Bronchopulmonary dysplasia (BPD) is a severe lung disease in preterm infants, the abnormal proliferate and differentiate ability of type II epithelial cells (AEC II) is the key to the pathological basis of BPD. Mechanisms regarding abnormal AEC II in BPD remain unclear. The present work investigated the role and mechanisms of invariant natural killer T (iNKT) cells in lung disorder in BPD using public datasets, clinical samples, a hyperoxia-induced BPD mouse model and AEC II-iNKT cells transwell co-culture system. Firstly, we found that the NKT cells development factor IL-15 increased over time in patients with BPD in public databases, and clinically collected peripheral blood NKT cells in patients with BPD were increased. Subsequently, the percentage of iNKT cells increased in hyperoxia group compared with normoxia group, with the highest at P7, accompanied by increased activation with abnormal lung development. The administration of anti-CD1d neutralizing antibody to inhibit iNKT cells could alleviate the abnormal lung development of hyperoxia group mice, while α-GalCer administration could aggravate lung injury in hyperoxia group mice, and adoptive transfer of iNKT cells could aggravate the abnormal lung development in hyperoxia group mice. In addition, to further verify the role of iNKT cells on AEC II, AEC II-iNKT cells co-culture system was established. The presence of iNKT cells could aggravate the abnormal expression of SP-C and T1α under hyperoxia. Meanwhile, RNA-seq analysis showed that ferroptosis-related genes were highly expressed in AEC II co-cultured with iNKT cells under hyperoxia. We further validated the effect of the presence of iNKT cells under hyperoxia environment on AEC II ferroptosis levels, suggested that iNKT cells promote AEC II ferroptosis under hyperoxia, accompanied by decreased expression of SP-C and T1α. Our study found that the recruitment of iNKT cells in the lung may be an important cause of alveolarization disorder in BPD.

中文翻译：

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iNKT 细胞的过度激活加重了支气管肺发育不良小鼠的肺损伤


支气管肺发育不良 （BPD） 是一种严重的早产儿肺部疾病，II 型上皮细胞 （AEC II） 的异常增殖和分化能力是 BPD 病理基础的关键。BPD 中 AEC II 异常的机制仍不清楚。本研究使用公共数据集、临床样本、高氧诱导的 BPD 小鼠模型和 AEC II-iNKT 细胞 transwell 共培养系统，研究了不变自然杀伤 T （iNKT） 细胞在 BPD 肺部疾病中的作用和机制。首先，我们发现公共数据库中 BPD 患者的 NKT 细胞发育因子 IL-15 随着时间的推移而增加，临床收集的 BPD 患者外周血 NKT 细胞增加。随后，与常氧组相比，高氧组 iNKT 细胞的百分比增加，在 P7 最高，伴有激活增加伴肺发育异常。给予抗 CD1d 中和抗体抑制 iNKT 细胞可减轻高氧组小鼠肺部发育异常，而 α-GalCer 给药可加重高氧组小鼠肺损伤，过继转移 iNKT 细胞可加重高氧组小鼠肺部发育异常。此外，为了进一步验证 iNKT 细胞对 AEC II 的作用，建立了 AEC II-iNKT 细胞共培养系统。iNKT 细胞的存在可加重高氧下 SP-C 和 T1α 的异常表达。同时，RNA-seq 分析显示，在高氧条件下与 iNKT 细胞共培养的 AEC II 中，铁死亡相关基因高表达。 我们进一步验证了高氧环境下 iNKT 细胞的存在对 AEC II 铁死亡水平的影响，表明 iNKT 细胞在高氧下促进 AEC II 铁死亡，伴有 SP-C 和 T1α 表达降低。我们的研究发现，肺部 iNKT 细胞的募集可能是 BPD 肺泡化障碍的重要原因。