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Am J Physiol Lung Cell Mol Physiol 277: L412-L422, 1999;
1040-0605/99 $5.00
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Vol. 277, Issue 2, L412-L422, August 1999

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

Jingsong Zhao1, Patricia J. Sime2, Pablo Bringas Jr.1, Jack Gauldie2, and David Warburton1

1 Center for Craniofacial Molecular Biology, Departments of Surgery and Pediatrics, and Cell and Developmental Biology Program, Childrens Hospital Los Angeles Research Institute, University of Southern California Schools of Dentistry and Medicine, Los Angeles, California 90033; and 2 Molecular Virology and Immunology Program, Department of Pathology and Biology, Health Science Center, McMaster University, Hamilton, Ontario, Canada L8N 3Z5

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.

transforming growth factor-beta ; intratracheal microinjection; epithelium-specific gene transfer; recombinant adenovirus; competitive polymerase chain reaction; antisense oligodeoxynucleotide inhibition


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