Transforming growth factor-β signaling mediates hypoxia-induced pulmonary arterial remodeling and inhibition of alveolar development in newborn mouse lung
Transforming growth factor-β signaling mediates hypoxia-induced pulmonary arterial remodeling and inhibition of alveolar development in newborn mouse lung
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DOI：
10.1152/ajplung.00534.2007
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发表时间：
2008-07-01
影响因子：
4.9
通讯作者：
Chen, Yiu-Fai
中科院分区：
文献类型：
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作者：
Ambalavanan, Namasivayam;Nicola, Teodora;Chen, Yiu-Fai
缺氧可引起新生儿肺动脉重构（PAR）异常和肺泡发育抑制（IAD）。转化生长因子（TGF）-β是肺发育和损伤修复的重要调节因子。我们检验了抑制TGF-β信号传导减弱缺氧诱导的PAR和IAD的假设。将TGF-β II型受体（DNTGF β RII）的可诱导显性阴性突变小鼠和非转基因野生型（WT）小鼠从出生到14天暴露于缺氧（12%O-2）或空气中。DNTGF β RII的表达由从出生起每天腹腔内给予20 μ g/g硫酸锌诱导。评估PAR、IAD、细胞增殖和细胞外基质（ECM）蛋白的表达。在WT小鼠中，缺氧导致肺动脉阻力变厚，肌化程度更高，肺泡化受损，同时伴有活性TGF-β和磷酸化Smad 2的增加。与WT对照小鼠和未给予硫酸锌的DNTGF β RII小鼠相比，给予硫酸锌的DNTGF β RII小鼠中缺氧诱导的PAR和IAD大大减弱。在给予硫酸锌的DNTGF β RII小鼠中，缺氧暴露对肺动脉细胞增殖和肺ECM蛋白的刺激作用被消除。这些数据支持的结论，TGF-β在缺氧诱导的肺血管适应和IAD的新生动物模型中起着重要作用。
Hypoxia causes abnormal neonatal pulmonary artery remodeling (PAR) and inhibition of alveolar development (IAD). Transforming growth factor TGF)-beta is an important regulator of lung development and repair from injury. We tested the hypothesis that inhibition of TGF-beta signaling attenuates hypoxia-induced PAR and IAD. Mice with an inducible dominant-negative mutation of the TGF-beta type II receptor (DNTGF beta RII) and nontransgenic wild-type (WT) mice were exposed to hypoxia (12% O-2) or air from birth to 14 days of age. Expression of DNTGF beta RII was induced by 20 mu g/g ZnSO4 given intraperitoneally daily from birth. PAR, IAD, cell proliferation, and expression of extracellular matrix (ECM) proteins were assessed. In WT mice, hypoxia led to thicker, more muscularized resistance pulmonary arteries and impaired alveolarization, accompanied by increases in active TGF-beta and phosphorylated Smad2. Hypoxia-induced PAR and IAD were greatly attenuated in DNTGF beta RII mice given ZnSO4 compared with WT control mice and DNTGF beta RII mice not given ZnSO4. The stimulatory effects of hypoxic exposure on pulmonary arterial cell proliferation and lung ECM proteins were abrogated in DNTGF beta RII mice given ZnSO4. These data support the conclusion that TGF-beta plays an important role in hypoxia-induced pulmonary vascular adaptation and IAD in the newborn animal model.