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Fishman'sPulmonaryDiseasesandDisorders,5e>

Chapter44:TheBiologyofAsthma
MatthewC.BellWilliamW.Busse

Introduction
Asthmaischaracterizedbyrecurrentattacksofbreathlessnessandwheezing,whichvaryinseverityandfrequencyfrompersontoperson.1Morethan18millionadults
and7millionchildrenareaffectedintheUnitedStatesalone,makingasthmaoneofthemostcommonchronicdiseasesinthiscountry.2Attemptstoelucidatethe
underlyingpathophysiologyofthediseasehaveledtotherealizationthatasthmatrulyisaproteandiseasewithvariouscelltypesandmechanismsplayingvariablebut
importantrolesineachpatient.Thisdegreeofmechanisticvariationexplainsthenumerousphenotypesofthisdiseaseaswellasthedifferencesinresponsetotreatment.

Bythesimplestdefinition,thepathogenesisofasthmainvolvesbronchoconstriction,airwayinflammation,andairwayhyperresponsiveness.3Itis,however,thecomplex
interplaybetweenthesefactorsthatdefinesthediseaseingeneralandspecificallyinanindividualpatient.Acloserexaminationofthefactorsinvolvedineachofthese
componentsallowsabetterunderstandingofthiscomplexdisease.

TheAcuteInflammatoryResponseinAsthma
Perhapsthebestillustrationofthefeaturesoftheacuteinflammatoryresponse,thatiscentraltothepathogenesisofasthma,isthereactiontotheinitialandthen
subsequentexposurestoinhaledantigen.Whileimportantcellularandmolecularmediatorswillbedescribedlateringreaterdetail,abriefreviewoftheacute
inflammatoryresponseservesasafoundationuponwhichfurtherconceptscanbeintroducedtoillustratethevariablebutpersistentchangesthatoccurintheairwayin
asthma.Whenanovelantigenisintroducedtotheairwayofanatriskindividual,itinitiallybecomestrappedinthemucusliningtheairway.Hereitcanbetakenupby
antigenpresentingcells,mostnotablydendriticcells,whicharedistributedthroughtheepitheliumoftheairways.4,5Aftertheuptakeofallergen,thedendriticcellstravel
topulmonarylymphnodeswherebytheantigenispresentedtonaveCD4+ Tcells.5SignalsderivedfromthedendriticcelldeterminewhichtypeofCD4+ Tcellwillbe
produced.Priortothisevent,thedendriticcellisinfluencedbyacomplexnetworkofmolecularsignalsthatarederivedfromairwayepithelialcellsandotherlocalcell
types.Inallergicinflammation,forexample,thymicstromallymphopoietin(TSLP)andgranulocytemonocytecolonystimulatingfactor(GMCSF),whicharederived
frombronchialepithelialcells,andinducethedendriticcelltopromoteTH2differentiationofnaveCD4+ Tcells,thussettingupanenvironmentfavorabletothe
eventualdevelopmentofallergicinflammation.5Uponrechallengewiththesensitizingantigen,thesenowTH2differentiatedCD4+ Tcellsarerecruitedbacktothe
airwaybyothersignals,suchasthechemokinesCCL17andCCL22,secretedbydendriticcells.6Uponarrivalintheairway,theCD4+ TH2cellsbecomekeysourcesof
theTH2cytokines,namelyIL4,IL5,andIL13,whichserveasthemolecularcatalyststoestablishaframeworkforacuteallergicinflammation.6

Afterrechallengewithantigen,thelocalenvironmentoftheairwaysisnowrichwithTH2cytokines,whichactonothercelltypes,eitherpresentorrecruitedtothe
airway,topropagatetheacuteallergicinflammatoryresponse.Bcells,inthepresenceofIL4andIL13,areinfluencedtoproduceantigenspecificIgE,whichbindsto
highaffinityIgEreceptors(FcRI)onmastcells(MC).WheninhaledantigencrosslinksthemembraneboundIgEonthemastcells,avarietyofpreformedand
synthesizedmeditatorsarereleasedtocausebronchoconstriction,airwayedema,andlocaltissuedamage.7Mastcellsalsoreleasechemoattractantssuchasleukotrienes
andcytokines,torecruitavarietyofothercells,includingeosinophils,basophils,neutrophils,andlymphocytes,whichthencontributetothelatephaseinflammatory
response.7Theeosinophilappearstobe,inmostcases,themostimportantandabundantinflammatorycellassociatedwiththelatephaseresponseandpossibly
contributestothesubsequentairflowobstruction.8Thevastnumbersofmediatorstheeosinophilproducesarereviewedlaterinthechapter.Eosinophilproductscan
causelocaltissuedamage,mucushypersecretion,increasedvascularpermeability,smoothmusclecontraction,andasustainedinflammatoryresponsewherebyothercell
typesarerecruitedtothesiteofinflammationtoperpetuatethereaction.7,8Therolesofneutrophilsandbasophilsinthepathogenesisoftheacuteandlatephaseallergic
inflammatoryresponsesarelesswelldefined.

Whiletheacuteallergicresponsetoallergenillustratesthepatternofinflammationseeninasthma,itshouldbenotedthatotherformsofinflammationcananddoplay
importantrolesinasthma.Viralrespiratoryinfections,especiallywithhumanrhinovirus(HRV),areimportanttriggersforasthmaexacerbations.9TheresponsetoHRVis
aprimarilyTH1drivenresponsewithincreasedproductionofIL8andIL1andtheappearanceofairwayneutrophilia,asopposedtothestrongTH2responseseenafter
allergenexposure.9,10Inasthma,thereisevidencethatdiminishedproductionofthetypeIandIIIinterferons,antiviralcytokines,maybedeficientinsomepatientswith
asthmathusleadingtoincreasedriskforviralrespiratoryinfectionsandagreatersusceptibilitytoexacerbationsofasthma.9,10

Thispatternofacuteandlatephaseinflammatoryresponsetoantigenis,however,acentralcomponentofasthma.Chronicinflammationisalaterdevelopmentofthe
diseaseandwillbedescribedlater.Manyofthecelltypesandinflammatorymediatorsseeninasthmawerebrieflytoucheduponintheprecedingparagraphsandwill
nowbefurtherdeveloped.

CellTypesinAsthma
Astudyofthepathogenesisofanycomplexdiseasebeginsatthecellularlevel.Theimportanceofcellsoftheimmunesystem,includingmastcells,basophils,CD4+ T
cells,eosinophils,neutrophils,macrophages,dendriticcells,andTlymphocytes,aswellastheirmolecularmediatorshaslongbeenrecognizedandappreciatedinthe
developmentandregulationofinflammation.Thecontributionofairwaysmoothmusclecells,especiallyinrelationshiptotheacuteasthmaticresponse,hasalsobeen
welldocumented.Morerecently,epithelialcellsoftheairwayhavebecomethefocusofintenseresearchandemergingimportancetobothacuteandchronic
inflammationinasthma.Theirroleinairwayinflammation,andespeciallyintheairwayremodelingasisseeninthechronicformsofasthma,isbeingincreasinglycited
asamajorcontributortotheseverityofthisdisease.

CellsoftheImmuneSysteminAsthma

MastCells

HumanmastcellsarederivedfromthesameCD34+ /cKit+ hematopoieticstemcellpopulationthatalsogivesrisestoeosinophils,basophils,neutrophils,and

monocytes.11Theyareresidentcellsinmosttissuesofthebodyandarecommonlyfoundinassociationwithbloodvessels,nerves,andsurfacesthathavecontactwith
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theexternalenvironment.12Mastcellsexistintwotypesinhumansandaredifferentiatedbytheirimmunohistochemicalstainingproperties.13MCTmastcellscontain
onlytheneutralproteasetryptase,whileMCTCmastcellscontainchymase,carboxypeptidaseA3,andcathepsinGlikeproteaseinadditiontotryptase.1315Innormal
lungtissue,mastcellsarelocatedinthesubepitheliumofthebronchi,bronchioles,andalveolarwallsandarealmostexclusivelyoftheMCTtype.13Thisdistributionof
mastcelltypesisalsoseeninmildasthma.Insevereasthma,however,mastcellsinthesubmucosaaredecreasedinnumberandareprimarilyoftheMCTCtype.16MCTC
mastcellsarealsoseenintheairwayepitheliumofsevereasthma,afindingnotseeninnormallungsorinmilderdisease.16Mastcellsincreasinglyinfiltrateairway
smoothmusclebundlesinasthmawheretheylikelycontributetoongoingbronchoconstrictionthroughreleaseoftheirmediators.17

Whilemastcellsappeartohavesomeimportanceinnonallergicasthmaaswell,theyareessentialcomponentsoftheallergic(IgEmediated)responseseeninmany
asthmapatients.18AntigenspecificIgEmoleculesbindallergenandcrosslinkhighaffinityIgEreceptors(FcRI)presentonthemastcellsurface.Thisresultsinthe
releaseofpreformedmediators,suchashistamine,tryptase,chymase,andheparin,aswellastumornecrosisfactoralpha(TNF)andvascularendothelialgrowthfactor
(VEGF)insomecases(Fig.441).19Uponactivation,mastcellsalsogenerateandreleasenewlysynthesizedmediators,whichcontributetotheongoinginflammatory
milieu.Theseincludeleukotrienes(predominantlyLTC4),prostaglandins(predominantlyPGD2),thromboxaneA2,plateletactivatingfactor(PAF),growthfactors
includingGMCSF,fibroblastgrowthfactor2,andVEGF,andvariousothercytokinesincludingTNF,IL4,IL5,IL8,andIL13(Fig.441).19,20

Figure441

Themastcellanditsmediators.GMCSF,granulocytemonocytecolonystimulatingfactorFGF2,fibroblastgrowthfactor2VEGF,vascularendothelialgrowthfactor
TNF,tumornecrosisfactoralpha.

Theeffectofmastcellmediatorreleasecontributestonumerousfeaturesintheasthmaticresponse.7Histamine,leukotrienes,andthevariousproteasesincreasemucus
production.Prostaglandins,leukotrienes,thromboxaneA2,andhistaminecausebronchoconstrictionandincreasevascularpermeability.Thevariousproteasescauselocal
tissuedamageandareimportantintheactivationofvariousproteinprecursors.Finally,synthesizedcytokinescontributetotherecruitment,differentiation,andactivation
ofotherinflammatorycells,resultinginthepropagationoftheinflammatoryresponse.

Basophils

Inadditiontosharingacommonprogenitorcell,basophilssharemanysimilaritieswithmastcells,withtheexceptionthatbasophilsarepresentprimarilyintheperipheral
circulation.BothcellsexpressFcRIontheircellsurfaceandreleasebothpreformed,aswellasnewlysynthesizedmediatorsandcytokines,uponcrosslinkingbyIgE
antigencomplexes.Themajorpreformedmediatorreleasedfrombasophilsishistamine.Preformedheparinandtryptasearealsoreleased,albeitatlowerconcentrations
thanmastcells.21BasophilssynthesizeandreleaseLTC4uponactivation,butunlikemastcells,theydonotproducePGD2.21Uponactivation,basophilsproducelarge
quantitiesofIL4andIL13,cytokinesthatplayanimportantroleintheTH2differentiation,whichwillbediscussedlater.21Morerecently,twootherrolesofbasophils
inthepathogenesisofasthmahavebeendiscovered,bothofwhichalsoplayimportantrolesinTH2differentiation.First,basophilscanactasantigenpresentingcellsvia

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theirexpressionofmajorhistocompatibilitycomplex(MHC)classIIandcostimulatorymolecules.22Second,basophils,alongwitheosinophils,arealsotheprimary
targetofIL33,apotentpromoterofallergicinflammationandTH2polarization.23

Eosinophils

Eosinophils,likebasophilsandmastcells,aregranulocytesderivedfromCD34+ hematopoieticstemcells.Earlyeosinophilproductionishighlydependentuponthe
presenceofGMCSFandIL3.24Eosinophilprecursorsarerecruitedtotheairwayinasthmaastheresultofcytokineandchemokinesignaling,whichinvolvesIL5,
eotaxins,RANTES,macrophageinflammatoryprotein(MIP)1,andmacrophagechemotacticfactors2,3,and4(MCP2,3,4).25IL5iscriticallyimportantforthe
terminaldifferentiationofeosinophilsandreleasefromthebonemarrow.24

Onceintheairway,eosinophilsareactivatedandcontributetotheinflammatoryresponsethroughreleasingawidevarietyofmediatorsincludingcytokines(IL1,IL2,
IL3,IL4,IL5,IL6,IL8,IL10,IL12,IL13,IL16,IL18,tumornecrosisfactor[TNF]andtransforminggrowthfactorand[TGFandTGF]),
chemokines(MIP1,MCP2,RANTESandeotaxin),andlipidmediators(PGE1,PGE2,thromboxaneB2,PAF,LTC4)(Fig.442).26,27Eosinophilssecretegranule
proteins,whichareimportantintheeosinophil'sprimordialroleastheprimarydefenderagainstparasites,aswellasinthepathogenesisofasthma.26,28Eosinophils
containbothprimaryandsecondarygranules.TheprimarygranulescontainCharcotLeydencrystalprotein,whilethesecondarygranulescontainthefourprincipal
cationicproteins:majorbasicprotein(MBP),eosinophilcationicprotein(ECP),eosinophilderivedneurotoxin(EDN),andeosinophilperoxidase(EPO).26These
cationicproteinsplayvariousrolesinthepathogenesisofasthmaincludingtheinductionofmastcellandbasophildegranulation(ECPandMBP),increasingairway
mucusproduction(ECP),andformationofreactiveoxygenspecies(EPO)(Fig.442).26

Figure442

Eosinophilproductsinasthma.EPO,eosinophilperoxidaseEDN,eosinophilderivedneurotoxinECP,eosinophilcationicproteinMBP,majorbasicproteinPGE2,
prostaglandinE2TBXA2,thromboxaneA2PAF,plateletactivatingfactorLTC4,leukotrieneC4RANTES,regulateduponactivationnormalTcellexpressedand
secretedMCP2,monocytechemotacticprotein2MIP1,macrophageinhibitoryprotein1TNF,tumornecrosisfactoralphaTGF,transforminggrowthfactorbeta.

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Overthepast30years,theroleoftheeosinophilinasthmahasundergoneconsiderablereevaluation.SincethediscoveryoftheeosinophilbyEhrlichin1879andthe
laterdiscoverythatEhrlich'scellswerepresentinthesputumofasthmaticpatients,theeosinophilhasbeenviewedastheprimaryeffectorcellinasthma.29Studieshave
notedthatperipheralbloodeosinophiliaisacharacteristicofasthmaandofteninrelationshiptodiseaseseverity,andthateosinophilicinfiltrateswerefoundinthe
airwaysofasthmapatientsatautopsy,regardlessofwhetherasthmawastheprimarycauseofdeath.30,31Laterstudiesdetectedincreasedeosinophilsandeosinophil
productsinbronchoalveolarlavage(BAL)fluidafterantigenchallenge.32Theviewthattheeosinophilwastheprincipaleffectorofasthmawaslargelyunchallenged
untilthenewmillenniumbroughtnewtherapies,includingmonoclonalantibodiestoIL5,intoevaluation.

TheimportanceofIL5tothedifferentiationandsurvivaloftheeosinophilhasbeenpreviouslynoted.InitialstudieswithmonoclonalantibodiestoIL5inasthma
showedadecreaseinsputumandperipheralbloodeosinophilia,asexpected,butfailedtodemonstratesignificantbenefitinawidevarietyofclinicaloutcomemeasures,
thatis,symptomsorimprovedairflowobstruction.33,34Althoughthislackofeffectonparametersofclinicalasthmawasasurprise,itledtoanincreasinginterestinthe
heterogeneityofasthmawiththerealizationthateosinophilsmayplaygreaterorlesserrolesindifferentpatients.

LaterstudieswithantiIL5wereconductedinpatientswhohadpersistenteosinophiliadespitetreatmentwithinhaledcorticosteroids(ICS),andinthesepatientswere
notedclinicaloutcomes,thepreventionofexacerbations.35,36Eosinophilsplayanimportantroleinacertainsubsetofasthma,butthecontributionoftheirroleappearsto
bedefinedbyphenotypesandisnotnecessarilygeneralizabletotheentireasthmaticpopulation.Finally,eosinophilsarelikelyaprimecontributortoairwayremodeling
seeninchronicasthma,andwillbediscussedinthiscapacitylaterinthechapter.

Neutrophils

NeutrophilsaregranulocytesderivedfromCD34+ hematopoieticstemcellsandarenormallypresentinthebloodstream,aswellasinvarioustissues,includingthelung.
Theycontainprimary(azurophilic)andsecondary(specific)granules,whichcontainavarietyofantimicrobialenzymes,neutralproteases,andacidhydrolases.37
NeutrophilsareattractedtotheairwaybyvariouscytokinesandchemokinesincludingIL8,IL17,andgranulocytecolonystimulatingfactor(GCSF).38,39Airway
neutrophiliacanbeseeninmanyrespiratoryconditions,viralrespiratoryinfections,COPD,andasthma.10,39

Theroleofneutrophilsinresponsetoviralrespiratoryinfectionswasintroducedpreviously.Inresponsetoinoculationwitharespiratoryvirus,suchasHRV,dendritic
cells,andothermononuclearcellsproduceproinflammatorycytokinesandchemokines,whichrecruitneutrophilstotheairway.10Neutrophilscontributetothe
inflammatorymilieubysecretingcytokinessuchasTNF,IL1,IL8,andIL18,toattractotherinflammatorycells,upregulatecytokineproduction,andproduceairway
inflammationandenhancebronchialhyperresponsiveness.40Neutrophilproducts,suchaselastase,canhavemoredirecteffectsontheairwayandcausemucus
production.10Inaddition,becauseneutrophilsarefoundinsevereasthma,theyareproposedtoplayamoreprominentroleinthisphenotype.41Prominentneutrophilic
inflammationhasbeennotedinthesputumofpatientswithsevereasthmaexacerbations,inBALfluidfrompatientswithnoninfectiousstatusasthma,andinautopsy
specimensfromtheairwayinpatientswithacute,fatalasthma.4244Otherstudieshavedemonstratedsubgroupsofpatientswithchronicasthmainwhomtheprimary
inflammatorycelltypeisneutrophilsratherthaneosinophils.45,46Thesepatientsareoftenmoredifficulttotreatandlessresponsivetotreatmentwithcorticosteroids.

Lymphocytes

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Unlikethepreviouslydiscussedcelltypes,Tcellsarelymphocytesandderivedfromthecommonlymphoidprogenitor.NumeroussubsetsofTcellshavebeenidentified
andareimportantcontributorstoasthma,includingCD4+ helperTcellsandtheirsubsets(TH1,TH2,TH9,andTH17),CD8+ cytotoxicTcells,andregulatoryTcells
(TREG).

CD4+ helperTcellsrecognizeantigenspresentedtothembyantigenpresentingcells(APCs)and,inturn,secretecytokinestoinfluencetheinflammatoryresponse.In
theairway,thedendriticcellisthemostimportantAPCanditsrolewillbedescribedlater.Acomplexseriesofeventsinvolvingcytokinesandvarioustranscription
factorsdetermineswhetherCD4+ TcellswilldifferentiateintoTH1cells,TH2cells,TH9cells,orTH17cells(Fig.443).47

Figure443

CD4+ TLymphocytesubsets.IFN,interferongammaTGF,transforminggrowthfactorbetaTFHcell,TfollicularhelpercellTREGcell,regulatoryTcell.

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TH2cellsarerecognizedastheprimarydriversofinflammationinasthmaandallergicdisease.WhenTH2cellsencounterantigenpresentedbydendriticcells,they
produceIL4,IL5,andIL13,allofwhichplaycriticalrolesinthepathogenesisofasthmaandarepartoftheclinicaldiseaseasdemonstratedbydetectionofincreased
levelsofthesecytokinesintheBALfluidofpatientswithasthma.48,49IL4increasesIgEproductionbyplasmacells.Asmentionedpreviously,IL5iscriticalinthe
terminaldifferentiationandhomingofeosinophilstotheairway.IL13alsoincreasesIgEproductionandplaysaprominentroleinairwayhyperresponsivenessandtissue
remodeling.50

TheroleofTH1cellsinasthmaisnotaswelldefinedasTH2cells.AlthoughithasbeenpresumedthatTH1cellscounteracttheasthmainducingeffectsofTH2cells,this
likelyisanoversimplification.TH1productshavebeenshowntobeincreasedduringasthmaexacerbation.51SomestudieshavealsosuggestedthatTH1cellsmayplaya

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moreprominentroleinchronicsevereasthmaasevidencedbyincreasedlevelsoftheprimaryTH1cytokine,interferon(IFN),intheBALfluidofpatientswithsevere
asthma.52

TH9cellsarearelativelynewlydefinedcellpopulationwhoseprimarycytokineisgenerationofIL9.TH9cellsfunctionsimilarlytoTH2cellsinthattheyincrease
allergicinflammation.MastcellsaretheprimaryIL9receptorbearingcell,andTH9cellsareimportantcontributorstothepreviouslydescribedincreasedmastcell
activationseeninasthma.20BecausemastcellsalsoproduceVEGFandfibroblastgrowthfactor2,TH9cellslikelycontributetoairwayremodelingseeninchronic
asthma.20

TheroleofTH17cellsinasthmaisanareaofintenseresearch.Withtheidentificationofsubphenotypesofasthmapatientswithprimarilyneutrophilicinflammation,the
roleofIL17(theprimarycytokineproducedbyTH17cells)inasthmahasbecomeofconsiderableinterest.AlthoughIL17isfoundtobeincreasinglyexpressedin
patientswithsevereasthma,53itis,however,alsofoundinhighconcentrationsinpatientswithmildasthma(FEV1>70%predicted)andthesevaluescorrelatenegatively
withthePC20.54Thus,whileTH17cellsmostcertainlyplayaroleinpatientswithprimarilyneutrophilicasthma,theyarealsolikelyimportantinmilderformsofdisease
aswell.

TheprimaryfunctionofCD8+ cytotoxicTcellsisthedestructionofhumancellsthatareinfectedwithvirusesorotherintracellularpathogens.CD8+ Tcellsalsolikely

playaroleinasthma,thoughtheextentoftheircontributionhasyettobefullyelucidated.50IL4andIL5producingCD8+ Tcellsarepresentintheairwaysofasthmatic
patients.55IL5productionbyCD8+ Tcellsisincreasedinthepresenceofaviralrespiratoryinfection,andtheoverallcytokineproductionbyCD8+ Tcellscorrelates
withasthmaseverity.56,57WhetherCD8+ Tcellsfunctionasdirectcontributorsorbystandersintheworseningofasthmahasyettobedetermined.50

TREGcellsalsoappeartoplayacriticalroleinasthmadevelopment.TREGcellsservetolimitinflammatoryresponsesandpromoteimmunetolerancethroughthe
productionofIL10andTGF.50,58Inpatientswithasthmaandotherallergicdisorders,TREGcellsappeartobelesseffectiveinlimitingTH2inflammation.59,60
However,afterallergenimmunotherapy,forexample,TREGcellsincreaseinthenasalmucosaandmayacttopromoteallergentolerance.61Interestingly,farmexposure
earlyinlifeisassociatedwithadecreasedincidenceofallergicdiseaseandasthma,afactthatmayberelatedtoincreasednumbersandfunctionofTREGcellsininfants
livinginthisenvironment.62

Naturalkillercells(NKcells)aremembersoftheinnateimmunesystemandserveasafirstlineofdefenseagainstinfections.Theirroleinthepathogenesisofasthma
hasyettobefullyelucidated.Theyobviouslyappearinresponsetoviralrespiratoryinfections,andNKcellsincreaseduringasthmaexacerbations.63NKcellsare
capableofproducingnumerouscytokinesincludingIFN,IL4,IL5,andIL13.64NKcellsfrompatientswithatopicasthmaareskewedtowardtheproductionofIL4
asopposedtoIFNuponactivation.64IFNproductionbyNKcellsisalsoinhibitedbyprostaglandinD2,aTH2promotinglipidmediatorproducedbymastcells.65
NKcellsmayalsoplayaroleindendriticcelleditingbykillingimmaturedendriticcells,whichmightinfluenceacertaintypeofTHresponse.66

MacrophagesandDendriticCells

MacrophagesanddendriticcellsaredescendantsfromtheCD34+ hematopoieticstemcellandarisefromacommoncommittedprecursorcell.67Macrophagesarisefrom
circulatingmonocytesandfunction,primarily,tocleardebrisandmicrobesfromtheairway.Theymayalsofunctionasantigenpresentingcells,althoughthisroleis
likelylessimportantthanthatofthedendriticcell.68AlveolarmacrophagesmayfurtherdifferentiateintoM1orM2subsetsbasedonexposuretovariouscytokinesand
tolllikereceptor(TLR)agonists.67M1macrophagesareclassicmacrophages,andclearmicrobesfromtheairway.Theyalsoproducecytokines,suchasIL12,IL6,
andTNF,aswellashighlevelsofnitricoxide(NO).67M1macrophageshavetraditionallybeendescribedassuppressingallergicinflammation,primarilythroughtheir
secretionofTH1cytokinessuchasIL12thisisnotfullyresolved.67

DifferentiationintoM2macrophagesisinfluencedbyanenvironmentrichinTH2cytokinessuchasIL4andIL13,thusimplicatingtheirroleinasthma.When
comparedwithM1macrophages,M2macrophagesarepooratclearingintracellularpathogens.67TheyreleasecytokinessuchasIL13andthusarelikelycontributeto
theairwayhyperresponsiveness.67

Dendriticcellsarethelung'sprimarypresenterofantigentoTcells.TheirroleastheprimaryAPCplacesthedendriticcellatacriticaljunctionindeterminingwhattype
ofTcellresponsewillbedirectedtowardtheantigen(i.e.,TH1,TH2).Dendriticcellsinhumansexistintwobroadcategories:themyeloiddendriticcell(mDC)andthe
plasmacytoiddendriticcell(pDC).Whilebothtypesofdendriticcellsarepresentinthehumanlung,theiranatomiclocalizationwithinthelungispoorlyunderstood.5
Uponencounteringantigenintheairway,dendriticcellsmigratetolocallymphnodeswheretheypresentantigentoTlymphocytes.BothpDCandmDClevelsincrease
intheairway(andcoincidentlydecreaseintheblood)afterexposuretoinhaledallergen.6971Becausedendriticcellslieclosetotheepithelialbarrier,theyreceive
numeroussignalsfromepithelialcells,whichcaninfluencetheireffectonTcells.TSLPisproducedbyepithelialcellsandpromotesdendriticcellstodirectTH2
differentiationandrecruitTH2cellstotheairway.5Otherepithelialcellderivedfactors,suchasGMCSF,TNF,CCL20,IL1,andTNFrelatedapoptosisinducing
ligand(TRAIL),havesimilarTH2promotingeffects.5pDCrepresentthelung'sprimarysourceofIFN,apotentantiviralcytokine,andtheyarerecruitedtothelung
duringtimesofviralinfections.72Asviralinfectionscommonlyprecedeasthmaexacerbationsandmaypredisposeinfantstodevelopasthma,thisroleofthepDCcannot
beunderstated.73TheimportanceofpDCtothedevelopmentofasthmawasillustratedbyarecentstudywhichshowedthatdecreasedpDClevelsinchildhoodwas
directlycorrelatedtoincreasednumberandseverityofviralrespiratoryinfections,increasedepisodesofwheeze,andincreasedasthmadiagnosis.74ThefunctionofmDC
isnotaswellknowninhumanasthma,buttheroleofbothdendriticcelltypesincontributingtothedevelopmentandpropagationofthediseasewillcontinuetobean
importantareaofasthmaresearch.

ResidentCellsoftheAirway

AirwaySmoothMuscle

Giventhatbronchospasmandbronchialconstrictionarecriticalcomponentsofasthma,itisintuitivethatthecelltyperesponsibleforthiscomponent,theairwaysmooth
musclecell,wouldbeakeyfactorinasthmapathogenesisandpathophysiology.Whileitsimportanceseemsobvious,thedetailsofwhyairwaysmoothmusclefunctionis
sodifferentintheasthmaticairwaycomparedwiththenormalairwayhavebeenelusive.Ithasbeenwelldocumentedthatthesmoothmusclelayersurroundingthe
airwayisthickerinasthmacomparedtononasthmaticcontrols.Thesedifferenceareduetobothsmoothmusclehypertrophyandhyperplasia.75Increasedinflammatory
cells,includingmastcells,canbefoundwithinthesmoothmusclebundlesofasthmaticairways,andtheinterplaybetweenthesecells,theairwayepithelium,andthe
smoothmusclelayer,isanimportantdeterminantoftheasthmaticresponse.17Numerouscytokines,chemokines,andgrowthfactorsareinvolvedinthisinteraction
includingthoseproducedbytheairwaysmoothmusclecellitselfandthoseproducedbyothercelltypeswithwhichtheairwaysmoothmusclecellcommunicates.

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Airwaysmoothmusclecellsinasthmaaremoreprolificproducersofthesecytokines,andthisfunctionlikelyplaysaroleintheirabilitytoproliferatemorerapidlythan
thoseofnonasthmaticsubjects.76

Thetreatmentofasthmahaslongfocusedonpreventingorreversingcontractionofbronchialsmoothmuscles.2agonists,bothshortandlongacting,havelongbeen
keytothetreatmentofasthma,andthesemedicationsactdirectlyontheairwaysmoothmuscle.Morerecently,debulkingofairwaysmoothmuscle,withtheuseof
bronchialthermoplasty,hasshownimprovementinasthmacontrol,which,intheory,furthersupportstherolethatairwaysmoothmuscleplaysinasthma
pathophysiology.77,78

AirwayEpithelialCells

Theepithelialliningoftheairwayisanareaofintenseresearch,anditsimportance,beyondbeingasimpleanatomicbarrier,isbeingincreasinglyrecognizedand
appreciated.Theairwayepitheliumrepresentsavastsurfacearea(100m2)thatisincontactwithsome10,000Lofinhaledairdaily.79Astheareaofinitialcontact
betweenthelungandtheexternalairborneenvironment,functionsoftheairwayepitheliumarelikelykeytodeterminethebody'sresponsetoairbornesubstances.

Theairwayepitheliumiscomposedofthreemajorcelltypes:theciliatedcolumnarepithelialcell,themucussecretinggobletcell,andthesurfactantsecretingClara
cell.79BothoverproductionofmucusbygobletcellsandunderproductionofimportantantiinflammatorypeptidesbyClaracellshavebeennotedinpatientswith
asthma.80,81Thetightjunctionsbetweenepithelialcellshavealsobeennotedtobedefectiveinpatientswithasthma,whichcanservetodecreasetheabilityoftheairway
epitheliumtoactasaprotectivebarrier.79Theairwayepitheliuminasthmaisalsolesscapableofdefendingitselfagainstreactiveoxygenspecies,adefectthatleadsto
furtherdamagetothisairwaybarrier.82EpithelialcellsinasthmaproduceloweramountsofTypeIinterferoninresponsetorespiratoryviruses,whichcanincreasethe
severitytorespiratoryinfectionsandpromoteasthmaexacerbations.83TSLPpromotesTH2driveninflammationandisoverproducedbyepithelialcellsinasthmatic
patients,thusprovidingacruciallinkbetweentheairwayepitheliumandtheTH2typeinflammationseeninasthma.84,85Finally,epithelialcellsarecapableofsecreting
endothelins,whicharepeptideswithsignificantbronchoconstrictiveactivity.86

MolecularMediatorsinAsthma
Theabovementionedcellsareabletoinitiate,perpetuate,coordinate,andregulatetheinflammatoryprocesswiththesynthesisandsecretionofseveraldifferentclasses
ofmolecularmediators.Thesemediatorshaveavarietyoffunctions,asdiscussedbelow.

Cytokines

Cytokinesaresmallmolecularweightglycosylatedsignalingmoleculesthataresecretedbyanumberofdifferentcelltypeswithautocrine,paracrine,orendocrine
directiveactivities.87Cytokineisabroadtermandincludesmanysubcategoriesincludinginterleukins,interferons,andgrowthfactors.87Cytokinesecretionisusuallya
brief,selflimitedevent.Itmay,however,requirenewmRNAandproteinsynthesis,whichtakesplaceoveramatterofhoursratherthansecondsorminutes.88Avariety
ofcytokineshavebeenimplicatedintheregulationofairwayinflammationandthusinthepathogenesisofasthma(Table441).89Thesupportforcytokineinvolvement
ininflammationwasfirstobtainedbythedetectionofthesemediatorsintheairwaysofpatientswithasthma,particularlyinbronchoalveolarlavagefluidafterallergen
challengeandinsituhybridizationofretrievedcellsorbiopsymaterials.90,91

Table441CytokinesandLipidMediatorsinAsthma
Cytokines
Cytokine CellSources ProposedCellTargets/FunctionsinAsthma
Interleukins
Basophils:Increasedproductionofcytokinesandhistamine
DCs:Increasedcytokineproduction,upregulationofMHCandcostimulatory
molecules
DCs,monocytes,macrophages,mastcells,BandTcells, Macrophages:Increasedcytokineproduction
IL1 Mastcells:Increasedcytokineproduction,degranulation,andsurvival
neutrophils,endothelialcells,airwayepithelialcells
Neutrophils:Increasedsurvivalandreleaseofproteases
Bcells:Increasedantibodyproduction
Tcells:IncreasedproliferationespeciallyforTH2andTH17cells
IL2 CD4+ TCells Tcells:Increasedsurvivalandproliferation,increasedTH2cytokineproduction
Basophils:IncreasedsurvivalandreleaseofIL4,IL6,andhistamine
Eosinophils:Increaseddegranulation
IL3 TCells,mastcells Mastcells:Increasedsurvivalandhistaminerelease
Hematopoieticstemcells:Increasedproductionofmastcells,basophils,neutrophils,
eosinophils,macrophages,erythrocytes,megakaryocytes,anddendriticcells
Airwaysmoothmusclecells:Increasedairwayhyperresponsiveness
Basophils:Increasedrecruitment
Eosinophils:Increasedrecruitment
Gobletcells:Increasedmucusproduction
Mastcells:Increasedrecruitment,upregulationofFCRI
IL4 Tcells,mastcells,basophils,eosinophils Bcells:IncreasedclassswitchingtoIgE,upregulationofFCRII
Tcells:Increasedrecruitment,increasedTH2differentiation,increasedproductionof
TH2cytokines,decreaseddifferentiationofTH1cells,decreasedIFNproductionby
TH1cells
Basophils:Increasedproliferation,maturation,andfunctionalactivation
IL5 Tcells,mastcells Eosinophils:Increasedproliferation,chemoattraction,maturation,functional
activation,anddegranulation
Tcells:IncreasedproductionofTH2cytokines,decreaseddifferentiationofTH1cells,
Macrophages,DCs,mastcells,neutrophils,BandTcells, decreasedIFNproductionbyTH1cells,promotesdifferentiationofTH17cells,
IL6
endothelialcells,airwayepithelialcells
downregulationofTREGcells

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Cytokines
Cytokine CellSources ProposedCellTargets/FunctionsinAsthma
Eosinophils:Increasedactivationandsurvival
IL7 Bonemarrowstromalcells Bcells:Increasedproliferationandsurvival
Tcells:Increasedmaturationandsurvival
Airwayepithelialcells,neutrophils,eosinophils, Eosinophils:Chemoattraction
IL8
monocytes/macrophages Neutrophils:Chemoattraction
Mastcells:Increasedrecruitmentandmaturation,increasedexpressionofproteases,
IL9 Tcells upregulationofFCRI
Tcells:Increasedgrowthandproliferation
DCs:InhibitsexpressionofcostimulatorymoleculesthusinhibitingTHcell
activation
Eosinophils:Inhibitssurvival,recruitment,andmaturation
Monocytes/macrophages,Bcells,Tcells(specificallyTREG Monocytes/macrophages:DownregulatesMHCClassIIexpression,downregulates
IL10 inflammatorycytokineproduction
cells)
Tcells:DownregulatesIFNandIL2productionbyTH1cellsandIL4andIL5
productionby
TH2cells
Airwayepithelialcells:Regulateproliferation
Airwayepithelialcells,eosinophils,airwaysmoothmuscle Macrophages:InhibitproductionofTNF,IL1,IL12
IL11
cells Bcells:Increasesimmunoglobulinproduction
Tcells:InhibitsproductionofTH1cytokines,IncreasesIL4andIL10production
NKcells:IncreasedIFNproduction
IL12 Dendriticcells,Bcells,macrophages Tcells:IncreasedIFNproduction,increasedTH1differentiation,decreasedTH2
andTH17differentiation
Airwayepithelialcells:Increasedpermeability,increasedmucusproduction,
productionofinduciblenitricoxidesynthase
Airwaysmoothmusclecells:Increasedairwayhyperreactivity
IL13 Mastcells,Tcells
Eosinophils:Promotesmigrationandsurvival
Macrophages:ActivationandenhancedMHCClassIIexpression
Bcells:IncreasedclassswitchingtoIgEandproductionofIgE
IL14 Tcells Bcells:Increasedproliferation,suppressionofIgsecretion
DCs:Increasedactivationandsurvival,increasedproductionofIFN
Mastcells:Increasedsurvival
Monocytes/macrophages:Increasedphagocyticactivity,increasedproductionofIL8,
IL12,MCP1
Neutrophils:Increasedsurvivalandphagocyticactivity,increasedIL8production
IL15 Monocytes/macrophages,DCs NKcells:Increasedmaturationandsurvival,increasedproductionofIFN,TNF,
and
GMCSF
Tcells:IncreasedproliferationofmemoryCD8+ Tcells,Increasedproliferationof
TH17cells
DCs:Increasedchemoattraction
Eosinophils:Increasedchemoattraction
IL16 Tcells,airwayepithelialcells,DCs,eosinophils,mastcells Monocytes/macrophages:Increasedchemoattraction,upregulationofMHCclassII
expression
Tcells:Increasedmigration,maturation,andproliferation
Airwayepithelialcells:IncreasedproductionofIL6,IL8,GCSF,PGE2
IL17 Tcells,NKcells Eosinophils:Increasedchemoattraction
Neutrophils:Increasedproductionfromstemcells,increasedchemoattraction
Basophils:Increasedproductionofcytokinesandhistamine
DCs:Increasedcytokineproduction,upregulationofMHCandcostimulatory
molecules
DCs,monocytes,macrophages,neutrophils,airwayepithelial Macrophages:Increasedcytokineproduction
IL18 Mastcells:Increasedcytokineproduction,degranulation,andsurvival
cells
Neutrophils:Increasedsurvivalandreleaseofproteases
NKcells:IncreasedIFNproduction.
Tcells:PromotesTH1differentiation.
Tcells:IncreasedproductionofTH2cytokinesanddownregulationofIFN
IL19 Monocytes
production
IL20 Monocytes Unclear
Bcells:IncreasedproliferationofIgA,IgG,IgMproducingplasmacellsanddecrease
inIgEproducingplasmacells
IL21 Tcells Tcells:IncreaseddifferentiationintoTH17cells,upregulationofTH1cytokine
production
IL22 Tcells,NKcells Respiratoryepithelialcells:Increasedproductionofantimicrobialpeptides
Macrophages:IncreasedTNFproduction
IL23 DCs Tcells:IncreasedIL17production,promotionofTH17differentiation
IL24 Monocytes,Tcells Unclear
IL25 Airwayepithelialcells,eosinophils,mastcells Tcells:IncreasedproductionofTH2cytokines
IL26 Monocytes,Tcells Unclear
Tcells:IncreaseddifferentiationintoIL10producingTREGandTH1cells,decreased
IL27 Macrophages,DCs
developmentofTH2andTH17cells

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Cytokines Inhibitsviralreplication
IL28(IFN2,3) DCs DCs:IncreaseabilitytostimulateproductionofT
Cytokine CellSources ProposedCellTargets/FunctionsinAsthma REGcells
Inhibitsviralreplication
IL29(IFN1) DCs DCs:IncreaseabilitytostimulateproductionofTREGcells
IL31 Tcells Airwayepithelialcells:Attenuateproliferationofepithelialcells
Macrophages:Upregulationofproinflammatorycytokines
IL32 NKcells,Airwayepithelialcells,Tcells
Airwayepithelialcells:Decreasedproductionofproangiogenicfactors
Basophils:Increasedproductionofcytokinesandhistamine
DCs:Increasedcytokineproduction,upregulationofMHCandcostimulatory
molecules
Eosinophils:Increasedproliferation,survival,andchemokineproduction
IL33 Endothelialcells,airwayepithelialcells,dyingcells Macrophages:Increasedcytokineproduction
Mastcells:Increasedcytokineproduction,degranulation,andsurvival
Neutrophils:Increasedsurvivalandreleaseofproteases
NKcells:IncreasedIFNandTH2cytokines
Tcells:PromotesTH2differentiation,enhancesreleaseofTH2cytokines
IL35 TREGcells Tcells:DecreasedproductionofTH2cytokines,suppressionofTcellproliferation
IL36 Airwayepithelialcells Tcells:IncreasedTH1differentiation
Macrophages:Decreasedsecretionofproinflammatorycytokines
IL37 Hematopoieticcells
Airwayepithelialcells:Decreasedsecretionofproinflammatorycytokines
Interferons
IFN Monocytes/macrophages Virusinfectedcells:Inhibitionofviralreplication
IFN Monocytes/macrophages Virusinfectedcells:Inhibitionofviralreplication
Macrophages:Differentiation,activation,andexpressionofFcreceptor.Increased
IFN Tcells,NKcells cytokineproduction
Tcells:IncreaseddifferentiationtoTH1cells,increasedcytotoxicityofCD8+ Tcells
IFN Seeabove Seeabove
Growthfactors
bFGF Endothelialcells Fibroblasts:Proliferationandextracellularmatrixformation
GCSF Monocytes,fibroblasts,airwayepithelialcells Neutrophils:Proliferationanddifferentiation
DCs:Maturation
Eosinophils:Increasedsurvival,degranulation
GMCSF Tcells,airwayepithelialcells,macrophages
Macrophages:Differentiation,increasedsurvival,increasedcytokineproduction
Neutrophils:Increasedchemotaxisandsurvival
Fibroblasts,endothelialcells,macrophages,airwaysmooth
MCSF Hematopoieticstemcells:Differentiationofmonocytes
musclecells
PDGF Platelets,monocytes,macrophages Fibroblasts:Proliferationandchemoattraction
Mastcells:Chemoattraction,inductionofhistaminerelease,differentiation,
SCF Bonemarrowstromalcells,fibroblasts
proliferation
Fibroblasts:Chemoattractionandincreasedconversiontomyofibroblasts,increased
synthesisofcollagen
Eosinophils,Tcells,macrophages,airwayepithelialcells, Macrophages:Chemoattraction
TGF Neutrophils:Chemoattraction
endothelialcells,airwaysmoothmusclecells
Tcells:IncreaseddifferentiationofTREG,TH9,andTH17cells,inhibitionofTH1and
TH2differentiation
Airwaysmoothmusclecells:Hyperplasiaandincreasedairwayhyperresponsiveness
DCs:Increasedproliferationandactivation
VEGF Macrophages,airwayepithelialcells,Tcells,eosinophils Endothelialcells:Increasedangiogenesisandvascularpermeability
Airwayepithelialcells:Increasedproliferation,mucusproduction
Fibroblasts:Promotionofsubepithelialfibrosis
Other
Airwayepithelialcells:Upregulationofadhesionmolecules
Airwaysmoothmusclecells:Increasedairwayhyperresponsiveness
Endothelialcells:Upregulationofadhesionmolecules
Monocytes/macrophages,DCs,mastcells,eosinophils, Eosinophils:Chemoattraction,increasedactivation
TNF neutrophils,BandTcells,airwayepithelialcells,airway Fibroblasts:Increasedconversiontomyofibroblasts
smoothmusclecells,fibroblasts Macrophages:Chemoattraction
Mastcells:Increasedhistaminerelease
Neutrophils:Chemoattraction
Tcells:Increasedactivationandcytokinerelease
DCs:IncreasedabilitytoattractTH2cells
Eosinophils:Inducedreleaseofproinflammatorycytokinesandchemokines
TSLP Airwayepithelialcells Mastcells:IncreasedproductionofTH2cytokines
Tcells:IncreaseddifferentiationtoTH2cells
LipidMediators
Mediator Cellsources Proposedcelltargets/functionsinasthma
Leukotrienes

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Cytokines
Cytokine CellSources ProposedCellTargets/FunctionsinAsthma
Blymphocytes:IncreasedexpressionofCD23,CD54,andCD105
DCs:Recruitment,increasedskewingofTH0cellstoTH1type
Eosinophils:Recruitment
Dihydroxyacid Mastcells:Recruitment
leukotriene DCs,monocytes/macrophages,neutrophils Monocytes/macrophages:IncreasedproductionofIL6,TNF,MCP1
(LTB4) Neutrophils:Recruitmentandactivation
Airwaysmoothmusclecells:Increasedproliferation
Tlymphocytes:Recruitment
Airwaysmoothmusclecells:Bronchoconstriction
DCs:Increasedmigrationtolymphnodes
Cysteinyl Endothelialcells:Increasedvascularpermeabilityandupregulationofadhesion
leukotrienes molecules
(LTC4,LTD4, DCs,eosinophils,mastcells,monocytes/macrophages Eosinophils:Recruitment
Gobletcells:Increasedmucusproduction
LTE4) Mastcells:IncreasedproductionofIL5,IL8,TNF,andMIP1
Monocytes/macrophages:IncreasedproductionofMCP1,TNF,andMMP9
Tlymphocytes:IncreasedTH2immuneresponse
Prostanoids
Airwaysmoothmusclecells:Bronchoconstriction
Eosinophils:Recruitment,increaseddegranulation
Monocytes/macrophages:Increasedcytokineproduction
PGD2 Mastcells Neutrophils:Inhibitionofactivation
Tlymphocytes:Recruitment,increasedproductionofTH2cytokines,inhibitionof
IFNproduction
Airwaysmoothmusclecells:Inhibitionofallergeninducedbronchoconstriction
Eosinophils:Inhibitsrecruitment
PGE2 Airwaysmoothmusclecells,airwayepithelialcells, Monocytes/macrophages:Decreasedcytokineproduction,downregulationofMHC
endothelialcells,macrophages ClassIIexpression
Tcells:Decreasedproliferation,decreasedTH2cytokineproduction
Endothelialcells:Vasodilatation
PGI2
Endothelialcells,monocyte/macrophages Eosinophils:Inhibitionofrecruitment
(Prostacyclin)
Tcells:IncreasedIL10production
ThromboxaneA2 Platelets,endothelialcells,monocyte/macrophages Airwaysmoothmusclecells:Bronchoconstriction
Eosinophils:Recruitment

Theoveralleffectofthecomplexcytokinenetworkintheairwaydependsonanumberoffactors,includingtherelativeabundanceofthevariouscytokines,theirability
torecruitandperpetuatetheactionsofinflammatorycellssuchaseosinophilsandlymphocytes,andtheirabilitytoamplifyorsuppressinflammationbyinteractingwith
structuralcellssuchasfibroblasts,endothelialcells,andepithelialcells.Thereisnoquestion,however,thatcytokinesarekeymediatorsinthepathogenesisofthechronic
inflammationcharacteristicofasthma.

Chemokines

Thechemokinesaresmallmolecularweightproteins,8to12kD,thatareclassifiedintofourcategoriesbasedontheorganizationofspecificcysteineresiduesintheir
proteinsequence:XC,CC,CXC,CX3C.92Thepredominantfunctionofchemokinesistherecruitmentorchemotaxisofinflammatorycells.92Somechemokinesalso
haveadditionalsignalingfunction.Therearecorrespondingfamiliesofchemokinereceptorsforeachclassofchemokines.Notably,thereisconsiderableoverlapand
redundancyinthechemokinesandtheirtargetreceptors.

Sincethelocalizationofinflammatorycellsintotheairwayisdependenttoalargeextentonchemotaxisviachemokinesignaling,thechemokinereceptorshavebecome
anattractivetargetforasthmatherapy.TherearecurrentlychemokinereceptorinhibitorsforCCR5aswellasothersindevelopmentaspotentialtherapyforasthma.93,94

Ige

TheinitialassociationofIgEwithasthmawasbasedonseveralepidemiologicalstudies.9597Withtheincreasedunderstandingoftheroleofmastcellmediatorsinthe
pathogenesisofasthma,theimportanceofIgEintriggeringmastcellactivationandtheresultingairwayinflammationhasbeenunderscored.Thisrelationshipbetween
IgElevelsandasthma,anditsfunction,ledtothedevelopmentofahumanizedmonoclonalantibodydirectedtoIgEforasthmatherapy.98Thisantibody(omalizumab,
Xolair)hasbeenshowntobeeffectiveinthetreatmentofsevereasthma,specificallyallowingasignificantreductionindosageofcorticosteroidsandpreventionof
asthmaexacerbation,furthersupportingakeyroleofIgEinasthma.99

Leukotrienes

Theleukotrienes(LT)areafamilyoflipidcompoundsgeneratedfromthemetabolismofarachidonicacidviathelipoxygenasepathway(Fig.444).100Thesecompounds
aretypicallynotpreformedandstoredincellsforreleaseuponactivationrather,theyarerapidlysynthesizedfollowingactivationofthesourcecell.LTC4,LTD4,and
LTE4arepotentbronchoconstrictorsthatareproducedbyseveralcelltypes,includingeosinophilsandmastcells,whereasLTB4isaneutrophilattractant.100The
leukotrienesarealsoabletoincreasemucussecretionintheairwayandfacilitateaplasmaleakgeneratingedemaintheairway.100,101Leukotrienereceptorantagonists
(e.g.,montelukast,Singulair)arecurrentlyusedinthetreatmentofasthma.102Althougheffectiveinsomepatients,theleukotrienemodifiershavelimitationsasregards
overallpotency,thusraisingquestionsastowhataretheconditions,orphenotypes,inwhichleukotrienesdominate.103

Figure444

Formationofarachidonicacidmetabolites.PG,prostaglandinTXA2,thromboxaneA2LT,leukotrieneFLAP,5lipoxygenaseactivatingprotein.

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Prostanoids

Theprostanoids(PG)areafamilyoflipidcompoundsgeneratedfromthemetabolismofarachidonicacidviathecyclooxygenasepathway(Fig.444).104Mostofthe
prostanoids,thatis,PGD2,PGF2,andTXA2,arepotentbronchoconstrictorsandproductsofseveralcelltypesincludingeosinophilsandmastcells.104However,another
prostanoid,PGE2,hasbronchodilatoryandantiinflammatoryactivity.105,106Theuseofnonsteroidalantiinflammatorymedicationstoinhibitcyclooxygenaseactivity
hasnotbeenshowntohaveanappreciableeffectonairwayinflammation.IthasbeenobservedthatPGD2isthepredominantprostanoidinvolvedinasthma.107
Therefore,specificPGD2receptorantagonistsarecurrentlybeingconsideredtoamelioratesomeofthebronchoconstrictioninasthma.108110

NitricOxide

Theroleofnitricoxide(NO)inthepathogenesisofasthmaremainsunclear.NOiscontinuallysynthesizedatlowlevelsintheairwaysofnormalsubjects.SourcesofNO
intherespiratorytractincludeairwayepithelialcells,smoothmusclecells,sensorynerves,endothelialcells,andmacrophages.111Atlowlevels,NOisabronchodilator
andvasodilatorthatantagonizesendothelinandhasprotectiveeffectsintheairway.111HigherlevelsofNOarefoundinasthma,secondarytoincreasedinducibleNO
synthaseexpression,andmaybedetrimentaltoairwayepithelium.112ThismaybemediatedbytheabilityofNOtoreactwithsuperoxideanionininflamedtissueto
producebiologicoxidantsthatcontributetoongoingtissuedamageandchronicasthmaticinflammation.111TheproductionofNOisalsothoughttoreflectthelevelor
severityofairwayinflammation.Thus,exhaledNOmeasurementhasbeenutilizedsuccessfullyasatooltoreflecttheextentofairwayinflammationasameasureof
asthmacontrol.112

GranuleProteins

Granulocytes,thatis,mastcells,basophils,eosinophils,andneutrophils,arecapableofreleasinggranuleproteins,manyofwhichhasbeenproposedtoplaysignificant
rolesinthepathogenesisofasthma.

InsightsintothekineticsandimportanceofmastcellmediatorshavebeenobtainedfrommeasurementsofBALhistamineandtryptase.113Thesestudieshave
demonstratedthatmastcellactivationisanearlyevent,withelevatedBALhistamineandtryptaselevelsbeingseen12minutesafterendobronchialantigenchallengethe
levelsoftryptasereturningtonormal48hoursafterantigenchallenge.113Thelevelsofhistamineremainelevatedafter48hours,raisingthepossibilitythatnonmast
cells(e.g.,basophils)aresubsequentlyrecruitedandactivatedtoproducehistamineattheselaterpointsorthatmastcellsgenerateandcontinuetoreleasehistamineover

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timefollowinganinitialactivation.113Furthermore,BALofallergicasthmaticsubjectshadonlymoderatelyelevatedlevelsoftryptaseatbaselinebuthigher
concentrationsoftryptasefollowingantigenchallenge.113

Histamineiscapableofinducingbronchoconstriction,increasingvascularpermeabilitytocauseedema,andincreasingmucussecretion.114Theroleoftryptaseisnot
wellestablished,althoughtherearedatatosuggestthatitcanactivateinflammatorycellssuchaseosinophils,mastcells,andepithelialcellsbycleavingafamilyof
proteaseactivatedreceptors(PARs)ontheircellsurfaces.

Majorbasicprotein(MBP)istheprincipalproteinconstituentofeosinophilgranules.Itistoxictoepithelialtissues,inducesairwayhyperresponsiveness,andcauses
histaminereleasefrombasophils.115ECPismorecytotoxictotheepitheliumthanMBPanddamagestargetcellsbymembraneporeformation.116Eosinophilderived
neurotoxin(EDN),asthenameimplies,damagesmyelinatedneurons.117EPOdiffersfromneutrophilandmonocytemyeloperoxidases(MPOs)itcausesLTC4and
LTD4degradationandcauseshistaminereleasefrommastcells.118

NeutrophilreleaseofMPOandneutrophilelastaseenhanceshostdefensefunctionsbutisalsopotentiallyinjurioustonormaltissues,includingairwayepithelium.119The
primarygranulesofneutrophilscontainMPOandlysozymeaswellashydrolasesandproteinases,whichareimportantintissuepenetrationbyneutrophils.119Secondary
granulescontainlysozymeandcollagenases,whichcanalsopotentiallydamageairwaytissue.119Neutrophilgranuleproteinsareconsideredtoxictoairwayepithelium
andtissue.

RemodelinginAsthma
Asoccursinmostchronicinflammatorydisordersinwhichthereisaninjuryrepaircycle,tissueremodelingisakeycomponentofasthma.Airwayremodelingin
asthmainvolvesepithelialchanges,increasesinsmoothmusclemass,increasedangiogenesis,increasedfibroblast/myofibroblastactivity,increasedfibrosis,andmany
otherimportantchangesthataffectthestructureandfunctionofthelargeandsmallairwaysofthelung.120Prolongedinfiltrationofinflammatorycellsandthecytokines,
chemokines,andgrowthfactors,whichtheygenerate,contributetothesestructuralchanges,whichhelpdefinethefeaturesofasthmainsomepatients.

Asmentionedpreviously,airwayepitheliumservesnotonlyasananatomicbarrier,butalsoasakeyplayerinasthmapathogenesis.Defectsinairwayepitheliumare
ubiquitousinhumanasthmaand,wheninjuryoccurs,therepairprocesshasbeenlikenedtoachronicwound,whichmaynothealnormallyasaresultofrepetitiveand
ongoinginsults.121Aswithothertypesofchronicwounds,thebodyattemptstohealtheepithelialdamagebypromotingthereleaseofgrowthfactorsfromthe
underlyingmesenchyme.This,inturn,leadstoincreasedextracellularmatrixdeposition,fibrosis,andsizeandnumberofairwaysmoothmusclecells.122Theseeven
havebeenlikenedtothefunctionoftheepithelialmesangialtrophicunit(EMTU),akeycomponentofearlylungmorphogenesis,which,inasense,becomesreactivated
inchronicasthma.122TheconsequenceofprolongedepithelialinjuryisaprotractedreleaseofproinflammatorycytokinesandprofibrogenicgrowthfactorssuchasTGF
.Whenthesereactionsarecombinedwiththeinflammatorymilieuderivedfromtheimmunecellsrecruitedtotheairwaybythislongtermdamage,theeffectsofthese
morphologicchangesaremanifestedinchronicairflowobstruction,whichisoftenresistanttopharmacologictreatment,andresultsinpermanentairflowobstruction.

PhenotypicClustersinAsthma
Severalrecentstudieshavebeguntoidentifyphenotypes,orsubphenotypes,ofasthma.Thesestudieshaveconfirmedthatasthmaisaveryheterogeneousdisease.123,124
Specifically,studiesbyHaldarandcolleaguesintheUnitedKingdomusedsputumeosinophilia,inadditiontomeasurementsofatopicstatusandothercharacteristics,to
identifythesesubphenotypes.123Interestingly,theyidentifiedaclusterofpatientswithsymptomaticdiseasewhohadverylittleeosinophilicinvolvementandlacked
evidenceofatopicsensitization.Othergroupsfitamoreclassicpatternofasthmawithevidenceofeosinophilicinvolvementandatopicsensitization.Otherclustersfell
somewherebetweenthetwo.Thisstudy,andothers,areprobingtheheterogeneityofthediseaseanddiscoveringthereasonsbehinddifferencesindiseasecourseand
responsetoconventionalasthmatherapy.

Conclusion
Asthmaisacomplexdiseaseinwhichthecontributionsofmanydifferentimmunecells,structuralcells,molecularmediators,andexternalfactorscombinetoproduce
acuteandchronicinflammationandairflowobstruction.Thestudyofthesedifferentfactorshasledtoagreaterunderstandingandappreciationofthebreadthofthis
diseaseandarecognitionofitscomplexityandheterogeneity.Ithasalsoledtotherealizationthatdifferentphenotypesofasthmaexistandtreatmentofasthmabasedon
thespecificphenotyperepresentsanemerging,potentiallymorespecificandeffectivepossibility.Overthelastdecade,manynewadvancesintherapyhavebeenmade
thattargetspecificinflammatorymediatorsinasthma.Thefactthatthesehavenotbeenuniversallysuccessfulspeakstotheheterogeneityandredundancyofasthma.As
researchdelvesfurtherintothepathogenesisandpathophysiologyofasthma,manymoretargetswillemerge,whichwillhopefullyleadtonoveltherapiestoimprovethe
livesofasthmaticpatientsandwiththeseinterventionsgreaterinsightintotheeffectsofindividualmediatorsandinwhomtheymayberelevant.

References
1.
WorldHealthOrganization.OfficeofHealthCommunicationsandPublicRelations.Asthma.Geneva:WorldHealthOrganization2006.
2.
AkinbamiLJ,MoormanJE,BaileyC,etalTrendsinasthmaprevalence,healthcareuse,andmortalityintheUnitedStates,20012010.NCHSDataBrief.2012
(94):18.
3.
NationalAsthmaEducationandPreventionProgram.ExpertPanelReport3(EPR3):GuidelinesfortheDiagnosisandManagementofAsthmaSummaryReport2007.J
AllergyClinImmunol.2007120(5Suppl):S94S138.[PubMed:17983880]
4.
VermaelenKY,CarroMuinoI,LambrechtBN,PauwelsRA.Specificmigratorydendriticcellsrapidlytransportantigenfromtheairwaystothethoraciclymphnodes.
JExpMed.2001193(1):5160.
[PubMed:11136820]
5.
GillMA.Theroleofdendriticcellsinasthma.JAllergyClinImmunol.2012129(4):889901.
[PubMed:22464668]
6.
LambrechtBN,HammadH.Theroleofdendriticandepithelialcellsasmasterregulatorsofallergicairwayinflammation.Lancet.2010376(9743):835843.
[PubMed:20816550]
7.
PearlmanDS.Pathophysiologyoftheinflammatoryresponse.JAllergyClinImmunol.1999104(4Pt1):S132S137.[PubMed:10518809]
8.

13/19
24/1/2017
BusseWW,CalhounWF,SedgwickJD.Mechanismofairwayinflammationinasthma.AmRevRespirDis.1993147(6Pt2):S20S24.[PubMed:8494196]
9.
BrooksGD,BuchtaKA,SwensonCA,GernJE,BusseWW.Rhinovirusinducedinterferongammaandairwayresponsivenessinasthma.AmJRespirCritCareMed.
2003168(9):10911094.
[PubMed:12928311]
10.
GernJE.Viralrespiratoryinfectionandthelinktoasthma.PediatrInfectDisJ.200827(10Suppl):S97S103.[PubMed:18820588]
11.
KirshenbaumAS,GoffJP,SemereT,FosterB,ScottLM,MetcalfeDD.DemonstrationthathumanmastcellsarisefromaprogenitorcellpopulationthatisCD34(+),
ckit(+),andexpressesaminopeptidaseN(CD13).Blood.199994(7):23332342.
[PubMed:10498605]
12.
MetcalfeDD,BaramD,MekoriYA.Mastcells.PhysiolRev.199777(4):10331079.
[PubMed:9354811]
13.
IraniAA,SchechterNM,CraigSS,DeBloisG,SchwartzLB.Twotypesofhumanmastcellsthathavedistinctneutralproteasecompositions.ProcNatlAcadSciUS
A.198683(12):44644468.
[PubMed:3520574]
14.
IraniAM,GoldsteinSM,WintroubBU,BradfordT,SchwartzLB.Humanmastcellcarboxypeptidase.SelectivelocalizationtoMCTCcells.JImmunol.
1991147(1):247253.
[PubMed:2051021]
15.
SchechterNM,IraniAM,SprowsJL,AbernethyJ,WintroubB,SchwartzLB.IdentificationofacathepsinGlikeproteinaseintheMCTCtypeofhumanmastcell.J
Immunol.1990145(8):26522661.
[PubMed:2212656]
16.
BalzarS,FajtML,ComhairSA,etalMastcellphenotype,location,andactivationinsevereasthma.DatafromtheSevereAsthmaResearchProgram.AmJRespir
CritCareMed.2011183(3):299309.
[PubMed:20813890]
17.
BrightlingCE,BraddingP,SymonFA,HolgateST,WardlawAJ,PavordID.Mastcellinfiltrationofairwaysmoothmuscleinasthma.NEnglJMed.
2002346(22):16991705.
[PubMed:12037149]
18.
RobinsonDS.Theroleofthemastcellinasthma:inductionofairwayhyperresponsivenessbyinteractionwithsmoothmuscle?JAllergyClinImmunol.
2004114(1):5865.
[PubMed:15241345]
19.
WilliamsCM,GalliSJ.Thediversepotentialeffectorandimmunoregulatoryrolesofmastcellsinallergicdisease.JAllergyClinImmunol.2000105(5):847859.
[PubMed:10808163]
20.
KearleyJ,ErjefaltJS,AnderssonC,etalIL9governsallergeninducedmastcellnumbersinthelungandchronicremodelingoftheairways.AmJRespirCritCare
Med.2011183(7):865875.
[PubMed:20971830]
21.
StoneKD,PrussinC,MetcalfeDD.IgE,mastcells,basophils,andeosinophils.JAllergyClinImmunol.2010125(2Suppl2):S73S80.[PubMed:20176269]
22.
SokolCL,ChuNQ,YuS,NishSA,LauferTM,MedzhitovR.BasophilsfunctionasantigenpresentingcellsforanallergeninducedThelpertype2response.Nat
Immunol.200910(7):713720.
[PubMed:19465907]
23.
PecaricPetkovicT,DidichenkoSA,KaempferS,SpieglN,DahindenCA.HumanbasophilsandeosinophilsarethedirecttargetleukocytesofthenovelIL1family
memberIL33.Blood.2009113(7):15261534.
[PubMed:18955562]
24.
SandersonCJ.Interleukin5,eosinophils,anddisease.Blood.199279(12):31013109.
[PubMed:1596561]
25.
WardlawAJ.Molecularbasisforselectiveeosinophiltraffickinginasthma:amultistepparadigm.JAllergyClinImmunol.1999104(5):917926.
[PubMed:10550733]
26.
RothenbergME,HoganSP.Theeosinophil.AnnuRevImmunol.200624:147174.
[PubMed:16551246]
27.
GleichGJ.Mechanismsofeosinophilassociatedinflammation.JAllergyClinImmunol.2000105(4):651663.
[PubMed:10756213]
28.
AbuGhazalehRI,DunnetteSL,LoegeringDA,etalEosinophilgranuleproteinsinperipheralbloodgranulocytes.JLeukocBiol.199252(6):611618.
[PubMed:1464733]
29.
WenzelSE.Eosinophilsinasthmaclosingthelooporopeningthedoor?NEnglJMed.2009360(10):10261028.
[PubMed:19264692]
30.
HornBR,RobinED,TheodoreJ,VanKesselA.Totaleosinophilcountsinthemanagementofbronchialasthma.NEnglJMed.1975292(22):11521155.
[PubMed:1124105]
31.
FilleyWV,HolleyKE,KephartGM,GleichGJ.Identificationbyimmunofluorescenceofeosinophilgranulemajorbasicproteininlungtissuesofpatientswith
bronchialasthma.Lancet.19822(8288):1116.
[PubMed:6177986]
32.

14/19
24/1/2017
WoolleyKL,AdelrothE,WoolleyMJ,EllisR,JordanaM,O'ByrnePM.Effectsofallergenchallengeoneosinophils,eosinophilcationicprotein,andgranulocyte
macrophagecolonystimulatingfactorinmildasthma.AmJRespirCritCareMed.1995151(6):19151924.
[PubMed:7767540]
33.
LeckieMJ,tenBrinkeA,KhanJ,etalEffectsofaninterleukin5blockingmonoclonalantibodyoneosinophils,airwayhyperresponsiveness,andthelateasthmatic
response.Lancet.2000356(9248):21442148.
[PubMed:11191542]
34.
FloodPageP,SwensonC,FaifermanI,etalAstudytoevaluatesafetyandefficacyofmepolizumabinpatientswithmoderatepersistentasthma.AmJRespirCrit
CareMed2007176(11):10621071.
[PubMed:17872493]
35.
HaldarP,BrightlingCE,HargadonB,etalMepolizumabandexacerbationsofrefractoryeosinophilicasthma.NEnglJMed.2009360(10):973984.
[PubMed:19264686]
36.
NairP,PizzichiniMM,KjarsgaardM,etalMepolizumabforprednisonedependentasthmawithsputumeosinophilia.NEnglJMed.2009360(10):985993.
[PubMed:19264687]
37.
BaintonDF,UllyotJL,FarquharMG.Thedevelopmentofneutrophilicpolymorphonuclearleukocytesinhumanbonemarrow.JExpMed.1971134(4):907934.
[PubMed:4106490]
38.
KellyJT,BusseWW.Hostimmuneresponsestorhinovirus:mechanismsinasthma.JAllergyClinImmunol.2008122(4):671682quiz683674.
[PubMed:19014757]
39.
LindenA,HoshinoH,LaanM.Airwayneutrophilsandinterleukin17.EurRespirJ.200015(5):973977.
[PubMed:10853869]
40.
SimsJE,SmithDE.TheIL1family:regulatorsofimmunity.NatRevImmunol.201010(2):89102.
[PubMed:20081871]
41.
JatakanonA,UasufC,MaziakW,LimS,ChungKF,BarnesPJ.Neutrophilicinflammationinseverepersistentasthma.AmJRespirCritCareMed.1999160(5Pt
1):15321539.
[PubMed:10556116]
42.
FahyJV,KimKW,LiuJ,BousheyHA.Prominentneutrophilicinflammationinsputumfromsubjectswithasthmaexacerbation.JAllergyClinImmunol.
199595(4):843852.
[PubMed:7722165]
43.
LamblinC,GossetP,TillieLeblondI,etalBronchialneutrophiliainpatientswithnoninfectiousstatusasthmaticus.AmJRespirCritCareMed.1998157(2):394402.
[PubMed:9476849]
44.
SurS,CrottyTB,KephartGM,etalSuddenonsetfatalasthma.Adistinctentitywithfeweosinophilsandrelativelymoreneutrophilsintheairwaysubmucosa?Am
RevRespirDis.1993148(3):713719.
[PubMed:8368644]
45.
GreenRH,BrightlingCE,WoltmannG,ParkerD,WardlawAJ,PavordID.Analysisofinducedsputuminadultswithasthma:identificationofsubgroupwithisolated
sputumneutrophiliaandpoorresponsetoinhaledcorticosteroids.Thorax.200257(10):875879.
[PubMed:12324674]
46.
SimpsonJL,ScottR,BoyleMJ,GibsonPG.Inflammatorysubtypesinasthma:assessmentandidentificationusinginducedsputum.Respirology.200611(1):5461.
[PubMed:16423202]
47.
ZhouL,ChongMM,LittmanDR.PlasticityofCD4+Tcelllineagedifferentiation.Immunity.200930(5):646655.
[PubMed:19464987]
48.
RobinsonDS,HamidQ,YingS,etalPredominantTH2likebronchoalveolarTlymphocytepopulationinatopicasthma.NEnglJMed.1992326(5):298304.
[PubMed:1530827]
49.
PrietoJ,LensmarC,RoquetA,etalIncreasedinterleukin13mRNAexpressioninbronchoalveolarlavagecellsofatopicpatientswithmildasthmaafterrepeatedlow
doseallergenprovocations.RespirMed.Aug200094(8):806814.
[PubMed:10955758]
50.
LloydCM,HesselEM.FunctionsofTcellsinasthma:morethanjustT(H)2cells.NatRevImmunol.201010(12):838848.
[PubMed:21060320]
51.
CorriganCJ,KayAB.CD4Tlymphocyteactivationinacutesevereasthma.IntArchAllergyApplImmunol.199194(14):270271.
[PubMed:1682273]
52.
ShannonJ,ErnstP,YamauchiY,etalDifferencesinairwaycytokineprofileinsevereasthmacomparedtomoderateasthma.Chest.2008133(2):420426.
[PubMed:18071017]
53.
ChangY,AlAlwanL,RissePA,etalTh17associatedcytokinespromotehumanairwaysmoothmusclecellproliferation.FasebJ.201226(12):51525160.
[PubMed:22898922]
54.
BarczykA,PierzchalaW,SozanskaE.Interleukin17insputumcorrelateswithairwayhyperresponsivenesstomethacholine.RespirMed.200397(6):726733.
[PubMed:12814161]
55.
YingS,HumbertM,BarkansJ,etalExpressionofIL4andIL5mRNAandproteinproductbyCD4+andCD8+Tcells,eosinophils,andmastcellsinbronchial
biopsiesobtainedfromatopicandnonatopic(intrinsic)asthmatics.JImmunol.1997158(7):35393544.
[PubMed:9120316]
56.

15/19
24/1/2017
ThurauAM,StreckertHJ,RiegerCH,SchauerU.IncreasednumberofTcellscommittedtoIL5productionafterrespiratorysyncytialvirus(RSV)infectionofhuman
mononuclearcellsinvitro.ClinExpImmunol.1998113(3):450455.
[PubMed:9737676]
57.
ChoSH,StanciuLA,HolgateST,JohnstonSL.Increasedinterleukin4,interleukin5,andinterferongammainairwayCD4+andCD8+Tcellsinatopicasthma.AmJ
RespirCritCareMed.2005171(3):224230.
[PubMed:15502111]
58.
SeroogyCM,GernJE.TheroleofTregulatorycellsinasthma.JAllergyClinImmunol.2005116(5):996999.
[PubMed:16275366]
59.
LingEM,SmithT,NguyenXD,etalRelationofCD4+CD25+regulatoryTcellsuppressionofallergendrivenTcellactivationtoatopicstatusandexpressionof
allergicdisease.Lancet.2004363(9409):608615.
[PubMed:14987885]
60.
GrindebackeH,WingK,AnderssonAC,SuriPayerE,RakS,RudinA.DefectivesuppressionofTh2cytokinesbyCD4CD25regulatoryTcellsinbirchallergies
duringbirchpollenseason.ClinExpAllergy.200434(9):13641372.
[PubMed:15347368]
61.
RadulovicS,JacobsonMR,DurhamSR,NouriAriaKT.GrasspollenimmunotherapyinducesFoxp3expressingCD4+CD25+cellsinthenasalmucosa.JAllergy
ClinImmunol.2008121(6):14671472,1472.e1.
[PubMed:18423565]
62.
SchaubB,LiuJ,HopplerS,etalMaternalfarmexposuremodulatesneonatalimmunemechanismsthroughregulatoryTcells.JAllergyClinImmunol.
2009123(4):774782,e775.[PubMed:19348917]
63.
LinSJ,ChangLY,YanDC,HuangYJ,LinTJ,LinTY.Decreasedintercellularadhesionmolecule1(CD54)andLselectin(CD62L)expressiononperipheralblood
naturalkillercellsinasthmaticchildrenwithacuteexacerbation.Allergy.200358(1):6771.
[PubMed:12580810]
64.
CulleyFJ.Naturalkillercellsininfectionandinflammationofthelung.Immunology.2009128(2):151163.
[PubMed:19740372]
65.
ChenY,PerussiaB,CampbellKS.ProstaglandinD2suppresseshumanNKcellfunctionviasignalingthroughDprostanoidreceptor.JImmunol.2007179(5):2766
2773.
[PubMed:17709490]
66.
MorettaA.Naturalkillercellsanddendriticcells:rendezvousinabusedtissues.NatRevImmunol.20022(12):957964.
[PubMed:12461568]
67.
MoreiraAP,HogaboamCM.Macrophagesinallergicasthma:finetuningtheirproandantiinflammatoryactionsfordiseaseresolution.JInterferonCytokineRes.
201131(6):485491.
[PubMed:21631355]
68.
KugathasanK,RoedigerEK,SmallCL,McCormickS,YangP,XingZ.CD11c+antigenpresentingcellsfromthealveolarspace,lungparenchymaandspleendiffer
intheirphenotypeandcapabilitiestoactivatenaiveandantigenprimedTcells.BMCImmunol.20089:48.
[PubMed:18700962]
69.
BratkeK,LommatzschM,JuliusP,etalDendriticcellsubsetsinhumanbronchoalveolarlavagefluidaftersegmentalallergenchallenge.Thorax.200762(2):168175.
[PubMed:16928719]
70.
UphamJW,DenburgJA,O'ByrnePM.Rapidresponseofcirculatingmyeloiddendriticcellstoinhaledallergeninasthmaticsubjects.ClinExpAllergy.
200232(6):818823.
[PubMed:12047425]
71.
JahnsenFL,MoloneyED,HoganT,UphamJW,BurkeCM,HoltPG.Rapiddendriticcellrecruitmenttothebronchialmucosaofpatientswithatopicasthmain
responsetolocalallergenchallenge.Thorax.200156(11):823826.
[PubMed:11641504]
72.
GillMA,PaluckaAK,BartonT,etalMobilizationofplasmacytoidandmyeloiddendriticcellstomucosalsitesinchildrenwithrespiratorysyncytialvirusandother
viralrespiratoryinfections.JInfectDis.2005191(7):11051115.
[PubMed:15747246]
73.
GernJE,RosenthalLA,SorknessRL,LemanskeRFJr.Effectsofviralrespiratoryinfectionsonlungdevelopmentandchildhoodasthma.JAllergyClinImmunol.
2005115(4):668674quiz675.
[PubMed:15805982]
74.
UphamJW,ZhangG,RateA,etalPlasmacytoiddendriticcellsduringinfancyareinverselyassociatedwithchildhoodrespiratorytractinfectionsandwheezing.J
AllergyClinImmunol.2009124(4):707713.
[PubMed:19733903]
75.
JamesAL,ElliotJG,JonesRL,etalAirwaysmoothmusclehypertrophyandhyperplasiainasthma.AmJRespirCritCareMed.2012185(10):10581064.
[PubMed:22403800]
76.
BorgerP,TammM,BlackJL,RothM.Asthma:isitduetoanabnormalairwaysmoothmusclecell?AmJRespirCritCareMed.2006174(4):367372.
[PubMed:16690983]
77.
CastroM,RubinAS,LavioletteM,etalEffectivenessandsafetyofbronchialthermoplastyinthetreatmentofsevereasthma:amulticenter,randomized,doubleblind,
shamcontrolledclinicaltrial.AmJRespirCritCareMed2010181(2):116124.
[PubMed:19815809]
78.

16/19
24/1/2017
PavordID,CoxG,ThomsonNC,etalSafetyandefficacyofbronchialthermoplastyinsymptomatic,severeasthma.AmJRespirCritCareMed.2007176(12):1185
1191.
[PubMed:17901415]
79.
HolgateST.Epitheliumdysfunctioninasthma.JAllergyClinImmunol.2007120(6):12331244quiz12451236.
[PubMed:18073119]
80.
ShijuboN,ItohY,YamaguchiT,etalSerumlevelsofClaracell10kDaproteinaredecreasedinpatientswithasthma.Lung.1999177(1):4552.
[PubMed:9835633]
81.
HauberHP,FoleySC,HamidQ.Mucinoverproductioninchronicinflammatorylungdisease.CanRespirJ.200613(6):327335.
[PubMed:16983448]
82.
BucchieriF,PuddicombeSM,LordanJL,etalAsthmaticbronchialepitheliumismoresusceptibletooxidantinducedapoptosis.AmJRespirCellMolBiol.
200227(2):179185.
[PubMed:12151309]
83.
WarkPA,JohnstonSL,BucchieriF,etalAsthmaticbronchialepithelialcellshaveadeficientinnateimmuneresponsetoinfectionwithrhinovirus.JExpMed.
2005201(6):937947.
[PubMed:15781584]
84.
SoumelisV,RechePA,KanzlerH,etalHumanepithelialcellstriggerdendriticcellmediatedallergicinflammationbyproducingTSLP.NatImmunol.20023(7):673
680.
[PubMed:12055625]
85.
YingS,O'ConnorB,RatoffJ,etalThymicstromallymphopoietinexpressionisincreasedinasthmaticairwaysandcorrelateswithexpressionofTh2attracting
chemokinesanddiseaseseverity.JImmunol.2005174(12):81838190.
[PubMed:15944327]
86.
GoldieRG,HenryPJ.Endothelinsandasthma.LifeSci.199965(1):115.
[PubMed:10403488]
87.
O'SheaJJ.Jaks,STATs,cytokinesignaltransduction,andimmunoregulation:arewethereyet?Immunity.19977(1):111.[PubMed:9252115]
88.
SchenaFP,GesualdoL,GrandalianoG,MontinaroV.Progressionofrenaldamageinhumanglomerulonephritides:istheresleightofhandinwinningthegame?
KidneyInt.199752(6):14391457.
[PubMed:9407490]
89.
MathurSK,BusseWW.Thebiologyofasthma,inFishman'sPulmonaryDiseasesandDisorders,vol1,FourthEdition.In:FishmanAP,EliasJA,FishmanJA,Grippi
MA,SeniorRM,PackAL,eds.NewYork,NY:McGrawHill2008,773785.
90.
BatraV,KhuranaS,MusaniAI,etalConcentrationofcytokinesandgrowthfactorsinBALfluidafterallergenchallengeinasthmaticsandtheireffectonalpha
smoothmuscleactinandcollagenIIIsynthesisbyhumanlungfibroblasts.Chest.2003123(3Suppl):398S399S.
[PubMed:12629001]
91.
KupermanDA,HuangX,KothLL,etalDirecteffectsofinterleukin13onepithelialcellscauseairwayhyperreactivityandmucusoverproductioninasthma.NatMed.
20028(8):885889.
[PubMed:12091879]
92.
GarroodT,LeeL,PitzalisC.Molecularmechanismsofcellrecruitmenttoinflammatorysites:generalandtissuespecificpathways.Rheumatology(Oxford).
200645(3):250260.
[PubMed:16319101]
93.
SuzakiY,HamadaK,NomiT,etalAsmallmoleculecompoundtargetingCCR5andCXCR3preventsairwayhyperresponsivenessandinflammation.EurRespirJ.
200831(4):783789.
[PubMed:18094012]
94.
FryerAD,SteinLH,NieZ,etalNeuronaleotaxinandtheeffectsofCCR3antagonistonairwayhyperreactivityandM2receptordysfunction.JClinInvest.
2006116(1):228236.
[PubMed:16374515]
95.
TurnerKJ,RosmanDL,O'MahonyJ.PrevalenceandfamilialassociationofatopicdiseaseanditsrelationshiptoserumIgElevelsin1,061schoolchildrenandtheir
families.IntArchAllergyApplImmunol.197447(5):650664.
[PubMed:4430508]
96.
BurrowsB,MartinezFD,HalonenM,BarbeeRA,ClineMG.AssociationofasthmawithserumIgElevelsandskintestreactivitytoallergens.NEnglJMed.
1989320(5):271277.
[PubMed:2911321]
97.
SearsMR,BurrowsB,FlanneryEM,HerbisonGP,HewittCJ,HoldawayMD.RelationbetweenairwayresponsivenessandserumIgEinchildrenwithasthmaandin
apparentlynormalchildren.NEnglJMed.1991325(15):10671071.
[PubMed:1891008]
98.
PrestaLG,LahrSJ,ShieldsRL,etalHumanizationofanantibodydirectedagainstIgE.JImmunol.1993151(5):26232632.
[PubMed:8360482]
99.
BusseW,CorrenJ,LanierBQ,etalOmalizumab,antiIgErecombinanthumanizedmonoclonalantibody,forthetreatmentofsevereallergicasthma.JAllergyClin
Immunol.2001108(2):184190.
[PubMed:11496232]
100.

17/19
24/1/2017
BusseWW.Theroleofleukotrienesinasthmaandallergicrhinitis.ClinExpAllergy.199626(8):868879.
[PubMed:9011329]
101.
WenzelSE.Theroleofleukotrienesinasthma.ProstaglandinsLeukotEssentFattyAcids.200369(23):145155.
102.
HorwitzRJ,McGillKA,BusseWW.Theroleofleukotrienemodifiersinthetreatmentofasthma.AmJRespirCritCareMed.1998157(5Pt1):13631371.
[PubMed:9603110]
103.
O'ByrnePM,GauvreauGM,MurphyDM.Efficacyofleukotrienereceptorantagonistsandsynthesisinhibitorsinasthma.JAllergyClinImmunol.2009124(3):397
403.
[PubMed:19608262]
104.
ChungKF,BarnesPJ.Roleofinflammatorymediatorsinasthma.BrMedBull.199248(1):135148.
[PubMed:1617388]
105.
MainIH.TheInhibitoryactionsofprostaglandinsonrespiratorysmoothmuscle.BrJPharmacolChemother.196422:511519.
[PubMed:14211681]
106.
MatheAA,HedqvistP.EffectofprostaglandinsF2alphaandE2onairwayconductanceinhealthysubjectsandasthmaticpatients.AmRevRespirDis.
1975111(3):313320.
[PubMed:1091185]
107.
RobinsonC,HardyCC,HolgateST.Pulmonarysynthesis,release,andmetabolismofprostaglandins.JAllergyClinImmunol.198576(2Pt2):265271.
[PubMed:2410475]
108.
SchmidtJ,BellF,AkamE,etalBiochemicalandpharmacologicalcharacterizationofAZD1981,anorallyavailableselectiveDP2antagonistinclinicaldevelopment
forasthma.BrJPharmacol.2013168(7):16261638.
[PubMed:23146091]
109.
SinghD,CaddenP,HunterM,etalInhibitionoftheasthmaticallergenchallengeresponsebytheCRTH2antagonistOC000459.EurRespirJ.201341(1):4652.
[PubMed:22496329]
110.
BusseWW,WenzelSE,MeltzerEO,etalSafetyandefficacyoftheprostaglandinD2receptorantagonistAMG853inasthmaticpatients.JAllergyClinImmunol.
2013131(2):339345.
[PubMed:23174659]
111.
RicciardoloFL.Multiplerolesofnitricoxideintheairways.Thorax.200358(2):175182.
[PubMed:12554905]
112.
BarnesPJ,DweikRA,GelbAF,etalExhalednitricoxideinpulmonarydiseases:acomprehensivereview.Chest.2010138(3):682692.
[PubMed:20822990]
113.
SedgwickJB,CalhounWJ,GleichGJ,etalImmediateandlateairwayresponseofallergicrhinitispatientstosegmentalantigenchallenge.Characterizationof
eosinophilandmastcellmediators.AmRevRespirDis.1991144(6):12741281.[PubMed:1741538]
114.
WhiteMV.Theroleofhistamineinallergicdiseases.JAllergyClinImmunol.199086(4Pt2):599605.
[PubMed:1699987]
115.
GundelRH,LettsLG,GleichGJ.Humaneosinophilmajorbasicproteininducesairwayconstrictionandairwayhyperresponsivenessinprimates.JClinInvest.
199187(4):14701473.
[PubMed:2010556]
116.
MotojimaS,FrigasE,LoegeringDA,GleichGJ.Toxicityofeosinophilcationicproteinsforguineapigtrachealepitheliuminvitro.AmRevRespirDis.
1989139(3):801805.
[PubMed:2923379]
117.
DurackDT,SumiSM,KlebanoffSJ.Neurotoxicityofhumaneosinophils.ProcNatlAcadSciUSA.197976(3):14431447.
[PubMed:286329]
118.
EverseJ,EverseKE,GrishamMB.PeroxidasesinChemistryandBiology.BocaRaton,FL:CRCPress1991.
119.
MonteseirinJ.Neutrophilsandasthma.JInvestigAllergolClinImmunol.200919(5):340354.
[PubMed:19862934]
120.
AlMuhsenS,JohnsonJR,HamidQ.Remodelinginasthma.JAllergyClinImmunol.2011128(3):451462quiz463454.
[PubMed:21636119]
121.
DaviesDE,WicksJ,PowellRM,PuddicombeSM,HolgateST.Airwayremodelinginasthma:newinsights.JAllergyClinImmunol.2003111(2):215225quiz226.
[PubMed:12589337]
122.
KnightDA,HolgateST.Theairwayepithelium:structuralandfunctionalpropertiesinhealthanddisease.Respirology.20038(4):432446.
[PubMed:14708552]
123.
HaldarP,PavordID,ShawDE,etalClusteranalysisandclinicalasthmaphenotypes.AmJRespirCritCareMed.2008178(3):218224.
[PubMed:18480428]
124.
MooreWC,MeyersDA,WenzelSE,etalIdentificationofasthmaphenotypesusingclusteranalysisintheSevereAsthmaResearchProgram.AmJRespirCritCare
Med.2010181(4):315323.
[PubMed:19892860]

18/19
24/1/2017
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