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细胞则充当修复受损肺泡的祖细胞。肺微血管内皮细胞（LMVEC）在调节肺泡修复中起着至关重要的作用，但人们对此知之甚少。在这里，我们研究了LMVEC衍生的生物活性脂质鞘氨醇-1-磷酸（S1P）在使用内皮鞘特异性缺失鞘氨醇激酶1（Sphk1）的小鼠促进肺泡修复中的作用，鞘氨醇激酶1（Sphk1）是促进S1P产生的关键酶。在铜绿假单胞菌-铜绿假单胞菌之后，这些突变的肺部形成了空域扩大的病变，并表现出AT1细胞数量减少引起的肺损伤。我们证明了LMVECs释放的S1P通过其受体S1PR2作用于AT2细胞，并诱导了yes相关蛋白（YAP）（AT2向AT1过渡的调节剂）的核易位。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，从而促进肺泡修复所需的AT2分化为AT1。