Pulmonary fibrosis is a relentlessly progressive and often fatal disease with a paucity of available therapies. Genetic evidence implicates disordered epithelial repair, which is normally achieved by the differentiation of small cuboidal alveolar type 2 (AT2) cells into large, flattened alveolar type 1 (AT1) cells as an initiating event in pulmonary fibrosis pathogenesis. Using models of pulmonary fibrosis in young adult and old mice and a model of adult alveologenesis after pneumonectomy, we show that administration of ISRIB, a small molecule that restores protein translation by EIF2B during activation of the integrated stress response (ISR), accelerated the differentiation of AT2 into AT1 cells. Accelerated epithelial repair reduced the recruitment of profibrotic monocyte-derived alveolar macrophages and ameliorated lung fibrosis. These findings suggest a dysfunctional role for the ISR in regeneration of the alveolar epithelium after injury with implications for therapy.

肺纤维化是一种无情的进展性疾病，通常是致命的疾病，缺乏可用的治疗方法。遗传证据表明上皮修复紊乱，这通常是通过将小立方肺泡 2 型 (AT2) 细胞分化为大的扁平肺泡 1 型 (AT1) 细胞作为肺纤维化发病机制的起始事件来实现的。使用年轻成年和老年小鼠的肺纤维化模型以及肺切除术后的成年肺泡发生模型，我们表明 ISRIB 是一种在激活综合应激反应 (ISR) 期间通过 EIF2B 恢复蛋白质翻译的小分子，可加速分化AT2 进入 AT1 细胞。加速上皮修复减少了促纤维化单核细胞衍生的肺泡巨噬细胞的募集并改善了肺纤维化。