Journal Article

Lung endothelial cells regulate pulmonary fibrosis through FOXF1/R-Ras signaling

Deng, Zicheng, Tipograf, Yuliya, Hozain, Ahmed Emad, Le, Tien, Shukla, Samriddhi, Bacchetta, Matthew, Kalin, Tanya V., Lan, Ying-Wei, Kalinichenko, Vladimir V., Chen, Ya-Wen, Xu, Yan, Shi, Donglu, Bian, Fenghua, Zhao, Shuyang, Acharya, Anusha, Donovan, Johnny, Milewski, David

2023

Overview

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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13 / 13/51 / 14 / 14/19 / 38 / 38/109 / 45 / 45/91 / 631/337/572 / 64 / 64/60 / 692/699/1785 / Animals / Bleomycin / Bleomycin - toxicity / Collagen / DNA, Complementary - metabolism / Endothelial cells / Endothelial Cells - metabolism / Fibroblasts / Fibroblasts - metabolism / Fibrosis / Forkhead Transcription Factors - metabolism / Foxf1 gene / Gene sequencing / Gene therapy / Humanities and Social Sciences / Humans / Idiopathic Pulmonary Fibrosis - chemically induced / Idiopathic Pulmonary Fibrosis - genetics / Idiopathic Pulmonary Fibrosis - metabolism / Interleukin 6 / Leukocyte migration / Lung - metabolism / Lung diseases / Lungs / Macrophages / Mice / Monocyte chemoattractant protein 1 / multidisciplinary / Nanoparticles / Pulmonary fibrosis / Science / Science (multidisciplinary) / Signaling / Transcription activation / Transcription factors / Tumor Necrosis Factor-alpha - metabolism / Tumor necrosis factor-α