Harbor-UCLA Medical Center, Department of Pediatrics, Torrance, CA, USA; The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USA.
The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USA.
Pulm Pharmacol Ther. 2023 Jun;80:102209. doi: 10.1016/j.pupt.2023.102209. Epub 2023 Mar 11.
Hyperoxia-induced lung injury is characterized by acute alveolar injury, disrupted epithelial-mesenchymal signaling, oxidative stress, and surfactant dysfunction, yet currently, there is no effective treatment. Although a combination of aerosolized pioglitazone (PGZ) and a synthetic lung surfactant (B-YL peptide, a surfactant protein B mimic) prevents hyperoxia-induced neonatal rat lung injury, whether it is also effective in preventing hyperoxia-induced adult lung injury is unknown.
Using adult mice lung explants, we characterize the effects of 24 and 72-h (h) exposure to hyperoxia on 1) perturbations in Wingless/Int (Wnt) and Transforming Growth Factor (TGF)-β signaling pathways, which are critical mediators of lung injury, 2) aberrations of lung homeostasis and injury repair pathways, and 3) whether these hyperoxia-induced aberrations can be blocked by concomitant treatment with PGZ and B-YL combination.
Our study reveals that hyperoxia exposure to adult mouse lung explants causes activation of Wnt (upregulation of key Wnt signaling intermediates β-catenin and LEF-1) and TGF-β (upregulation of key TGF-β signaling intermediates TGF-β type I receptor (ALK5) and SMAD 3) signaling pathways accompanied by an upregulation of myogenic proteins (calponin and fibronectin) and inflammatory cytokines (IL-6, IL-1β, and TNFα), and alterations in key endothelial (VEGF-A and its receptor FLT-1, and PECAM-1) markers. All of these changes were largely mitigated by the PGZ + B-YL combination.
The effectiveness of the PGZ + B-YL combination in blocking hyperoxia-induced adult mice lung injury ex-vivo is promising to be an effective therapeutic approach for adult lung injury in vivo.
高氧诱导的肺损伤的特征是急性肺泡损伤、上皮-间充质信号转导中断、氧化应激和表面活性物质功能障碍，但目前尚无有效的治疗方法。虽然联合应用雾化吡格列酮（PGZ）和合成肺表面活性剂（B-YL 肽，一种表面活性蛋白 B 模拟物）可预防新生大鼠高氧诱导的肺损伤，但它是否也能有效预防成人高氧诱导的肺损伤尚不清楚。
我们使用成年小鼠肺组织，研究了高氧暴露 24 和 72 小时（h）对以下方面的影响：1）Wingless/Int（Wnt）和转化生长因子（TGF）-β信号通路的改变，这些通路是肺损伤的关键介质；2）肺内稳态和损伤修复通路的改变；3）这些高氧诱导的改变是否可以通过同时使用 PGZ 和 B-YL 联合治疗来阻断。
我们的研究表明，高氧暴露于成年小鼠肺组织会导致 Wnt（关键 Wnt 信号转导中间物β-连环蛋白和 LEF-1 的上调）和 TGF-β（关键 TGF-β信号转导中间物 TGF-βI 型受体（ALK5）和 SMAD3 的上调）信号通路的激活，同时伴有肌球蛋白蛋白（钙调蛋白和纤维连接蛋白）和炎症细胞因子（IL-6、IL-1β和 TNFα）的上调，以及关键内皮（VEGF-A 及其受体 FLT-1 和 PECAM-1）标志物的改变。所有这些变化在很大程度上都被 PGZ+B-YL 联合治疗所缓解。
PGZ+B-YL 联合治疗在阻止高氧诱导的成年小鼠肺损伤的体外有效性表明，它可能是一种有效的体内成人肺损伤治疗方法。
