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Dysregulation of TGF-beta activation contributes to pathogenesis in Marfan syndrome

Enid R Neptune1, Pamela A Frischmeyer, Dan E Arking

  • 1Division of Pulmonary and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.

Nature Genetics
|February 25, 2003
PubMed

Insights

Marfan syndrome causes lung emphysema due to fibrillin-1 deficiency. Targeting transforming growth factor-beta (TGF-beta) in early development can prevent lung abnormalities and emphysema.

Area of Science:

  • Connective tissue biology
  • Genetics and disease pathogenesis
  • Pulmonary medicine

Background:

  • Marfan syndrome, an inherited connective tissue disorder, is linked to fibrillin-1 mutations.
  • A subset of patients exhibit lung emphysema and pneumothorax, suggesting a genetic basis for lung disease.
  • Fibrillin-1 is a key component of extracellular microfibrils, influencing tissue structure and growth factor bioavailability.

Purpose of the Study:

  • To investigate the role of fibrillin-1 deficiency in the development of lung emphysema.
  • To elucidate the molecular mechanisms underlying Marfan syndrome-associated lung disease.
  • To explore potential therapeutic targets for preventing Marfan syndrome-related pulmonary complications.

Main Methods:

  • Analysis of lung phenotype in fibrillin-1-deficient mice, a model for Marfan syndrome.
  • Assessment of alveolar development and lung structure in postnatal and aged mice.
  • Investigation of transforming growth factor-beta (TGF-beta) activation, signaling, and apoptosis in the developing lung.
  • Experimental intervention using perinatal TGF-beta antagonism.

Main Results:

  • Fibrillin-1 deficiency leads to impaired distal alveolar septation in early development.
  • Aged fibrillin-1-deficient mice develop destructive emphysema, mimicking human disease.
  • Dysregulated TGF-beta activation and signaling, causing apoptosis, were observed in the developing lungs of deficient mice.
  • Perinatal TGF-beta antagonism reduced apoptosis and rescued alveolar septation.

Conclusions:

  • Early developmental defects in fibrillin-1-deficient mice predispose to late-onset emphysema.
  • Matrix sequestration of cytokines like TGF-beta is critical for regulated activation and signaling.
  • Perturbation of this matrix-cytokine interaction contributes to Marfan syndrome-associated lung disease pathogenesis.
  • Targeting TGF-beta signaling during development offers a potential strategy to prevent lung abnormalities in Marfan syndrome.

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