Division of Critical Care Medicine, Department of Pediatrics, Stanford University School of Medicine, 300 Pasteur Dr., Stanford, CA 94305-5208, USA.
Am J Physiol Lung Cell Mol Physiol. 2012 May 15;302(10):L1023-36. doi: 10.1152/ajplung.00230.2011. Epub 2012 Feb 24.
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-κB, a transcription factor traditionally associated with inflammation, plays a unique protective role in the neonatal lung. Therefore, we hypothesized that constitutive NF-κB activity is essential for postnatal lung development. Blocking NF-κB 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-κB in neonatal lung and in primary pulmonary endothelial cells (PEC) compared with adult. Moreover, inhibiting constitutive NF-κB 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-κB 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-κB in promoting physiological angiogenesis and alveolarization in the developing lung. Our data suggest that disruption of NF-κB signaling may contribute to the pathogenesis of BPD and that enhancement of NF-κB may represent a viable therapeutic strategy to promote lung growth and regeneration in pulmonary diseases marked by impaired angiogenesis.
支气管肺发育不良(BPD)是一种婴儿期慢性肺部疾病,其特征是肺泡发育停滞。由血管内皮生长因子(VEGF)通路介导的肺血管生成对于肺泡化至关重要。然而,介导肺血管生成的转录调节剂尚不清楚。我们之前的研究表明,NF-κB 是一种传统上与炎症相关的转录因子,在新生儿肺中发挥独特的保护作用。因此,我们假设组成型 NF-κB 活性对于出生后肺发育是必需的。在 6 天大的新生小鼠中阻断 NF-κB 活性会诱导肺泡简化,类似于在 BPD 中观察到的情况,并显著降低肺毛细血管密度。确定这种作用的机制的研究表明,与成人相比,新生肺和原代肺内皮细胞(PEC)中的 NF-κB 活性更大。此外,用药理学抑制剂或 RNA 干扰抑制新生 PEC 中的组成型 NF-κB 活性会阻断 PEC 的存活、减少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-κB 是新生儿肺血管中血管生成介质 VEGF 受体-2 的直接调节剂。总之,我们的数据确定了 NF-κB 在促进发育中肺的生理血管生成和肺泡化中的全新作用。我们的数据表明,NF-κB 信号的破坏可能导致 BPD 的发病机制,而增强 NF-κB 可能代表促进血管生成受损的肺部疾病中肺生长和再生的可行治疗策略。