Application of 18FFDG PET for Monitoring the Therapeutic Effect of Antiinflammatory Drugs on Stabil.docx

Application of 18FFDG PET for Monitoring the Therapeutic Effect of Antiinflammatory Drugs on Stabil.docx

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Applicationof18FFDGPETforMonitoringtheTherapeuticEffectofAntiinflammatoryDrugsonStabil

Applicationof18F-FDGPETforMonitoringtheTherapeuticEffectofAntiinflammatoryDrugsonStabilizationofVulnerableAtheroscleroticPlaques

MikakoOgawa1,2,YasuhiroMagata1,TakashiKato2,KentaroHatano2,SeigoIshino3,TakahiroMukai4,MasashiShiomi5,KengoIto2andHideoSaji3

1LaboratoryofGenomeBio-PhotonicsPhotonMedicalResearchCenter,HamamatsuUniversitySchoolofMedicine,Hamamatsu,Japan;2DepartmentofBrainScienceandMolecularImaging,NationalInstituteforLongevitySciences,NationalCenterforGeriatricsandGerontology,Obu,Japan;3DepartmentofPatho-FunctionalBioanalysis,GraduateSchoolofPharmaceuticalSciences,KyotoUniversity,Kyoto,Japan;4DepartmentofChemo-PharmaceuticalSciences,GraduateSchoolofPharmaceuticalSciences,KyushuUniversity,Fukuoka,Japan;and5InstituteforExperimentalAnimals,KobeUniversitySchoolofMedicine,Kobe,Japan

Correspondence:

Forcorrespondenceorreprintscontact:

HideoSaji,PhD,DepartmentofPatho-FunctionalBioanalysis,GraduateSchoolofPharmaceuticalSciences,KyotoUniversity,Sakyo-ku,Kyoto606-8501,Japan.E-mail:

hsaji@pharm.kyoto-u.ac.jp

  ABSTRACT

TOP

ABSTRACT

INTRODUCTION

MATERIALSANDMETHODS

RESULTS

DISCUSSION

CONCLUSION

References

Theruptureofatheroscleroticvulnerableplaquesandsubsequentformationofthrombiarethemainfactorsresponsibleformyocardialandcerebralinfarctions.Becausemacrophageinfiltrationplaysanessentialroleinplaquerupturing,pharmacologictherapythatreducesmacrophageinfiltrationisrequiredtostabilizethevulnerableplaques.Themonitoringoftherapeuticeffectisimportantinassessingthetherapeuticeffectsofdrugsforindividualpatients.Wepreviouslyreportedthat18F-FDGaccumulatesinmacrophage-richplaques.Thepresentstudywasundertakentoinvestigatetheusefulnessof18F-FDGPETformonitoringtherapiesthattargetvascularinflammation.Methods:

Myocardialinfarction–proneWatanabeheritablehyperlipidemicrabbitswereusedinthisstudy.Theantioxidantprobucolwasincludedinthedietfedto4rabbitsstartingat10moofage（probucolgroup）.Inacontrolstudy,4rabbitsreceivedstandardrabbitchow（controlgroup）.18F-FDGPETexperimentswereperformedonbothgroupsbeforethestudyandat1,3,and6moaftertreatment.Afterthelastimagingsession,therabbitsweresacrificedat3hafterinjectionof18F-FDG,andtheaortaswereremoved.Theaccumulatedradioactivitywasthenmeasured,andthenumberofmacrophageswasdeterminedbyexaminationofstainedsections.Results:

Attheageof10mo,beforethetreatment,theaortacouldbeimagedby18F-FDGPETinallrabbits.Theaortacouldnotbeimagedafter6moofprobucoltreatment,whereasintenseradioactivitywasobservedinthecontrolrabbitsthroughouttheinvestigation.Thestandardizeduptakevalues（SUVs）oftheaortaweredecreasedsignificantlyintheprobucolgroupafter3moofinterventionascomparedwiththepretreatmentperiod.TheSUVsofthecontrolgroupwereincreasedgraduallyat6mo.Radioactivityintheaortawassignificantlylowerintheprobucolgroupthanthatinthecontrolgroup.Macrophageswerealreadypresentatthebeginningofthestudy,andprobucoltreatmentfor6moresultedinasignificantreductionofmacrophageinfiltration.Conclusion:

18F-FDGPETwasabletoimagethereductionofinflammationbyprobucol.18F-FDGPETshouldbeusefulforevaluatingthetherapeuticeffectofdrugsclinicallyandforthedevelopmentofnewdrugsthatcanstabilizevulnerableplaques.18F-FDGPETshouldbeusefulforevaluatingthetherapeuticeffectofdrugsclinicallyandforthedevelopmentofnewdrugsthatcanreduceinflammationofvulnerableplaques.

KeyWords:

18F-FDGPET•atherosclerosis•vulnerableplaque•therapeuticeffect•probucol

  INTRODUCTION

TOP

ABSTRACT

INTRODUCTION

MATERIALSANDMETHODS

RESULTS

DISCUSSION

CONCLUSION

References

Theruptureofatheroscleroticplaqueandensuingthrombusformationareprimarilyresponsibleformyocardialandcerebralinfarctions（1–3）.Atheroscleroticplaquesareclassifiedinto2types,stableandvulnerable,withthelatterhavingahighriskofrupture.Thus,thedetectionofatheroscleroticplaquespronetoruptureisclinicallyimportantforriskstratificationandtoprovideearlytreatment.Inflammationplaysanessentialroleinplaquerupturing,andmacrophageinfiltrationischaracteristicofthevulnerableplaques（4）.Recently,weandanothergrouphaveshownthat18F-FDGaccumulatesinmacrophage-richplaques,and18F-FDGPEThasbeensuggestedtobeusefulfortheselectivedetectionofvulnerableplaques（5–7）.

Manydrugshavebeentestedfortheirabilitytostabilizeplaque（8）,andmacrophagesareoneofthetargetsofthesepharmacologictherapies（9）.However,becausedrugeffectsvaryamongindividuals,monitoringthetherapeuticeffectisimportantforselectingtheappropriatedrugforindividualpatients.Thepresentstudywasundertakentoinvestigatetheusefulnessof18F-FDGPETformonitoringtherapiesthattargetvascularinflammation.WeusedprobucolinWatanabeheritablehyperlipidemicrabbitswithmyocardialinfarction（WHHLMIrabbits）（10）—awidelyusedanimalmodelofatherosclerosis（11,12）—becauseprobucolisanantioxidantknowntoreducetheextentofmacrophageinfiltrationinatheroscleroticlesionsintheserabbits（13）.TheatheroscleroticplaqueofWHHLMIrabbitsdoesnotrupturebutitspathologiccharacteristicshavebeenreportedtoresemblethoseofthehumanlesion（10,14,15）.

  MATERIALSANDMETHODS

TOP

ABSTRACT

INTRODUCTION

MATERIALSANDMETHODS

RESULTS

DISCUSSION

CONCLUSION

References

AnimalsandDiets

PureprobucolpowderwaskindlysuppliedbyDaiichiPharmaceuticalCo.Ltd.WHHLMIrabbitsbredatKobeUniversitywereusedinthisstudy.Theanimalswerefedstandardrabbitchow（typeRC4;OrientalYeastCo.,Ltd.）untiltheageof10mo.Onerabbitwaskilledunderanesthesiawithsodiumpentobarbital,andtheaortawasremovedatthebeginningoftheexperimenttobeusedasapretreatmentcontroltoinvestigateatheroscleroticlesionsoftheaorta.Otherrabbitsweredividedinto2groups.Fourrabbitswerefedchow（130g/d）containing1%（w/w）probucolfor6mo（probucolgroup）.Wechosethisdoseaccordingtopreviouslypublishedmethods（16–19）,althoughthisdoseisabout20timeshigherthantherecommendedhumandose.Fourrabbitsinthecontrolgroupweregivenstandardrabbitchow（130g/d）for6mo.Waterwasavailableadlibitumforallrabbits.Beforedrugtreatmentandat1,3,and6moafterdrugadministration,bodyweightandplasmalevelsoftotal,low-densitylipoprotein（LDL）,andhigh-densitylipoprotein（HDL）cholesterolandtriglycerideswereevaluated.TheAnimalCareandUseCommitteeoftheHamamatsuUniversitySchoolofMedicineapprovedallexperiments.

PETandCT

Theanimalswerefastedforatleast6hbeforereceiving18F-FDG.Beforetheimagingstudy,theindividualbodyshapewastakenwithurethanehardeningfoamtomaintainthestereotacticposition.18F-FDGPETandCTexperimentswereperformedat10moofageandafter1,3,and6moofinterventioninbothgroupsaccordingtoapreviouslyreportedmethodwithslightmodification（5）.Briefly,therabbitswereanesthetizedand18F-FDG（37–185MBq）wasinjectedintoamarginalearvein.PETwasperformedfor15minat180minafterinjectionof18F-FDGusinganECATEXACTHRPETscanner（SiemensAG）.WechosethistimepointaccordingtothemethodofTawakoletal.（6）.AfterthePETstudy,aCTangiogramwasacquiredwithanX-forceCTscanner（ToshibaMedicalCorp.）usingiohexolasacontrastagent.PETimageswerecalibratedtotheinjecteddoseof18F-FDG.Formeasurementofradioactivityinthethoracicaorta,4circularregionsofinterests（ROIs）（3mm2foreachROI）weredrawnontheaorta.Theanalysiswasundertakenwithnoknowledgeoftheanimalgroup.Thestandardizeduptakevalue（SUV）wascalculatedbydividingthetissueconcentration（kBq/mL）bytheinjecteddosepergramofbodyweight（kBq/g）.

18F-FDGBiodistributionStudy

ThebiodistributionstudywasperformedonthedayaftertheCTandPETstudy,6moafterprobucoladministration.Therabbitswereanesthetizedand18F-FDG（370MBq）wasinjectedintoamarginalearvein.Threehoursafterthe18F-FDGinjection,theanimalsweresacrificedwithanoverdoseofsodiumpentobarbital.PerfusionfixationwasthenperformedusingPLPsolution（75mmol/LL-（+）-lysinehydrochlorideand4%paraformaldehydein37.5mmol/Lphosphatebuffer,pH7.4）.Thethoracicandabdominalaortasweresubsequentlyremoved,cutinto10-mmsegments,andweighed.ThesegmentswereimmediatelypostfixedinPLPsolution,andradioactivitywasmeasuredwithawell-type

-counter（COBRA;PackardCo.Ltd.）.Theresultsareexpressedasthedifferentialuptakeratio（DUR）:

Histology

Eacharterialsegmentwasembeddedinparaffinaftertheradioactivitywasmeasured.Consecutive4-µm-thicksectionswerepreparedfromeachsegmentandthesectionsweresubjectedtoimmunohistochemicalstainingorazan-Mallorystaining.ImmunohistochemistrywasperformedaccordingtothemethodreportedbyTsukadaetal.usingtherabbitmacrophage-specificmonoclonalantibodyRAM-11（DakoCorp.）（20）.Thesesliceswerealsocostainedwithhematoxylinforidentificationofthenucleus.ThenumberofmacrophageswasdeterminedbycountingthenucleiofRAM-11–positivecellsineachslice.Theintimaandwholeareaweremeasuredonanazan-Mallory–stainedconsecutivecros