Molecular Basis of Pulmonary Disease : Insights from Rare Lung Disorders Hardback

Dr. SharonRounds,theeditorforthisserieswhoinvitedustowriteabookonrare lungdiseases,developedtheideaafterattendingthe2004Lymphangioleiomyomatosis (LAM)Foundationannualresearchmeeting.

Shewasakeynotespeakeratthatevent (duringhertenureasthepresidentoftheAmericanThoracicSociety)andwasw- nesstothepowerofpatientadvocacyandthemission-basedscienti ceffortthathad broughtthisrarediseaseofwomenfromobscuritytoclinicaltrialswithtargetedmol- ulartherapiesinunderadecade.

Theprogressinpulmonaryalveolarproteinosis(PAP), pulmonaryalveolarmicrolithiasis(PAM),inheriteddisordersofsurfactantmetabolism, and pulmonary arterial hypertension, to name a few, has been no less astounding.

Advanceshavecomefromthemostsurprisingdirections;fruit iesforLAM,gen- ically engineered mice made for other purposes for PAP, and groundbreaking hi- densitySNP(single-nucleotidepolymorphism)analysesdoneonahandfuloffamilies forPAM. Inmanycases,insightsintobiologygainedfromrarediseaseshaveinformed researchapproachesandtreatmentstrategiesformorecommondiseases;forexample, knowledgegainedfromthestudyofPAPabouttheroleofGM-CSFinthelunghas sparkedinterestintheuseofantiGM-CSFapproachestocontrolbothpulmonaryand extrapulmonaryin ammationinavarietyofdiseases.

The ndingthatinterstitiallung diseasedevelopsinfamilieswithcytotoxicmutationsinsurfactantproteinC(SP-C), agenewhichisexpressedonlyinalveolartypecells,hasunderscoredtheimportance oftheintegrityofthealveolarepitheliuminthepathogenesisofparenchymal brosis.

Opportunitiestoapproachlungdiseasepathogenesisfromthevantagepointofap- marymoleculardefectaregiftsfromnaturethatareuniquelyabundantamongtherare lungdisorders.

WesalutetheNIHandtheNationalCenterforResearchResourcesfortheirvisionin facilitatingthetranslationofbasicresearchadvancesinrarelungdiseasesintoclinical realitythroughtheRareLungDiseaseConsortium,anetworkof13USandinter- tionalsitesthatiscurrentlyconductingclinicaltrialsandstudiesinLAM,alphaone antitrypsin de ciency, pediatric interstitial lung disease, and PAP. It has been a rare privilegetoworkonsuchfascinatingdiseaseswithsuchcapableinvestigatorsfromall overtheworldoverthepast6years. v vi Preface Theformatforthisvolumeisunique. Mostchaptershavebeenauthoredbyacli- cianandabasicscientistwhoareexpertinthediseasetopicandunderlyingmolecular defect,respectively.

Theirchargewastofocusonthegeneticbasisandmolecularpat- genesisofdisease,animalmodels,clinicalfeatures,diagnosticapproach,conventional managementandtreatment,andfuturetherapeutictargetsanddirections.

Theintentwas nottoprovideabroadoverview,butrathertoshedlightonthemolecularmechanisms thatevoketheclinicalpresentationandengendertreatmentstrategiesforeachdisease.

Wehopethatthisapproachwillproveusefulforpulmonarycliniciansandscientists alike.

Wethankourwives,Holly,Jean,andVicky,fortheirsupportandindulgencewith latenightemailsandwork- lledweekends,Dr. Roundsfortheinvitationtowritethe book,andalloftheauthorswhocontributed.

FrancisMcCormack,MD RalphPanos,MD BruceTrapnell,MD Contents Preface...v Contributors...ix 1 AClinicalApproachtoRareLungDiseases...1 RalphJ.

Panos 2 ClinicalTrialsforRareLungDiseases...31 JeffreyKrischer 3 IdiopathicandFamilialPulmonaryArterialHypertension ...39 JeanM. Elwing,GailH. Deutsch,WilliamC. Nichols, andTimothyD. LeCras 4 Lymphangioleiomyomatosis...85 ElizabethP. HenskeandFrancisX. McCormack 5 AutoimmunePulmonaryAlveolarProteinosis...111 BruceC.

Trapnell,KohNakata,andYoshikazuInoue 6 MutationsinSurfactantProteinCandInterstitialLungDisease ...133 RalphJ.

PanosandJamesP. Bridges 7 HereditaryHaemorrhagicTelangiectasia ...167 ClaireShovlinandS.

PaulOh 8 Hermansky-Dr. SharonRounds,theeditorforthisserieswhoinvitedustowriteabookonrare lungdiseases,developedtheideaafterattendingthe2004Lymphangioleiomyomatosis (LAM)Foundationannualresearchmeeting.

Shewasakeynotespeakeratthatevent (duringhertenureasthepresidentoftheAmericanThoracicSociety)andwasw- nesstothepowerofpatientadvocacyandthemission-basedscienti ceffortthathad broughtthisrarediseaseofwomenfromobscuritytoclinicaltrialswithtargetedmol- ulartherapiesinunderadecade.

Theprogressinpulmonaryalveolarproteinosis(PAP), pulmonaryalveolarmicrolithiasis(PAM),inheriteddisordersofsurfactantmetabolism, and pulmonary arterial hypertension, to name a few, has been no less astounding. Advanceshavecomefromthemostsurprisingdirections;fruit iesforLAM,gen- ically engineered mice made for other purposes for PAP, and groundbreaking hi- densitySNP(single-nucleotidepolymorphism)analysesdoneonahandfuloffamilies forPAM.

Inmanycases,insightsintobiologygainedfromrarediseaseshaveinformed researchapproachesandtreatmentstrategiesformorecommondiseases;forexample, knowledgegainedfromthestudyofPAPabouttheroleofGM-CSFinthelunghas sparkedinterestintheuseofantiGM-CSFapproachestocontrolbothpulmonaryand extrapulmonaryin ammationinavarietyofdiseases.

The ndingthatinterstitiallung diseasedevelopsinfamilieswithcytotoxicmutationsinsurfactantproteinC(SP-C), agenewhichisexpressedonlyinalveolartypecells,hasunderscoredtheimportance oftheintegrityofthealveolarepitheliuminthepathogenesisofparenchymal brosis.

Opportunitiestoapproachlungdiseasepathogenesisfromthevantagepointofap- marymoleculardefectaregiftsfromnaturethatareuniquelyabundantamongtherare lungdisorders. WesalutetheNIHandtheNationalCenterforResearchResourcesfortheirvisionin facilitatingthetranslationofbasicresearchadvancesinrarelungdiseasesintoclinical realitythroughtheRareLungDiseaseConsortium,anetworkof13USandinter- tionalsitesthatiscurrentlyconductingclinicaltrialsandstudiesinLAM,alphaone antitrypsin de ciency, pediatric interstitial lung disease, and PAP.

It has been a rare privilegetoworkonsuchfascinatingdiseaseswithsuchcapableinvestigatorsfromall overtheworldoverthepast6years. v vi Preface Theformatforthisvolumeisunique. Mostchaptershavebeenauthoredbyacli- cianandabasicscientistwhoareexpertinthediseasetopicandunderlyingmolecular defect,respectively.

Theirchargewastofocusonthegeneticbasisandmolecularpat- genesisofdisease,animalmodels,clinicalfeatures,diagnosticapproach,conventional managementandtreatment,andfuturetherapeutictargetsanddirections.

Theintentwas nottoprovideabroadoverview,butrathertoshedlightonthemolecularmechanisms thatevoketheclinicalpresentationandengendertreatmentstrategiesforeachdisease.

Wehopethatthisapproachwillproveusefulforpulmonarycliniciansandscientists alike. Wethankourwives,Holly,Jean,andVicky,fortheirsupportandindulgencewith latenightemailsandwork- lledweekends,Dr. Roundsfortheinvitationtowritethe book,andalloftheauthorswhocontributed.

FrancisMcCormack,MD RalphPanos,MD BruceTrapnell,MD Contents Preface...v Contributors...ix 1 AClinicalApproachtoRareLungDiseases...1 RalphJ.

Panos 2 ClinicalTrialsforRareLungDiseases...31 JeffreyKrischer 3 IdiopathicandFamilialPulmonaryArterialHypertension ...39 JeanM.

Elwing,GailH. Deutsch,WilliamC. Nichols, andTimothyD. LeCras 4 Lymphangioleiomyomatosis...85 ElizabethP. HenskeandFrancisX. McCormack 5 AutoimmunePulmonaryAlveolarProteinosis...111 BruceC.

Trapnell,KohNakata,andYoshikazuInoue 6 MutationsinSurfactantProteinCandInterstitialLungDisease ...133 RalphJ.

PanosandJamesP. Bridges 7 HereditaryHaemorrhagicTelangiectasia ...167 ClaireShovlinandS.

PaulOh 8 Hermansky-Dr. SharonRounds,theeditorforthisserieswhoinvitedustowriteabookonrare lungdiseases,developedtheideaafterattendingthe2004Lymphangioleiomyomatosis (LAM)Foundationannualresearchmeeting. Shewasakeynotespeakeratthatevent (duringhertenureasthepresidentoftheAmericanThoracicSociety)andwasw- nesstothepowerofpatientadvocacyandthemission-basedscienti ceffortthathad broughtthisrarediseaseofwomenfromobscuritytoclinicaltrialswithtargetedmol- ulartherapiesinunderadecade.

Theprogressinpulmonaryalveolarproteinosis(PAP), pulmonaryalveolarmicrolithiasis(PAM),inheriteddisordersofsurfactantmetabolism, and pulmonary arterial hypertension, to name a few, has been no less astounding.

Advanceshavecomefromthemostsurprisingdirections;fruit iesforLAM,gen- ically engineered mice made for other purposes for PAP, and groundbreaking hi- densitySNP(single-nucleotidepolymorphism)analysesdoneonahandfuloffamilies forPAM.

Inmanycases,insightsintobiologygainedfromrarediseaseshaveinformed researchapproachesandtreatmentstrategiesformorecommondiseases;forexample, knowledgegainedfromthestudyofPAPabouttheroleofGM-CSFinthelunghas sparkedinterestintheuseofantiGM-CSFapproachestocontrolbothpulmonaryand extrapulmonaryin ammationinavarietyofdiseases. The ndingthatinterstitiallung diseasedevelopsinfamilieswithcytotoxicmutationsinsurfactantproteinC(SP-C), agenewhichisexpressedonlyinalveolartypecells,hasunderscoredtheimportance oftheintegrityofthealveolarepitheliuminthepathogenesisofparenchymal brosis.

Opportunitiestoapproachlungdiseasepathogenesisfromthevantagepointofap- marymoleculardefectaregiftsfromnaturethatareuniquelyabundantamongtherare lungdisorders.

WesalutetheNIHandtheNationalCenterforResearchResourcesfortheirvisionin facilitatingthetranslationofbasicresearchadvancesinrarelungdiseasesintoclinical realitythroughtheRareLungDiseaseConsortium,anetworkof13USandinter- tionalsitesthatiscurrentlyconductingclinicaltrialsandstudiesinLAM,alphaone antitrypsin de ciency, pediatric interstitial lung disease, and PAP.

It has been a rare privilegetoworkonsuchfascinatingdiseaseswithsuchcapableinvestigatorsfromall overtheworldoverthepast6years. v vi Preface Theformatforthisvolumeisunique. Mostchaptershavebeenauthoredbyacli- cianandabasicscientistwhoareexpertinthediseasetopicandunderlyingmolecular defect,respectively. Theirchargewastofocusonthegeneticbasisandmolecularpat- genesisofdisease,animalmodels,clinicalfeatures,diagnosticapproach,conventional managementandtreatment,andfuturetherapeutictargetsanddirections.

Theintentwas nottoprovideabroadoverview,butrathertoshedlightonthemolecularmechanisms thatevoketheclinicalpresentationandengendertreatmentstrategiesforeachdisease.

Wehopethatthisapproachwillproveusefulforpulmonarycliniciansandscientists alike.

Wethankourwives,Holly,Jean,andVicky,fortheirsupportandindulgencewith latenightemailsandwork- lledweekends,Dr. Roundsfortheinvitationtowritethe book,andalloftheauthorswhocontributed.

FrancisMcCormack,MD RalphPanos,MD BruceTrapnell,MD Contents Preface...v Contributors...ix 1 AClinicalApproachtoRareLungDiseases...1 RalphJ.

Panos 2 ClinicalTrialsforRareLungDiseases...31 JeffreyKrischer 3 IdiopathicandFamilialPulmonaryArterialHypertension ...39 JeanM.

Elwing,GailH. Deutsch,WilliamC. Nichols, andTimothyD. LeCras 4 Lymphangioleiomyomatosis...85 ElizabethP. HenskeandFrancisX. McCormack 5 AutoimmunePulmonaryAlveolarProteinosis...111 BruceC.

Trapnell,KohNakata,andYoshikazuInoue 6 MutationsinSurfactantProteinCandInterstitialLungDisease ...133 RalphJ. PanosandJamesP. Bridges 7 HereditaryHaemorrhagicTelangiectasia ...167 ClaireShovlinandS.

PaulOh 8 Hermansky-PudlakSyndrome...189 LisaR. YoungandWilliamA. Gahl 9 Alpha-1AntitrypsinDe ciency ...209 CharlieStrangeandSabinaJanciauskiene vii viii Contents 10 TheMarfanSyndrome ...225 AmareshNathandEnidR.

Neptune 11 SurfactantDe ciencyDisorders:SP-BandABCA3...247 LawrenceM.

Nogee 12 PulmonaryCapillaryHemangiomatosis ...267 EdwardD.

Chan,KathrynChmura,andAndrewSullivan 13 Anti-glomerularBasementDisease:Goodpasture'sSyndrome...275 GangadharTaduri,RaghuKalluri,andRalphJ.

Panos 14 PrimaryCiliaryDyskinesia...293 MichaelR. Knowles,HildaMetjian,MargaretW. Leigh, andMaimoonaA. Zariwala 15 PulmonaryAlveolarMicrolithiasis...325 KoichiHagiwara,TakeshiJohkoh,andTeruoTachibana 16 CysticFibrosis...339 AndreM.

Cantin 17 PulmonaryLangerhans'CellHistiocytosis-Advances intheUnderstandingofaTrueDendriticCellLungDisease...369 RobertVassallo 18 Sarcoidosis...389 RalphJ.

PanosandAndrewP. Fontenot 19 SclerodermaLungDisease...409 BrentW. Kinder SubjectIndex...421 Contributors JamesP. Bridges,PhD, DepartmentofNeonatologyinPulmonaryBiology,Children's HospitalMedicalCenter,Cincinnati,OH AndreM. Cantin,MD, Department of Medicine, University of Sherbrooke, Sherbrooke,QC,Canada EdwardD.

Chan,MD, DepartmentofInternalMedicine,NationalJewishMedicaland ResearchCenter,Denver,CO KathrynChmura,BA, Department of Medicine, University of Colorado School of Medicine,Denver,CO GailH.