Autophagy is a protective cellular mechanism in response to stress conditions. However, whether autophagy is required for maintenance of the alveolar epithelium is unknown. Here, we report that the loss of autophagy-related 5 (Atg5) in AT2 cells worsened bleomycin-induced lung injury. Mechanistically, during bleomycin injury, autophagy downregulated lipid metabolism but upregulated glucose metabolism in AT2 cells for alveolar repair. Chemical blockade of fatty acid synthesis promoted organoid growth of AT2 cells and counteracted the effects of autophagy loss on bleomycin injury. However, genetic loss of glucose transporter 1, interference with glycolysis, or interference with the pentose phosphate pathway reduced the proliferation of AT2 cells. Inhibition of glucose metabolism exacerbated the effects of bleomycin injury. Failure of autophagy generated additional hydrogen peroxide, which reduced AT2 cell proliferation. These data highlight an essential role for autophagy in reprogramming the metabolism of alveolar progenitor cells to meet energy needs for alveolar epithelial regeneration.

自噬是对压力条件的一种保护性细胞机制。然而，未知是否需要自噬来维持肺泡上皮细胞。在这里，我们报告说，AT2细胞中自噬相关5（Atg5）的丧失使博来霉素诱导的肺损伤恶化。机械上，在博来霉素损伤期间，自噬下调AT2细胞中的脂质代谢，但上调葡萄糖代谢，以修复肺泡。脂肪酸合成的化学阻断促进AT2细胞的类器官生长，并抵消自噬损失对博来霉素损伤的影响。但是，葡萄糖转运蛋白1，干扰糖酵解或磷酸戊糖途径的遗传损失降低了AT2细胞的增殖。葡萄糖代谢的抑制加剧了博来霉素损伤的作用。自噬失败会产生额外的过氧化氢，从而降低AT2细胞的增殖。这些数据突出了自噬在重新编程肺泡祖细胞的代谢以满足肺泡上皮再生的能量需求方面的重要作用。