Department of Pediatrics, Division of Neonatology, Batchelor Children's Research Institute, University of Miami Miller School of Medicine, Miami, FL 33101, USA.
Am J Respir Cell Mol Biol. 2013 May;48(5):578-88. doi: 10.1165/rcmb.2012-0383OC.
The pathological hallmarks of bronchopulmonary dysplasia (BPD), a chronic lung disease of premature infants, include inflammation, arrested alveolarization, and dysregulated angiogenesis. Severe BPD is often complicated by pulmonary hypertension (PH) that significantly increases morbidity and mortality. Glycogen synthase kinase (GSK)-3β plays a pivotal role in embryonic development, cell proliferation and survival, and inflammation by modulating multiple signaling pathways, particularly the nuclear transcription factor, NF-κB, and Wnt/β-catenin pathways. Aberrant GSK-3β signaling is linked to BPD. We tested the hypothesis that inhibition of GSK-3β is beneficial in preventing hyperoxia-induced neonatal lung injury, an experimental model of BPD. Newborn rats were exposed to normoxia or hyperoxia (90% oxygen), and received daily intraperitoneal injections of placebo (DMSO) or SB216763, a specific pharmacological inhibitor of GSK-3β, for 14 days. Hyperoxia exposure in the presence of the placebo increased GSK-3β phosphorylation, which was correlated with increased inflammation, decreased alveolarization and angiogenesis, and increased pulmonary vascular remodeling and PH. However, treatment with SB216763 decreased phosphorylation of NF-κB p65, expression of monocyte chemotactic protein-1, and lung inflammation during hyperoxia. Furthermore, treatment with the GSK-3β inhibitor also improved alveolarization and angiogenesis, and decreased pulmonary vascular remodeling and PH. These data indicate that GSK-3β signaling plays an important role in the pathogenesis of hyperoxia-induced neonatal lung injury, and that inhibition of GSK-3β is beneficial in preventing inflammation and protecting alveolar and vascular structures during hyperoxia. Thus, targeting GSK-3β signaling may offer a novel strategy to prevent and treat preterm infants with BPD.
支气管肺发育不良（BPD）是一种早产儿的慢性肺部疾病，其病理特征包括炎症、肺泡化停滞和血管生成失调。严重的 BPD 常伴有肺动脉高压（PH），这显著增加了发病率和死亡率。糖原合酶激酶（GSK）-3β 通过调节多个信号通路，特别是核转录因子 NF-κB 和 Wnt/β-连环蛋白通路，在胚胎发育、细胞增殖和存活以及炎症中发挥关键作用。异常的 GSK-3β 信号与 BPD 有关。我们假设抑制 GSK-3β 可预防高氧诱导的新生鼠肺损伤，这是 BPD 的一种实验模型。新生大鼠暴露于常氧或高氧（90%氧气）中，并接受每日腹腔注射安慰剂（DMSO）或 GSK-3β 的特异性药理学抑制剂 SB216763，共 14 天。在存在安慰剂的高氧暴露下，GSK-3β 磷酸化增加，这与炎症增加、肺泡化和血管生成减少以及肺血管重塑和 PH 增加有关。然而，用 SB216763 治疗可降低 NF-κB p65 的磷酸化、单核细胞趋化蛋白-1 的表达以及高氧时的肺部炎症。此外，GSK-3β 抑制剂的治疗还改善了肺泡化和血管生成，并减少了肺血管重塑和 PH。这些数据表明，GSK-3β 信号在高氧诱导的新生鼠肺损伤的发病机制中起重要作用，抑制 GSK-3β 可在高氧期间预防炎症并保护肺泡和血管结构。因此，靶向 GSK-3β 信号可能为预防和治疗患有 BPD 的早产儿提供一种新策略。
