Zhao J, Sime P J, Bringas P, Gauldie J, Warburton D
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.
Am J Physiol. 1999 Aug;277(2):L412-22. doi: 10.1152/ajplung.1999.277.2.L412.
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.
过度的转化生长因子（TGF）-β信号传导与支气管肺发育不良相关的肺发育不全有关，支气管肺发育不良是一种以肺纤维化为特征的人类早产慢性肺部疾病。这意味着TGF-β抑制剂可能是有用的治疗药物。由于已知外源性TGF-β配体在体外培养中可抑制小鼠胚胎肺中的肺分支形态发生和细胞分化，我们研究了一种天然存在的TGF-β活性抑制剂，即蛋白聚糖核心蛋白聚糖，克服外源性TGF-β抑制作用的能力。气管内微量注射含有核心蛋白聚糖cDNA的重组腺病毒导致气道上皮中外源性核心蛋白聚糖基因的过表达。虽然外源性TGF-β在对照培养物中有效地降低了上皮肺分支形态发生，但在核心蛋白聚糖基因上皮转移后，TGF-β诱导的肺生长抑制被消除。此外，在培养的胚胎肺中，核心蛋白聚糖消除了外源性TGF-β诱导的抗增殖作用以及表面活性蛋白C的下调。此外，通过在培养物中添加核心蛋白聚糖反义寡脱氧核苷酸可以恢复TGF-β对肺分支的抑制作用，这表明核心蛋白聚糖既特异性又直接参与抑制TGF-β介导的肺形态发生负调控。我们的研究结果表明，核心蛋白聚糖可以在肺生长和分化过程中拮抗生物活性TGF-β，为核心蛋白聚糖作为一种候选治疗方法以改善发育中肺中TGF-β信号传导的过量水平奠定了理论基础。
