Soluble TNF Mediates the Transition from Pulmonary Inflammation to Fibrosis 英文参考文献.docVIP

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Soluble TNF Mediates the Transition from Pulmonary Inflammation to Fibrosis 英文参考文献.doc

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Soluble TNF Mediates the Transition from Pulmonary Inflammation to Fibrosis 英文参考文献

SolubleTNFMediatestheTransitionfromPulmonary InflammationtoFibrosis NikosOikonomou1,VaggelisHarokopos1,JonathanZalevsky2,ChristosValavanis3,AnastasiaKotanidou4,DavidE.Szymkowski2 ,George Kollias1,VassilisAidinis1* 1Instituteof Immunology,Biomedical SciencesResearchCenter‘‘Alexander Fleming,’’ Athens,Greece,2Xencor,Inc., Monrovia, California, United StatesofAmerica,3MolecularPathologyUnit,DepartmentofPathology,MetaxaCancerHospital,Piraeus,Greece,4FirstDepartmentofCriticalCare, MedicalSchool,UniversityofAthens,Athens,Greece Background.Fibrosis,thereplacementoffunctionaltissuewithexcessivefibroustissue,canoccurinallthemaintissuesand organ systems, resulting in various pathological disorders. Idiopathic Pulmonary Fibrosis is a prototype fibrotic disease involvingabnormalwoundhealinginresponsetomultiplesitesofongoingalveolarepithelialinjury.Methodology/Principal Findings.TodeciphertheroleofTNFandTNF-mediatedinflammationinthedevelopmentoffibrosis,wehaveutilizedthe bleomycin-inducedanimalmodelofPulmonaryFibrosisandaseriesofgeneticallymodifiedmicelackingcomponentsofTNF signaling.TransmembraneTNFexpressionisshowntobesufficienttoelicitaninflammatoryresponse,butinadequateforthe transition to the fibrotic phase of the disease. Soluble TNF expression is shown to be crucial for lymphocyte recruitment, a prerequisite for TGF-b1 expression and the development of fibrotic lesions. Moreover, through a series of bone marrow transfers,thenecessaryTNFexpressionisshowntooriginatefromthenon-hematopoieticcompartmentfurtherlocalizedin apoptosing epithelialcells. Conclusions.TheseresultssuggestaprimarydetrimentalroleofsolubleTNFinthepathologic cascade,separatingitfromthebeneficialroleoftransmembraneTNF,andindicatetheimportanceofassessingtheefficacyof solubleTNFantagonistsinthetreatmentofIdiopathicPulmonaryFibrosis. Citation: Oikonomou N, Harokopos V, Zalevsky J, Valavanis C, Kotanidou A, et al (2006) Soluble TNF Mediates the Transition from Pulmonary InflammationtoFibrosis.PLoSONE1(1):e