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PAPER|MetallomicsMetallicelementsinexhaledbreathcondensateandserumofpatientswithexacerbationofchronicobstructivepulmonarydiseaseMassimoCorradi,aOlgaAcampa,bMatteoGoldoni,abRobertaAndreoli,abDonaldMilton,cSusanR.Sama,cdRichardRosiello,dGiuseppedePalma,ePietroApostolieandAntonioMutti*aReceived15thApril2009,Accepted28thMay2009FirstpublishedasanAdvanceArticleontheweb18thJune2009DOI:10.1039/b907635bBiomarkersinexacerbatedchronicobstructivepulmonarydiseasemaybeusefulinaidingdiagnosis,definingspecificphenotypesofdisease,monitoringthediseaseandevaluatingtheeffectsofdrugs.Theaimofthisstudywasthecharacterizationofmetallicelementsinexhaledbreathcondensateandserumasnovelbiomarkersofexposureandsusceptibilityinexacerbatedchronicobstructivepulmonarydiseaseusingreferenceanalyticaltechniques.C-Reactiveproteinandprocalcitoninwereassessedaspreviouslyvalidateddiagnosticandprognosticbiomarkerswhichhavebeenassociatedwithdiseaseexacerbation,thususefulasabasisofcomparisonwithmetallevels.Exhaledbreathcondensateandserumwereobtainedin28patientsatthebeginningofanepisodeofdiseaseexacerbationandwhentheyrecovered.Traceelementsandtoxicmetalsweremeasuredbyinductivelycoupledplasma-massspectrometry.Serumbiomarkersweremeasuredbyimmunoassay.Exhaledmanganeseandmagnesiumlevelswereinfluencedbyexacerbationofchronicobstructivepulmonarydisease,anincreaseintheirconcentrations—respectivelyby20and50%—beingobservedatexacerbationincomparisonwithvaluesobtainedatrecovery;serumelementalcompositionwasnotmodifiedbyexacerbation;serumlevelsofC-reactiveproteinandprocalcitoninatexacerbationwerehigherthanvaluesatrecovery.Inoutpatientswhoexperiencedamild–moderatechronicobstructivepulmonarydiseaseexacerbation,manganeseandmagnesiumlevelsinexhaledbreathcondensateareelevatedatadmissionincomparisonwithvaluesatrecovery,whereasnootherchangeswereobservedinmetallicelementsatboththepulmonaryandsystemiclevel.IntroductionChronicobstructivepulmonarydisease(COPD)isapreventableandpartiallytreatablediseasewithsomesignificantextrapulmonaryeffectsthatmaycontributetoseverityinindividualpatients.Itspulmonarycomponentischaracterizedbyairflowlimitationthatisnotfullyreversible.Theairflowlimitationisusuallyprogressiveandassociatedwithanabnormalinflammatoryresponseofthelungtonoxiousparticlesorgases.1TheclinicalcourseofCOPDisfrequentlyaggravatedbyepisodesofacuteworseningofrespiratorysymptomswithanincreaseinairflowobstructionandairtrapping,whichusuallyrequiresadditionaltherapies.1,2COPDexacerbationsacceleratetheprogressivedeclineinlungfunctionandareimportantcausesofmorbidityandmortalityassociatedwiththedisease.3–5COPDexacerbationsarecausedmainlybyrespiratorytractaLaboratoryofIndustrialToxicology,DepartmentofClinicalMedicine,NephrologyandHealthSciences,UniversityofParma,Italy.E-mail:antonio.mutti@unipr.it;Fax:+390521033076;Tel:+390521033075bISPESLResearchCentreattheUniversityofParma,ItalycDepartmentofWorkEnvironment,UniversityofMassachusetts,Lowell,MA,USAdFallonClinic,Worcester,MA,USAeLaboratoryofIndustrialHygiene,DepartmentofExperimentalandAppliedMedicine,UniversityofBrescia,ItalyThisjournaliscTheRoyalSocietyofChemistry2009infections,buttriggeringfactorsalsoincludenon-infectivecauses,suchasexposuretoenvironmentalpollutants.However,thecauseofexacerbationscannotbeidentifiedinapproximatelyone-thirdofallcases.1,2TheheterogeneityofCOPDexacerbations,duetotheirrangeofsymptomsandambiguousaetiologymakesthemdifficulttodefine,classifyandmanage.6BiomarkerswithpotentialutilityinthediagnosisandprognosisofCOPDexacerbationareneeded.7–12Exhaledbreathcondensate(EBC)obtainedbycoolingexhaledair,isabiologicalmatrixrepresentativeofthecompositionofairwayliningfluid,suitabletoassessairwayinflammation13–15andexposuretometallicelementspollutingthegeneralandworkingenvironment.16–18EBCcollectionissimpletoperformandcanberepeatedseveraltimeswithoutaffectingairwayfunctionorinflammation.Recently,weappliedtheelementalanalysisofEBCtoassessthetargettissuedoseofpneumotoxicmetalsandtransitionelementsinvolvedinredoxsystemsimplicatedinthecontrolofoxidativestress.WealsoproposedsuchanapproachtodevelopnewbiomarkersofexposureandsusceptibilityinCOPDpatients.19InEBCofpatientswithstableCOPD,wefoundhigherlevelsoftoxicelements(lead,cadmiumandaluminium)andlowerlevelsofessentialtransitionelements(copper,iron)comparedtononsmokingsubjects.19Recently,Metallomics,2009,1,339–345|339lowerlevelsofironhavealsobeenfoundbyotherauthorsinchildrenwithasthmacomparedtohealthycontrols.20TheevaluationofmetallicelementsduringCOPDexacerbationmayimprovetheknowledgeofpathophysiologicalpulmonarymechanismsassociatedwiththisclinicalcondition.Theworkinghypothesisisthattraceelementshaveeitheractivatingorinhibitingrolesinthedefencesystemsoftherespiratorytract(thuspossiblyapromotingroleinCOPDexacerbation),whereastoxicmetalscontainedintobaccosmokeandinpollutedambientairmaytriggermechanismsleadingtoCOPDexacerbation.Wealsolookedatbloodbiomarkers,suchasC-reactiveprotein(CRP)andprocalcitonin(PCT),assystemicbiomarkersusedforexacerbatedCOPDmanagement.7,10,11,21Experiment