Premature infants often require oxygen supplementation, which can elicit bronchopulmonary dysplasia (BPD) and lead to mitochondrial dysfunction. Mitochondria play important roles in lung development, in both normal metabolism and apoptosis. Enhancing our comprehension of the underlying mechanisms in BPD development can facilitate the effective treatments. Plasma samples from BPD and non-BPD infants were collected at 36 weeks post-menstrual age and used for metabolomic analysis. Based on hyperoxia-induced animal and cell models, changes in mitophagy and apoptosis were evaluated following treatment with itaconic acid (ITA). Finally, the mechanism of action of ITA in lung development was comprehensively demonstrated through rescue strategies and administration of corresponding inhibitors. An imbalance in the tricarboxylic acid (TCA) cycle significantly affected lung development, with ITA serving as a significant metabolic marker for the outcomes of lung development. ITA improved the morphological changes in BPD rats, promoted SP-C expression, and inhibited the degree of alveolar type II epithelial cells (AEC II) apoptosis. Mechanistically, ITA mainly promotes the nuclear translocation of transcription factor EB (TFEB) to facilitate dysfunctional mitochondrial clearance and reduces apoptosis in AEC II cells by regulating autophagic flux. The metabolic imbalance in the TCA cycle is closely related to lung development. ITA can improve lung development by regulating autophagic flux and promote the nuclear translocation of TFEB, implying its potential therapeutic utility in the treatment of BPD.

中文翻译：

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衣康酸调节 TFEB 介导的自噬通量可减轻高氧诱导的支气管肺发育不良


早产儿通常需要补充氧气，这会引起支气管肺发育不良（BPD）并导致线粒体功能障碍。线粒体在肺发育、正常代谢和细胞凋亡中发挥着重要作用。加强我们对 BPD 发展的潜在机制的理解可以促进有效的治疗。在月经后 36 周时收集 BPD 和非 BPD 婴儿的血浆样本，用于代谢组学分析。基于高氧诱导的动物和细胞模型，评估了衣康酸（ITA）治疗后线粒体自噬和细胞凋亡的变化。最后，通过救援策略和相应抑制剂的给药，全面论证了ITA在肺发育中的作用机制。三羧酸 (TCA) 循环的不平衡显着影响肺部发育，而 ITA 是肺部发育结果的重要代谢标志物。 ITA改善BPD大鼠的形态学变化，促进SP-C表达，抑制肺泡II型上皮细胞（AEC II）凋亡程度。从机制上讲，ITA 主要促进转录因子 EB (TFEB) 的核转位，以促进功能失调的线粒体清除，并通过调节自噬通量减少 AEC II 细胞的凋亡。 TCA循环代谢失衡与肺发育密切相关。 ITA可以通过调节自噬通量来改善肺部发育并促进TFEB的核转位，这意味着其在BPD的治疗中具有潜在的治疗作用。