Bronchopulmonary dysplasia (BPD) is a common and serious complication associated with preterm birth. The pathogenesis of BPD is incompletely understood, and there is an unmet clinical need for effective treatments. The role of autophagy as a potential cytoprotective mechanism in BPD remains to be fully elucidated. In the present study, we investigated the role and regulation of autophagy in experimental models of BPD. Regulation and cellular distribution of autophagic activity during postnatal lung development and in neonatal hyperoxia-induced lung injury (nHILI) were assessed in the autophagy reporter transgenic GFP-LC3 (GFP–microtubule-associated protein 1A/1B-light chain 3) mouse model. Autophagic activity and its regulation were also examined in a baboon model of BPD. The role of autophagy in nHILI was determined by assessing lung morphometry, injury, and inflammation in autophagy-deficient Beclin 1 heterozygous knockout mice (Becn1^+/−). Autophagic activity was induced during alveolarization in control murine lungs and localized primarily to alveolar type II cells and macrophages. Hyperoxia exposure of neonatal murine lungs and BPD in baboon lungs resulted in impaired autophagic activity in association with insufficient AMPK (5′-AMP–activated protein kinase) and increased mTORC1 (mTOR complex 1) activation. Becn1^+/− lungs displayed impaired alveolarization, increased alveolar septal thickness, greater neutrophil accumulation, and increased IL-1β concentrations when exposed to nHILI. Becn1^+/− alveolar macrophages isolated from nHILI-exposed mice displayed increased expression of proinflammatory genes. In conclusion, basal autophagy is induced during alveolarization and disrupted during progression of nHILI in mice and BPD in baboons. Becn1^+/− mice are more susceptible to nHILI, suggesting that preservation of autophagic activity may be an effective protective strategy in BPD.

支气管肺发育不良 (BPD) 是与早产相关的常见且严重的并发症。BPD 的发病机制尚不完全清楚，对有效治疗的临床需求尚未得到满足。自噬作为 BPD 中潜在细胞保护机制的作用仍有待充分阐明。在本研究中，我们研究了自噬在 BPD 实验模型中的作用和调节。在自噬报告基因转基因GFP -LC3中评估了出生后肺发育和新生儿高氧诱导肺损伤 (nHILI) 中自噬活性的调节和细胞分布（GFP-微管相关蛋白 1A/1B-轻链 3）小鼠模型。自噬活性及其调节也在 BPD 狒狒模型中进行了检查。自噬在 nHILI 中的作用是通过评估自噬缺陷Beclin 1杂合敲除小鼠 ( Becn1 ^+/- ) 的肺形态测定、损伤和炎症来确定的。自噬活动在对照鼠肺的肺泡化过程中被诱导，主要定位于肺泡 II 型细胞和巨噬细胞。新生鼠肺的高氧暴露和狒狒肺中的 BPD 导致自噬活性受损，这与 AMPK（5'-AMP 活化蛋白激酶）不足和 mTORC1（mTOR 复合物 1）激活增加有关。Becn1 ^+/-当暴露于 nHILI 时，肺显示出肺泡化受损、肺泡间隔厚度增加、中性粒细胞积聚更多以及 IL-1β 浓度增加。从暴露于 nHILI 的小鼠中分离的Becn1 ^+/-肺泡巨噬细胞表现出促炎基因的表达增加。总之，基础自噬在肺泡化过程中被诱导，在小鼠 nHILI 和狒狒 BPD 进展过程中被破坏。Becn1 ^+/-小鼠对 nHILI 更敏感，表明自噬活性的保持可能是 BPD 的有效保护策略。