Conditional overexpression of connective tissue growth factor disrupts postnatal lung development.
Conditional overexpression of connective tissue growth factor disrupts postnatal lung development.
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DOI：
10.1165/rcmb.2009-0068oc
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发表时间：
2010-05
影响因子：
6.4
通讯作者：
Shu Wu;Astrid Platteau;Shaoyi Chen;G. McNamara;J. Whitsett;E. Bancalari
中科院分区：
文献类型：
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作者：
Shu Wu;Astrid Platteau;Shaoyi Chen;G. McNamara;J. Whitsett;E. Bancalari
结缔组织生长因子(CTGF)是一个新兴的即刻早期基因产物家族的成员，它在发育、分化和组织修复过程中协调复杂的生物学过程。CTGF的过度表达与高潮气量机械通气和新生儿肺内氧气暴露有关。然而，CTGF在出生后肺发育和重塑中的作用还不是很清楚。在本研究中，建立了多西环素诱导的呼吸道上皮细胞CTGF过表达的双转基因小鼠模型。出生后1-14天CTGF过度表达导致肺泡间隔增厚，继发间隔形成减少。这与肌成纤维细胞分化增加和肺泡间隔中无组织的弹性纤维沉积有关。CTGF的过表达也减少了肺泡毛细血管网络的形成。在双转基因肺中，α-平滑肌肌动蛋白表达增加，胶原沉积增加，支气管/细支气管区和血管周围区显著增厚。此外，CTGF的过表达增加了整合素连接蛋白激酶的表达，激活了其下游信号转导靶点Akt，并增加了纤维连接蛋白的mRNA表达。这些数据表明，在肺泡发育的关键时期，CTGF的过度表达扰乱了肺泡的形成和毛细血管的形成，并诱导了纤维化。这些组织学改变与支气管肺发育不良婴儿的肺组织学改变相似。
Connective tissue growth factor (CTGF) is a member of an emerging family of immediate-early gene products that coordinates complex biological processes during development, differentiation, and tissue repair. Overexpression of CTGF is associated with mechanical ventilation with high tidal volume and oxygen exposure in newborn lungs. However, the role of CTGF in postnatal lung development and remodeling is not well understood. In the present study, a double-transgenic mouse model was generated with doxycycline-inducible overexpression of CTGF in respiratory epithelial cells. Overexpression of CTGF from Postnatal Days 1-14 resulted in thicker alveolar septa and decreased secondary septal formation. This is correlated with increased myofibroblast differentiation and disorganized elastic fiber deposition in alveolar septa. Overexpression of CTGF also decreased alveolar capillary network formation. There were increased alpha-smooth muscle actin expression and collagen deposition, and dramatic thickening in the peribronchial/peribronchiolar and perivascular regions in the double-transgenic lungs. Furthermore, overexpression of CTGF increased integrin-linked kinase expression, activated its downstream signaling target, Akt, as well as increased mRNA expression of fibronectin. These data demonstrate that overexpression of CTGF disrupts alveologenesis and capillary formation, and induces fibrosis during the critical period of alveolar development. These histologic changes are similar to those observed in lungs of infants with bronchopulmonary dysplasia.