Dysregulation of TGF-β activation

nature genetics • volume 33 • march 2003 407 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 syndrome4. 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-β (TGF-β) activation and signaling, resulting in apoptosis in the developing lung. Perinatal antagonism of TGF-β 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. Mice homozygous with respect to a centrally deleted Fbn1 allele (Fbn1tm1Rmz, herein called Fbn1mg∆; ref. 4) die at postnatal day (PD) 7–10 from aortic dissection and rupture, recapitulating the vascular phenotype of Marfan syndrome4. At PD9, we observed a graded increase in distal airspace caliber in Fbn1+/mg∆ and Fbn1mg∆/mg∆ mice compared with their wild-type (Fbn1+/+) littermates (Fig. 1a,b). Fbn1mg∆/mg∆ mice had rare secondary alveolar septae (Fig. 1c), but their proximal airway caliber and vasculature appeared grossly normal. There was no inflammation or overt tissue damage. Calculation of mean linear intercepts (Lm; ref. 5), a measure of the distance between alveolar structures, at PD1, PD4 and PD9 showed progressive distal airspace enlargement in the mutant mice, apparent from PD1 (Fig. 1a,b). Ratios of lung weight to body weight at PD5 were consistent in mice of all three genotypes (data not shown), arguing against overt lung hypoplasia. Thus, the early lung phenotype associated with deficiency in fibrillin-1 is most consistent with a