Adenovirus-mediated decorin gene transfer prevents TGF-beta-induced inhibition of lung morphogenesis.
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.
Zhao
J
J
Center for Craniofacial Molecular Biology, Department of Surgery, Childrens Hospital Los Angeles Research Institute, University of Southern California School of Dentistry, Los Angeles 90033, USA.
Sime
P J
PJ
Bringas
P
P
Gauldie
J
J
Warburton
D
D
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D019925:Cyclin A / Q000235:genetics; D058575:Decorin; D004622:Embryo, Mammalian / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D005314:Embryonic and Fetal Development / Q000187:drug effects / Q000502:physiology; D004848:Epithelium / Q000196:embryology; D016326:Extracellular Matrix Proteins; D015870:Gene Expression / Q000187:drug effects; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D008168:Lung / Q000196:embryology*; D051379:Mice; D008845:Microinjections; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D009924:Organ Culture Techniques; D011509:Proteoglycans / Q000235:genetics* / Q000378:metabolism; D011510:Proteolipids / Q000235:genetics; D011663:Pulmonary Surfactants / Q000235:genetics; D014132:Trachea; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors* / Q000494:pharmacology
D019925:Cyclin A; C546878:DCN protein, human; C546879:Dcn protein, mouse; D058575:Decorin; D016326:Extracellular Matrix Proteins; D016376:Oligonucleotides, Antisense; D011509:Proteoglycans; D011510:Proteolipids; D011663:Pulmonary Surfactants; D016212:Transforming Growth Factor beta