Targeting Glycogen Synthase Kinase-3β to Prevent Hyperoxia-Induced Lung Injury in Neonatal Rats
Targeting Glycogen Synthase Kinase-3β to Prevent Hyperoxia-Induced Lung Injury in Neonatal Rats
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DOI：
10.1165/rcmb.2012-0383oc
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发表时间：
2013-05-01
影响因子：
6.4
通讯作者：
Wu, Shu
中科院分区：
文献类型：
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作者：
Hummler, Stefanie C.;Rong, Min;Wu, Shu
支气管肺发育不良（BPD）是早产儿的一种慢性肺部疾病，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通常并发肺动脉高压（PH），显著增加发病率和死亡率。糖原合成酶激酶（GSK）-3 β通过调节多种信号通路，特别是核转录因子、NF-κ B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GSK-3 β信号传导与BPD相关。我们测试了抑制GSK-3 β有益于预防高氧诱导的新生儿肺损伤（BPD的实验模型）的假设。将新生大鼠暴露于常氧或高氧（90%氧气），每天腹腔注射安慰剂（DMSO）或GSK-3 β的特异性药理学抑制剂SB 216763，持续14天。在安慰剂存在下的高氧暴露增加GSK-3 β磷酸化，这与炎症增加、肺泡化和血管生成减少、肺血管重塑和PH增加相关。然而，SB 216763治疗降低了NF-κ B B p65磷酸化、单核细胞趋化蛋白-1表达和高氧期间的肺部炎症。此外，用GSK-3 β抑制剂治疗还改善肺泡化和血管生成，并降低肺血管重塑和PH。这些数据表明GSK-3 β信号传导在高氧诱导的新生儿肺损伤的发病机制中起重要作用，并且GSK-3 β的抑制有利于在高氧期间预防炎症和保护肺泡和血管结构。因此，靶向GSK-3 β信号可能为预防和治疗BPD早产儿提供一种新的策略。
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)-3 beta plays a pivotal role in embryonic development, cell proliferation and survival, and inflammation by modulating multiple signaling pathways, particularly the nuclear transcription factor, NF-kappa B, and Wnt/beta-catenin pathways. Aberrant GSK-3 beta signaling is linked to BPD. We tested the hypothesis that inhibition of GSK-3 beta 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-3 beta, for 14 days. Hyperoxia exposure in the presence of the placebo increased GSK-3 beta 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-kappa B p65, expression of monocyte chemotactic protein-1, and lung inflammation during hyperoxia. Furthermore, treatment with the GSK-3 beta inhibitor also improved alveolarization and angiogenesis, and decreased pulmonary vascular remodeling and PH. These data indicate that GSK-3 beta signaling plays an important role in the pathogenesis of hyperoxia-induced neonatal lung injury, and that inhibition of GSK-3 beta is beneficial in preventing inflammation and protecting alveolar and vascular structures during hyperoxia. Thus, targeting GSK-3 beta signaling may offer a novel strategy to prevent and treat preterm infants with BPD.