CTGF disrupts alveolarization and induces pulmonary hypertension in neonatal mice: implication in the pathogenesis of severe bronchopulmonary dysplasia
CTGF disrupts alveolarization and induces pulmonary hypertension in neonatal mice: implication in the pathogenesis of severe bronchopulmonary dysplasia
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DOI：
10.1152/ajplung.00270.2010
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发表时间：
2011-03-01
影响因子：
4.9
通讯作者：
Wu, Shu
中科院分区：
文献类型：
--
作者：
Chen, Shaoyi;Rong, Min;Wu, Shu
陈S，荣M，普拉特A，赫雷D，史密斯H，鲁伊斯P，惠特塞特J，班卡拉里E，吴S. CTGF破坏肺泡形成并诱导新生小鼠肺动脉高压：在严重支气管肺发育不良发病机制中的意义美国生理学杂志肺细胞分子生理学300：L330-L340，2011年。首次发表于2011年1月14日; doi：10.1152/ajplung.00270.2010.-支气管肺发育不良（BPD）是与早产相关的最常见的长期肺部并发症之一，其病理学特征包括肺泡化停滞、异常血管生长和可变间质纤维化。严重的BPD通常并发肺动脉高压，其特征在于过度的肺血管重构和右心室肥大，这显著地导致这些婴儿的死亡率和发病率。结缔组织生长因子（CTGF）是一种多功能蛋白质，在组织发育和重塑过程中协调复杂的生物学过程。我们先前已经表明，在新生小鼠中，在Clara细胞分泌蛋白启动子的控制下，气道上皮中CTGF的条件性过表达导致BPD样结构。在这项研究中，我们已经产生了一个多西环素诱导的双转基因小鼠模型与CTGF在肺泡II型上皮细胞（AT II）的表面活性蛋白C启动子的控制下过表达。CTGF在新生小鼠中的过表达引起肺泡气隙和血管周围区域中的巨噬细胞和中性粒细胞浸润。CTGF过表达也显著降低肺泡化和血管发育。此外，CTGF的过度表达可诱导肺血管重构和肺动脉高压。最重要的是，我们还证明了这些病理变化与整合素连接激酶（ILK）/葡萄糖合成激酶-3 β（GSK-3 β）/β-连环蛋白信号转导的激活有关。这些数据表明，CTGF在AT II细胞中的过表达导致与在患有严重BPD的婴儿中观察到的肺病理学相似的肺病理学，并且ILK/GSK-3 β/β-连环蛋白信号传导可能在严重BPD的发病机制中起重要作用。
Chen S, Rong M, Platteau A, Hehre D, Smith H, Ruiz P, Whitsett J, Bancalari E, Wu S. CTGF disrupts alveolarization and induces pulmonary hypertension in neonatal mice: implication in the pathogenesis of severe bronchopulmonary dysplasia. Am J Physiol Lung Cell Mol Physiol 300: L330-L340, 2011. First published January 14, 2011; doi:10.1152/ajplung.00270.2010.-The pathological hallmarks of bronchopulmonary dysplasia (BPD), one of the most common long-term pulmonary complications associated with preterm birth, include arrested alveolarization, abnormal vascular growth, and variable interstitial fibrosis. Severe BPD is often complicated by pulmonary hypertension characterized by excessive pulmonary vascular remodeling and right ventricular hypertrophy that significantly contributes to the mortality and morbidity of these infants. Connective tissue growth factor (CTGF) is a multifunctional protein that coordinates complex biological processes during tissue development and remodeling. We have previously shown that conditional overexpression of CTGF in airway epithelium under the control of the Clara cell secretory protein promoter results in BPD-like architecture in neonatal mice. In this study, we have generated a doxycycline-inducible double transgenic mouse model with overexpression of CTGF in alveolar type II epithelial (AT II) cells under the control of the surfactant protein C promoter. Overexpression of CTGF in neonatal mice caused dramatic macrophage and neutrophil infiltration in alveolar air spaces and perivascular regions. Overexpression of CTGF also significantly decreased alveolarization and vascular development. Furthermore, overexpression of CTGF induced pulmonary vascular remodeling and pulmonary hypertension. Most importantly, we have also demonstrated that these pathological changes are associated with activation of integrin-linked kinase (ILK)/glucose synthesis kinase-3 beta (GSK-3 beta)/beta-catenin signaling. These data indicate that overexpression of CTGF in AT II cells results in lung pathology similar to those observed in infants with severe BPD and that ILK/GSK-3 beta/beta-catenin signaling may play an important role in the pathogenesis of severe BPD.