Adenovirus-mediated decorin gene transfer prevents TGF-beta-induced inhibition of lung morphogenesis

Am J Physiol. 1999 Aug;277(2):L412-22. doi: 10.1152/ajplung.1999.277.2.L412.

Abstract

Excessive transforming growth factor (TGF)-beta signaling has been implicated in pulmonary hypoplasia associated with bronchopulmonary dysplasia, a chronic lung disease of human prematurity featuring pulmonary fibrosis. This implies that inhibitors of TGF-beta could be useful therapeutic agents. Because exogenous TGF-beta ligands are known to inhibit lung branching morphogenesis and cytodifferentiation in mouse embryonic lungs in ex vivo culture, we examined the capacity of a naturally occurring inhibitor of TGF-beta activity, the proteoglycan decorin, to overcome the inhibitory effects of exogenous TGF-beta. Intratracheal microinjection of a recombinant adenovirus containing decorin cDNA resulted in overexpression of the exogenous decorin gene in airway epithelium. Although exogenous TGF-beta efficiently decreased epithelial lung branching morphogenesis in control cultures, TGF-beta-induced inhibition of lung growth was abolished after epithelial transfer of the decorin gene. Additionally, exogenous TGF-beta-induced antiproliferative effects as well as the downregulation of surfactant protein C were abrogated by decorin in cultured embryonic lungs. Moreover, lung branching inhibition by TGF-beta could be restored by the addition of decorin antisense oligodeoxynucleotides in culture, indicating that decorin is both specifically and directly involved in suppressing TGF-beta-mediated negative regulation of lung morphogenesis. Our findings suggest that decorin can antagonize bioactive TGF-beta during lung growth and differentiation, establishing the rationale for decorin as a candidate therapeutic approach to ameliorate excessive levels of TGF-beta signaling in the developing lung.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adenoviridae / genetics*
  • Animals
  • Cyclin A / genetics
  • Decorin
  • Embryo, Mammalian / drug effects
  • Embryo, Mammalian / metabolism
  • Embryo, Mammalian / physiology
  • Embryonic and Fetal Development / drug effects
  • Embryonic and Fetal Development / physiology
  • Epithelium / embryology
  • Extracellular Matrix Proteins
  • Gene Expression / drug effects
  • Gene Transfer Techniques*
  • Genetic Vectors
  • Lung / embryology*
  • Mice
  • Microinjections
  • Oligonucleotides, Antisense / pharmacology
  • Organ Culture Techniques
  • Proteoglycans / genetics*
  • Proteoglycans / metabolism
  • Proteolipids / genetics
  • Pulmonary Surfactants / genetics
  • Trachea
  • Transforming Growth Factor beta / antagonists & inhibitors*
  • Transforming Growth Factor beta / pharmacology

Substances

  • Cyclin A
  • DCN protein, human
  • Dcn protein, mouse
  • Decorin
  • Extracellular Matrix Proteins
  • Oligonucleotides, Antisense
  • Proteoglycans
  • Proteolipids
  • Pulmonary Surfactants
  • Transforming Growth Factor beta