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

Excessive transforming growth factor (TGF)-beta signaling has been implicat ed in pulmonary hypoplasia associated with bronchopulmonary dysplasia, a ch ronic lung disease of human prematurity featuring pulmonary fibrosis. This implies that inhibitors of TGF-beta could be useful therapeutic agents. Bec ause exogenous TGF-beta ligands are known to inhibit lung branching morphog enesis and cytodifferentiation in mouse embryonic lungs in ex vivo culture, we examined the capacity of a naturally occurring inhibitor of TGF-beta ac tivity, the proteoglycan decorin, to overcome the inhibitory effects of exo genous TGF-beta. Intratracheal microinjection of a recombinant adenovirus c ontaining decorin cDNA resulted in overexpression of the exogenous decorin gene in airway epithelium. Although exogenous TGF-beta efficiently decrease d epithelial lung branching morphogenesis in control cultures, TGF-beta-ind uced inhibition of lung growth was abolished after epithelial transfer of t he decorin gene; Additionally, exogenous TGF-beta-induced antiproliferative effects as well as the downregulation of surfactant protein C were abrogat ed by decorin in cultured embryonic lungs. Moreover, lung branching inhibit ion by TGF-beta could be restored by the addition of decorin antisense olig odeoxynucleotides 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 bi oactive TGF-beta during lung growth and differentiation, establishing the r ationale for decorin as a candidate therapeutic approach to ameliorate exce ssive levels of TGF-beta signaling in the developing lung.