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

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

Research output: Contribution to journalArticlepeer-review

9 Scopus citations


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.

Original languageEnglish
Article number2560
JournalNature Communications
Issue number1
StatePublished - Dec 2023


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