FOXF1 maintains endothelial barrier function and prevents edema after lung injury
FOXF1 maintains endothelial barrier function and prevents edema after lung injury
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DOI：
10.1126/scisignal.aad1899
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发表时间：
2016-04-19
影响因子：
7.3
通讯作者：
Kalinichenko, Vladimir V.
中科院分区：
文献类型：
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作者：
Cai, Yuqi;Bolte, Craig;Kalinichenko, Vladimir V.
多种信号通路、结构蛋白和转录因子参与内皮屏障功能的调节。叉头蛋白FOXF 1是胚胎肺发育的关键转录调节因子，我们使用条件性敲除方法来研究FOXF 1在成人肺稳态、损伤和修复中的作用。他莫昔芬调节的成年小鼠（Pdgfb-iCreER/Foxf 1（-/-））内皮细胞中两个Foxf 1等位基因的缺失引起肺部炎症和水肿，导致呼吸功能不全和死亡。单个Foxf 1等位基因的缺失使杂合子Pdgfb-iCreER/Foxf 1（+/-）小鼠更容易发生急性肺损伤。急性肺损伤患者肺内皮细胞FOXF 1丰度降低。纯合FOXF 1缺失的肺内皮细胞的基因表达分析表明，对粘附连接的维持和调节至关重要的基因表达减少。FOXF 1在体外和体内的敲除破坏了粘附连接，增强了肺内皮通透性，并增加了1-磷酸鞘氨醇受体1（S1 PR 1）的mRNA和蛋白质的丰度，S1 PR 1是内皮屏障功能的关键调节因子。染色质免疫沉淀和荧光素酶报告分析表明，FOXF 1直接结合并诱导S1 pr 1启动子的转录活性。对受损的Pdgfb-iCreER/Foxf 1（+/-）小鼠进行S1 P药理学给药可恢复内皮屏障功能，减少肺水肿，并改善存活率。因此，FOXF 1通过激活S1 P/S1 PR 1信号通路增强内皮屏障功能，部分地促进正常的肺稳态和修复。
Multiple signaling pathways, structural proteins, and transcription factors are involved in the regulation of endothelial barrier function. The forkhead protein FOXF1 is a key transcriptional regulator of embryonic lung development, and we used a conditional knockout approach to examine the role of FOXF1 in adult lung homeostasis, injury, and repair. Tamoxifen-regulated deletion of both Foxf1 alleles in endothelial cells of adult mice (Pdgfb-iCreER/Foxf1(-/-)) caused lung inflammation and edema, leading to respiratory insufficiency and death. Deletion of a single Foxf1 allele made heterozygous Pdgfb-iCreER/Foxf1(+/-) mice more susceptible to acute lung injury. FOXF1 abundance was decreased in pulmonary endothelial cells of human patients with acute lung injury. Gene expression analysis of pulmonary endothelial cells with homozygous FOXF1 deletion indicated reduced expression of genes critical for maintenance and regulation of adherens junctions. FOXF1 knockdown in vitro and in vivo disrupted adherens junctions, enhanced lung endothelial permeability, and increased the abundance of the mRNA and protein for sphingosine 1-phosphate receptor 1 (S1PR1), a key regulator of endothelial barrier function. Chromatin immunoprecipitation and luciferase reporter assays demonstrated that FOXF1 directly bound to and induced the transcriptional activity of the S1pr1 promoter. Pharmacological administration of S1P to injured Pdgfb-iCreER/Foxf1(+/-) mice restored endothelial barrier function, decreased lung edema, and improved survival. Thus, FOXF1 promotes normal lung homeostasis and repair, in part, by enhancing endothelial barrier function through activation of the S1P/S1PR1 signaling pathway.