Humana Molecular Basis of Pulmonary Disease: Insights from Rare Lung Disorders (Respiratory Medicine)

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. . . . . . . . . . . . . .