Inhibiting NF-κB in the developing lung disrupts angiogenesis and alveolarization
Inhibiting NF-κB in the developing lung disrupts angiogenesis and alveolarization
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DOI：
10.1152/ajplung.00230.2011
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发表时间：
2012-05-01
影响因子：
4.9
通讯作者：
Alvira, Cristina M.
中科院分区：
文献类型：
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作者：
Iosef, Cristiana;Alastalo, Tero-Pekka;Alvira, Cristina M.
[10] Iosef C，Alastalo TP，Hou Y，Chen C，亚当斯ES，Lyu SC，Cornfield DN，Alvira CM.在发育中的肺中抑制NF-κ B破坏血管生成和肺泡化。美国生理学杂志肺细胞分子生理学302：L1023-L1036，2012年。首次发表于2012年2月24日; doi：10.1152/ajplung.00230.2011。支气管肺发育不良（BPD）是一种发生于婴儿期的慢性肺部疾病，其特征是肺泡发育受阻。由血管内皮生长因子（VEGF）途径介导的肺血管生成对于肺泡化是必不可少的。然而，转录调节介导的肺血管生成仍然是未知的。我们以前证明，NF-κ B B，一种传统上与炎症相关的转录因子，在新生儿肺中起着独特的保护作用。因此，我们假设组成性NF-κ B活性对出生后肺发育是必不可少的。阻断6日龄新生小鼠NF-κ B活性可诱导与BPD相似的肺泡简化，并显著降低肺毛细血管密度。确定这种作用机制的研究发现，与成人相比，新生儿肺和原代肺内皮细胞（PEC）中的NF-κ B组成性更强。此外，用药理学抑制剂或RNA干扰抑制新生儿PEC中的组成性NF-κ B活性阻断PEC存活，降低增殖，并损害体外血管生成。最后，通过染色质免疫沉淀，发现NF-κ B B是新生儿肺血管系统中血管生成介质VEGF受体2的直接调节剂。总之，我们的数据确定了NF-κ B在促进发育中的肺的生理性血管生成和肺泡化中的全新作用。我们的数据表明，NF-κ B信号传导的中断可能有助于BPD的发病机制，并且NF-κ B的增强可能代表一种可行的治疗策略，以促进以血管生成受损为标志的肺部疾病的肺生长和再生。
Iosef C, Alastalo TP, Hou Y, Chen C, Adams ES, Lyu SC, Cornfield DN, Alvira CM. Inhibiting NF-kappa B in the developing lung disrupts angiogenesis and alveolarization. Am J Physiol Lung Cell Mol Physiol 302: L1023-L1036, 2012. First published February 24, 2012; doi:10.1152/ajplung.00230.2011.-Bronchopulmonary dysplasia (BPD), a chronic lung disease of infancy, is characterized by arrested alveolar development. Pulmonary angiogenesis, mediated by the vascular endothelial growth factor (VEGF) pathway, is essential for alveolarization. However, the transcriptional regulators mediating pulmonary angiogenesis remain unknown. We previously demonstrated that NF-kappa B, a transcription factor traditionally associated with inflammation, plays a unique protective role in the neonatal lung. Therefore, we hypothesized that constitutive NF-kappa B activity is essential for postnatal lung development. Blocking NF-kappa B activity in 6-day-old neonatal mice induced the alveolar simplification similar to that observed in BPD and significantly reduced pulmonary capillary density. Studies to determine the mechanism responsible for this effect identified greater constitutive NF-kappa B in neonatal lung and in primary pulmonary endothelial cells (PEC) compared with adult. Moreover, inhibiting constitutive NF-kappa B activity in the neonatal PEC with either pharmacological inhibitors or RNA interference blocked PEC survival, decreased proliferation, and impaired in vitro angiogenesis. Finally, by chromatin immunoprecipitation, NF-kappa B was found to be a direct regulator of the angiogenic mediator, VEGF-receptor-2, in the neonatal pulmonary vasculature. Taken together, our data identify an entirely novel role for NF-kappa B in promoting physiological angiogenesis and alveolarization in the developing lung. Our data suggest that disruption of NF-kappa B signaling may contribute to the pathogenesis of BPD and that enhancement of NF-kappa B may represent a viable therapeutic strategy to promote lung growth and regeneration in pulmonary diseases marked by impaired angiogenesis.