Lung endothelial cells regulate pulmonary fibrosis through FOXF1/R-Ras signaling.
Lung endothelial cells regulate pulmonary fibrosis through FOXF1/R-Ras signaling.
复制标题
肺内皮细胞通过FOXF 1/R-Ras信号调节肺纤维化。
DOI：
10.1038/s41467-023-38177-2
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发表时间：
2023-05-04
影响因子：
16.6
通讯作者：
Kalin, Tanya V. V.
中科院分区：
文献类型：
--
作者：
Bian, Fenghua;Lan, Ying-Wei;Zhao, Shuyang;Deng, Zicheng;Shukla, Samriddhi;Acharya, Anusha;Donovan, Johnny;Le, Tien;Milewski, David;Bacchetta, Matthew;Hozain, Ahmed Emad;Tipograf, Yuliya;Chen, Ya-Wen;Xu, Yan;Shi, Donglu;Kalinichenko, Vladimir V. V.;Kalin, Tanya V. V.
肺纤维化是由肺修复失调引起的，涉及多种细胞类型。内皮细胞（EC）在肺纤维化中的作用尚不清楚。通过单细胞rna测序，我们确定了参与肺纤维化的内皮转录因子，包括FOXF1、SMAD6、ETV6和LEF1。重点研究FOXF1，我们发现在人特发性肺纤维化（IPF）和小鼠博莱霉素损伤肺中，EC中FOXF1降低。小鼠内皮特异性Foxf1抑制增加胶原沉积，促进肺部炎症，并损害R-Ras信号。在体外，foxf1缺陷EC通过分泌IL-6、TNFα、CCL2和CXCL1促进人肺成纤维细胞增殖、侵袭和活化，刺激巨噬细胞迁移。FOXF1通过直接转录激活Rras基因启动子抑制TNFα和CCL2。转基因过表达或内皮特异性纳米颗粒递送Foxf1 cDNA可减少博莱霉素损伤小鼠的肺纤维化。FOXF1 cDNA的纳米颗粒递送可以考虑用于IPF的未来治疗。肺纤维化是由肺修复失调引起的，但内皮细胞（EC）在纤维化中的作用尚不清楚。在这里，作者表明，EC中的FOXF1/R-Ras信号传导抑制促纤维化介质，ec特异性纳米颗粒FOXF1基因治疗减少小鼠肺纤维化。
Pulmonary fibrosis results from dysregulated lung repair and involves multiple cell types. The role of endothelial cells (EC) in lung fibrosis is poorly understood. Using single cell RNA-sequencing we identified endothelial transcription factors involved in lung fibrogenesis, including FOXF1, SMAD6, ETV6 and LEF1. Focusing on FOXF1, we found that FOXF1 is decreased in EC within human idiopathic pulmonary fibrosis (IPF) and mouse bleomycin-injured lungs. Endothelial-specific Foxf1 inhibition in mice increased collagen depositions, promoted lung inflammation, and impaired R-Ras signaling. In vitro, FOXF1-deficient EC increased proliferation, invasion and activation of human lung fibroblasts, and stimulated macrophage migration by secreting IL-6, TNFα, CCL2 and CXCL1. FOXF1 inhibited TNFα and CCL2 through direct transcriptional activation of Rras gene promoter. Transgenic overexpression or endothelial-specific nanoparticle delivery of Foxf1 cDNA decreased pulmonary fibrosis in bleomycin-injured mice. Nanoparticle delivery of FOXF1 cDNA can be considered for future therapies in IPF. Pulmonary fibrosis results from dysregulated lung repair, but the role of endothelial cells (EC) in fibrosis is unclear. Here, the authors show that FOXF1/R-Ras signalling in EC inhibits profibrotic mediators and that ECspecific nanoparticle FOXF1 gene therapy decreases lung fibrosis in mice.
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