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血管分泌鞘氨醇 1-磷酸通过激活肺泡 II 型细胞中的 S1PR2-YAP 信号轴对于肺修复至关重要。

Angiocrine Sphingosine-1-Phosphate Activation of S1PR2-YAP Signaling Axis in Alveolar Type II Cells Is Essential for Lung Repair.

机构信息

Department of Pharmacology and Regenerative Medicine, University of Illinois College of Medicine, Chicago, IL 60612, USA.

Department of Bioengineering, University of Illinois at Chicago, Chicago, IL 60607, USA.

出版信息

Cell Rep. 2020 Jun 30;31(13):107828. doi: 10.1016/j.celrep.2020.107828.

DOI:10.1016/j.celrep.2020.107828
PMID:32610129
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7371431/
Abstract

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.

摘要

肺肺泡上皮由肺泡 I 型 (AT1) 和 II 型 (AT2) 细胞组成。AT1 细胞介导气体交换，而 AT2 细胞作为祖细胞来修复受损的肺泡。肺微血管内皮细胞 (LMVEC) 在调节肺泡修复中起着至关重要但仍知之甚少的作用。在这里，我们使用内皮细胞特异性敲除鞘氨醇激酶 1 (Sphk1) 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，Sphk1 是促进 S1P 生成的关键酶。这些突变肺在铜绿假单胞菌诱导的肺损伤后发展出气腔扩大病变，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) 的核易位，YAP 是 AT2 向 AT1 转化的调节因子。因此，损伤后释放的血管旁 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。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b050/7371431/a0d23464211e/nihms-1608489-f0008.jpg
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