Hyperoxia (HO)-induced lung injury contributes to bronchopulmonary dysplasia (BPD) in preterm newborns. Intractable wheezing seen in BPD survivors is associated with airway remodeling (AWRM). Sphingosine kinase 1 (SPHK1)/ Sphingosine-1-phosphate (S1P) signaling promotes HO-mediated neonatal BPD; however, its role in the sequela of AWRM is not known. We noted an increased concentration of S1P in tracheal aspirates of neonatal infants with severe BPD, and earlier, demonstrated that Sphk1^-/- mice showed protection against HO-induced BPD. Role of SPHK1/S1P in promoting AWRM following exposure of neonates to HO was investigated in a murine model. Therapy using PF543, the specific SPHK1 inhibitor, during neonatal HO reduced alveolar simplification followed by reduced AWRM in adult mice. This was associated with reduced airway hyperreactivity (AHR) to intravenous methacholine. Neonatal HO exposure was associated with increased expression of SPHK1 in lung tissue of adult mice, which was reduced with PF543 therapy in the neonatal stage. This was accompanied by amelioration of HO-induced reduction of E-cadherin in airway epithelium. This may be suggestive of arrested partial epithelial mesenchymal transition (EMT) induced by HO. In vitro studies using human primary airway epithelial cells (HAEpCs) showed that SPHK1 inhibition or deletion restored HO-induced reduction in E-cadherin and reduced formation of mitochondrial reactive oxygen species (mtROS). Blocking mtROS with MitoTempo attenuated HO-induced partial EMT of HAEpCs. These results collectively support a therapeutic role for PF543 in preventing HO-induced BPD in neonates and the long-term sequela of AWRM, thus conferring a long-term protection resulting in improved lung development and function.

中文翻译：

---

PF543（一种鞘氨醇激酶 1 抑制剂）的新生儿治疗可改善支气管肺发育不良小鼠模型中高氧诱导的气道重塑。

高氧 (H2O) 诱导的肺损伤导致早产儿支气管肺发育不良 (BPD)。BPD 幸存者中出现的顽固性喘息与气道重塑 (AWRM) 相关。鞘氨醇激酶 1 (SPHK1)/1-磷酸鞘氨醇 (S1P) 信号促进 H2O 介导的新生儿 BPD；然而，它在 AWRM 后遗症中的作用尚不清楚。我们注意到在患有严重 BPD 的新生儿的气管抽吸物中 S1P 的浓度增加，并且更早地证明了 Sphk1 ^-/-小鼠表现出对 H2O 诱导的 BPD 的保护。在小鼠模型中研究了 SPHK1/S1P 在新生儿暴露于 H2O 后促进 AWRM 中的作用。在新生儿 H2O 期间使用 PF543（特定的 SPHK1 抑制剂）进行治疗可降低成年小鼠的肺泡简化，随后降低 AWRM。这与静脉注射乙酰甲胆碱的气道高反应性 (AHR) 降低有关。新生儿 H2O 暴露与成年小鼠肺组织中 SPHK1 的表达增加有关，而在新生儿阶段用 PF543 治疗会降低这种表达。这伴随着 H2O 诱导的气道上皮中 E-钙粘蛋白减少的改善。这可能暗示 H2O 诱导的部分上皮间质转化 (EMT) 停滞。使用人原代气道上皮细胞 (HAEpCs) 的体外研究表明，SPHK1 抑制或缺失恢复了 H2O 诱导的 E-钙粘蛋白减少，并减少了线粒体活性氧 (mtROS) 的形成。用 MitoTempo 阻断 mtROS 减弱了 H2O 诱导的 HAEpCs 部分 EMT。这些结果共同支持 PF543 在预防新生儿 H2O 诱导的 BPD 和 AWRM 的长期后遗症方面的治疗作用，从而提供长期保护，从而改善肺发育和功能。