006;is{4):160162

    ;Depressanteffectandmechanismofatorvastatinonthe

    ;chronicrejectionofaorticallograftinrats

    ;ZuoKeqiang(左克强),QianZhenyu(钱振宇),HuangDaojing(黄道景),

    ;GongKai(龚凯),TangJingdong(汤敬东)

    ;DepartmentofVascularSurgery,TongjiHospital,TongjiUniversity,Shanghai200065,China

    ;Abstract:ObjectiveToinvestigatethedepressanteffectandmechanismofatorvastafinonthechronicrejectionof

    ;aorticallogratinrats.Methods:Themodel~ofabdominalaortatransplantationweremadewithmicro-surgeryinrats.

    ;Therecipientsweredividedintothreegroups:allograftcontrolgroup,atorvastatin-treatedgroupandisograftcontrol

    ;group.Vascularintimalthicknessinallofthegroupswereobservedbyhistologicalexamination.TheexpressionofPCNA

    ;anda-SMAweredeterminedbyimmunohistochemistry.Thecontent0fnitricoxidewaSdeterminedbynitratereductase

    ;chromatometry.Results:Thevascularintimalthicknessinratsofatorvastatin-treatedgroup(11.60%?2.40%)were

    ;lowerthanthoseinallograftcontrolgroup(34.60%?6.40%;P<0.05)andhigherthanthoseinisograftcontrolgroup

    ;(1.15%?0.65%;P<0.05).TheexpressionlevelofPCNAwasdecreasedinatorvastatin-treatedgroup(4.80%?

    ;0.80%)thanallograftcontrolgroup(18.40%?1.80%;P<0.05)andhigherthanisograftgroup(1.20%?0.40%;

    ;P<0.05).Conclusion:TheexpressionofPCNAinthetransplantaortacouldbesuppressedbyatorvastafin,whichre

    ;suitedinreliefofchronicr6ectionofaorticallograft.

    ;Keywords:Atorvastatin;Transplant;Chronicection;Proliferationcellnuclear’antigen;a-smoothmuscleactin;

    ;Nitricoxide

    ;Introduction

    ;Chronicrejection(CR)maycausethelossofthe

    ;graft,whichisthemainreasonoftheorgantransplant

    ;patientsforlong-termsurviva1.Althougheffectiveim

    ;munosuppressantshavebeenusedinrecentyears,thefact

    ;thatlategraftlossledbyCRhasnotbeennoticeablyim

    ;proved.Astudyhasshowedthatatorvastatincaninhibit

    ;atherosderosiseffectively[1].ThecontentofNOcanbe

    ;measuredinarterialgraftbypathologicalimageanalysis, ;immunohistochemistryandnitratereductasechromatome

    ;try,onthebasisoftheestablishmentoftheanknalmodels ;intheCRofthegraftarteryOurexperimentaimstostudy ;theimpactoftheatorvastatinnotonlyonthepathological ;d~’geofgraftarteriosclerosis,butalsoontheinhibition

    ;andmechanismoftheCRofarterygraftinrats.

    ;MaterialsandMethods

    ;1.AnimalmodelsofCRMaleWistarandSDmale

    ;rats,2to3monthsold,weighing200to240g(from ;TongjiMedicalCollegeofHuazhongUniversityofScience ;andTechnologyLaboratoryCente),adaptabifityfeeding ;experiment12weekstomeettherequire.Openether

    ;anesthesiainducedbyinhalation.Forthedonorratab

    ;dominalaortafrom1to1.5cH1.itwastakeninto4?

    ;balancepreservationsolutionafterheparindripirrigation. ;Thenitwillberequiredfortheinsituratarteryinthe ;rat.endanastomosisoftheabdominalaortabythemicro

    ;scopicsurgicaltechniqueusedinthesurgery11/0nonin

    ;vasivevascularsuture,andweidentifynosignificant ;bleedingbeforerintraperitonealclosure.

    ;2.Packetprocessingandanimalmodel1]hedonor ;forSD,thereceptorforWistarrats,aredividedintoallo

    ;graftcontrolgroup(=10)andatorvastatintreated

    ;group(n=10)inrandom.Isograftcontrolgroupare ;fromSDrats.Sincethefirstdayaftertransplantion, ;(fromBeijingHongBiologicalPharmaceuticalCo,Ltd) ;theatorvastatin-treatedgroupareinjectedatorvastatin ;dailyintostomachindoseof15mg?kg?df0r60

    ;Correspondingauthor:TANGJing-dong,E-mail:drtangjingdong@126.com

    ;

    ;ChinaMedicalAbstracts{Surgery),2006i15(4):160162

    ;days.Allograftcontrolgroupandisograftcontrolgroup ;areonlyinjectedwaterintothestomachs.

    ;3.mv,omthologi~detectionTheratsweresacri

    ;ricedafter60days.~Decinlen8ofartery,

    araffin-embed

    ;ded,cut5thicknessOfeachslicesDee~ensflmm5,100 ;spachng,stainedbytheh~mtoxylln-Yihong(HE). ;totalvamdarsurfaceareaandintimasurfacearea,aremea- ;suredbytheoz~nputerh~4nganalysissystem.Theareaof ;thethicknessoftheintimashowstheproliferationdegree, ;whichcanbemeasuredbythearearatioofintimalthickening ;=

;(int~area/totalarea)×100%.

    ;4.DetermingNOofthegraftarteryPreparation ;Qf10%fromthetransplantedarteryhomogenatewithI1i

    ;tratereductasecolorimetricassay(NanjingInstituteof ;CompletedBiologicalEngineering)

    ;ealdetectionSPmethodwas

    SMAexpressionofthegraft,ac ;usedtodetectPCINA,a

    ;cordingtotheManual(Rabbitantiratmonoclonalanti

    ;bodyagainsta-SMAandPCNA,rabbitantiratmono

    ;donalantibodypurchasedfromWuhanBoshideBiological ;ProductsCompany).Findings:PCNAisavioletblue ;granularwhichlocatedinnucleus,aSMAisbrowngran

    ;ularwhichlocatedincytoplasm.ThepositivecellsPCNA. ;SMAwereelected10visionundereachsectionbycom

    ;puterimageanalysissysteminthehighpowermicroscope

    ;(10×20),withitscoloringareaasacriterion. ;6.StatisticalmethodsI-s11.0packagedealt ;ththeexperimentaldata.theresultwasdeten-ninedby ;me&rl?standarddeviation(?s),varianceanalysisand ;LSDtestmethods.

    ;Results

    ;1.rnIepathologicalchangeandtheintimaprolifer- ;ationdegreeofthegraftartery:?thereistypicalle

    ;sionofthegraftvesselallograftcontrolgroup:theinti

    ;n1athickenssignificantly.therearemanytransitional ;smoothmusclecells,accompaniedbyalargenumberof ;inflammatorycellsinfiltration.?theintimainatorvas

    ;tatin-treatedgroupdoesnotthickensosignificantlyasthat ;allograftcontrolgroup:therearesometransitional ;smoothmusdecells,accompaniedbyabitofinflammato

    ;rycellsinfiltration.?theintimaisograftcontrolgroup

    ;thickenslightly.Therearedifferentdegreesofendometri

    ;alhyperplasiainallografttreated,controlgroup(34.60% ;?6.40%.11.60%?2.40%;P<0.05);thereismild ;endometrialhyperplasiainisograftcontrolgroupf1.15% ;?0.650%;P<0.05).

    ;2.rnIeproteinexpressionofPI:NA,ff~-SMA?

    ;TheexpressionofPCINAallograftcontrolgroupishigh ;(18.40%?1.80%;P<0.05),whichmainlyconcen

    ;tratedintheendometrium,followedbymiddle;itexpress ;significantlylower(4.80%?0.80%)atorvastatin- ;treatedgroupthaninallograftcontrolgroup;itexpress ;lowest(1.20%?0.40%;P<0.05).misograftgroup, ;whichoccasionallyappearinasinglebulkofthepositive

;nudei.mendometria1.?Inendometrialhyperplasialay

    ;er,therearemostofthesmoothmuscleaSMA-positive

    ;cells;theexpressionoftheaSMAallograftcontrol

    ;group(18.60%?3.80%)isobviouslyhigherthanthat ;inatorvastatin-treatedgroup(4.60%?1.20%;P< ;0.05).Thereisnosignificantintimahyperplasia-niso

    ;graftcontrolgroup.whichaSMAcanonlybeseen-nme

    ;dia(1.10%?0.25%;P<0.05),(Fig1).

    ;3.rnIecontentoftheNOingraftvesselsthecon

    ;tentoftheNOingraftvesselsinallograftcontrolgroup, ;atorvastatin-treatedgroupandisograftcontrolgroupare: ;6.08?0.49pmol/gprot,14.58?0.86pmol/gprot, ;20.34?1.52pmol/gprot;P<0.05),whichisstatisfi

    ;callysignificantdifference.

    ;Disscution

    ;CRisthemaincauseofthe1ategraftloss-ntheor

    ;gantransplant,thehistologyoftheCRdifferentorgan ;transplantvary,howeverthereisonecomn’lonfeature:

    ;atherosclerosis[]ofgraftvesseldisease[.characterized

    ;byvascularendometrialhyperplasia.Vasculargraftneoin

    ;timalhyperplasiawereca1.ksedbyboththeproliferationof ;VSMCwhichmovedfromfilmtotheendometriumand ;extracellularmatrix.Inhibitingtheproliferationandmi

    ;grationoftheVSMCcarldecreaseendometrialhypertro

    ;phy.Therefore,proliferationandmigrationoftheVSMC ;istheimportantfactoroftheendometrialhyperplasiaand ;thedevelopmentofCR,inhibitionoftheproliferationand ;migrationoftheVSMCcouldbetheimportantwayto ;

    ;?

    ;162?ChinaMedicalAbstracts(Surgery).2006;15{4):160162

    ;preventtheformationanddevdopmentofatherosclerosisandCR ;Fig1ImmunostainingresultsofI~-’NAindifferentgroupsoftransplantabdominalaortasofrats(SP.x200).

    ;hyacinthinegranulesdenotespositivestaininginnuclei.A:proteinexpressionisstronginal

    lograft

    ;controlgroup.B:Weakinatorvastatin-treatedgroup.C:fewerinisograftcontrolgroup.

    ;Inourexperiment.thereistypicalgraftvessel ;diseaseofgraftarteryinallograftcontrolgroup,how

    ;ever,noappearanceinisograft,whichmimictothe ;atherosclerosisinthehuman’sgraftvessels.There

    ;fore,theanimalmodelareofimportantvalueinthe ;studyofCR.NowitisbelievedthatNOiscloselyre

    ;latedwithCR.Physiologically,vesselendothelial

    ;cellscanrelieveNOpersistently.AndNOcaninhabit ;theproliferationandmigrationoftheVSMC[.CR

    ;cancausethefunctiondisorderoftheendothelialcel1. ;themechanismisthedeclineofstabilityofthekey ;endothdialNOsynthesisofnitricoxidesynthase ;(eNOS)andreductionofNOproduction.Vastatin ;drugscaneffectivelyinhibittheproliferationofthe ;rat’sartery[.

    ;Atorvastatinisapotentstatindrugs

    ;ofthethirdgenerationlipidlowering,itcanreduces

    ;theactivationofendothelialcells,upregulattheactiv

    ;ityofeNOS,restoreorincreasethesynthesisofNO ;0fthedamagedbloodvesselsE.downregulatetheac

    ;tivityofbFGFE,inhibitthemigrationandprolifera

    ;tionofVSMC,antiinflammatory,irnmuno-regula

    ;ti0n[81.andantiatherosclerosis.ThecontentofNO ;ingraftvesselsinatorvastatintreatedgroup(14.58

    ;?0.86lol/gprot)ishigherthanthatofallograft ;controlgroup,(6.08?0.49/~mol/gprot),P<0. ;05),whichisstatisticallysignificantdifference. ;Experimentshowsthatitcansignificantlyinhib

    ;itthethicknessoftheintimaofthemodelratswitha

    ;torvastatin.Inendometrialhyperplasialayer,there ;arealargenumberofthesmoothmusclea-SMA-posi

    ;tivecellsintheintima,theconcentrationofithas ;beenanewindexinthediagnosisofCR[.Thehi

    ;expressionofa-SMAinallograftcontrolgroupshows ;thattheendometrialhyperplasiacellistheVSMCmi

    ;gratedfromthefilmtointima.Asanimportantindex ;inassessingtheproliferationofcells,PCNAinator

    ;vastatin-treatedgroupexpresseslessobviouslythan ;thatdoesinallograftcontrolgroup.Theextentofthe ;intimalhyperplasiaisthemostcrucialindicatorinas

    ;sessingthegraftatherosclerosis.Inhibitingtheprolif

    ;erationandmigrationoftheVSMC.atorvastatincan ;inhibitsignificantlythethicknessofintimasoasto ;inhibittheCRcausedbyatherosclerosis.Webelieve ;thatatorvastatincanreducetheintimalhyperplasiaof ;thegraftvesselbythedownregulationofthegenetic ;expressionofthePCNA.whichmaybeoneofthe ;mechanismofinhibitingintimalhyperplasiaofgraft ;arteryofCR”.

    ;References

    ;[1]

;[2]

    ;VanLeuvenSI,KasteleinJJ.Atorvastatin[J].Expert ;OpinPharmamther,2005,6(7):11911203.

    ;PaulJ,MichaelC,GregH,eta1.Redpientcellsform ;theintimalproliferativelesionintherataorticmodelof ;aUograftarteriosderods[J].Americanjournaloftrans. ;plantation,2002,2(3):207217?(下转封三页)