Lung alveolar epithelium is composed of alveolar type I (AT1) and type II (AT2) cells. AT1 cells mediate gas exchange, whereas AT2 cells act as progenitor cells to repair injured alveoli. Lung microvascular endothelial cells (LMVECs) play a crucial but still poorly understood role in regulating alveolar repair. Here, we studied the role of the LMVEC-derived bioactive lipid sphingosine-1-phosphate (S1P) in promoting alveolar repair using mice with endothelial-specific deletion of sphingosine kinase 1 (Sphk1), the key enzyme promoting S1P generation. These mutant lungs developed airspace-enlargement lesions and exhibited a reduced number of AT1 cells after Pseudomonas-aeruginosa-induced lung injury. We demonstrated that S1P released by LMVECs acted via its receptor, S1PR2, on AT2 cells and induced nuclear translocation of yes-associated protein (YAP), a regulator of AT2 to AT1 transition. Thus, angiocrine S1P released after injury acts via the S1PR2-YAP signaling axis on AT2 cells to promote AT2 to AT1 differentiation required for alveolar repair.

肺泡上皮由肺泡 I 型 (AT1) 和 II 型 (AT2) 细胞组成。 AT1 细胞介导气体交换，而 AT2 细胞则充当祖细胞来修复受损的肺泡。肺微血管内皮细胞（LMVEC）在调节肺泡修复中发挥着至关重要但仍知之甚少的作用。在这里，我们使用内皮特异性删除鞘氨醇激酶 1 ( Sphk1 )（促进 S1P 生成的关键酶）的小鼠，研究了 LMVEC 衍生的生物活性脂质 1-磷酸鞘氨醇 (S1P) 在促进肺泡修复中的作用。这些突变的肺在铜绿假单胞菌引起的肺损伤后出现了空腔扩大的病变，并表现出 AT1 细胞数量减少。我们证明，LMVEC 释放的 S1P 通过其受体 S1PR2 作用于 AT2 细胞，并诱导 yes 相关蛋白 (YAP) 的核转位，YAP 是 AT2 向 AT1 转变的调节因子。因此，损伤后释放的血管分泌素S1P通过S1PR2-YAP信号轴作用于AT2细胞，促进肺泡修复所需的AT2向AT1分化。