title: Dysregulation of TGF-beta activation contributes to pathogenesis in Marfan syndrome.
abstract: Marfan syndrome is an autosomal dominant disorder of connective tissue caused by mutations in fibrillin-1 (encoded by FBN1 in humans and Fbn1 in mice), a matrix component of extracellular microfibrils. A distinct subgroup of individuals with Marfan syndrome have distal airspace enlargement, historically described as emphysema, which frequently results in spontaneous lung rupture (pneumothorax; refs. 1-3). To investigate the pathogenesis of genetically imposed emphysema, we analyzed the lung phenotype of mice deficient in fibrillin-1, an accepted model of Marfan syndrome. Lung abnormalities are evident in the immediate postnatal period and manifest as a developmental impairment of distal alveolar septation. Aged mice deficient in fibrillin-1 develop destructive emphysema consistent with the view that early developmental perturbations can predispose to late-onset, seemingly acquired phenotypes. We show that mice deficient in fibrillin-1 have marked dysregulation of transforming growth factor-beta (TGF-beta) activation and signaling, resulting in apoptosis in the developing lung. Perinatal antagonism of TGF-beta attenuates apoptosis and rescues alveolar septation in vivo. These data indicate that matrix sequestration of cytokines is crucial to their regulated activation and signaling and that perturbation of this function can contribute to the pathogenesis of disease.
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
authors.forename: Enid R
authors.initials: ER
authors.lastname: Neptune
authors.forename: Pamela A
authors.initials: PA
authors.lastname: Frischmeyer
authors.forename: Dan E
authors.initials: DE
authors.lastname: Arking
authors.forename: Loretha
authors.initials: L
authors.lastname: Myers
authors.forename: Tracie E
authors.initials: TE
authors.lastname: Bunton
authors.forename: Barbara
authors.initials: B
authors.lastname: Gayraud
authors.forename: Francesco
authors.initials: F
authors.lastname: Ramirez
authors.forename: Lynn Y
authors.initials: LY
authors.lastname: Sakai
authors.forename: Harry C
authors.initials: HC
authors.lastname: Dietz
mesh_terms: D000818:Animals; D017209:Apoptosis; D004195:Disease Models, Animal; D004646:Emphysema / Q000209:etiology / Q000235:genetics / Q000276:immunology / Q000473:pathology; D005109:Extracellular Matrix / Q000276:immunology; D000071838:Fibrillin-1; D000071837:Fibrillins; D006801:Humans; D008168:Lung / Q000473:pathology; D008382:Marfan Syndrome / Q000209:etiology* / Q000235:genetics / Q000276:immunology / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008840:Microfilament Proteins / Q000172:deficiency / Q000235:genetics; D009500:Neutralization Tests; D010641:Phenotype; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000378:metabolism*; D054392:Adipokines
chemical_list: D000071838:Fibrillin-1; D000071837:Fibrillins; D008840:Microfilament Proteins; D016212:Transforming Growth Factor beta; C000605722:FBN1 protein, human; D054392:Adipokines; C000605724:Fbn1 protein, mouse