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 and Tanya V. Kalin ()
Additional contact information
Fenghua Bian: the Perinatal Institute of Cincinnati Children’s Research Foundation
Ying-Wei Lan: the Perinatal Institute of Cincinnati Children’s Research Foundation
Shuyang Zhao: the Perinatal Institute of Cincinnati Children’s Research Foundation
Zicheng Deng: the Perinatal Institute of Cincinnati Children’s Research Foundation
Samriddhi Shukla: the Perinatal Institute of Cincinnati Children’s Research Foundation
Anusha Acharya: the Perinatal Institute of Cincinnati Children’s Research Foundation
Johnny Donovan: the Perinatal Institute of Cincinnati Children’s Research Foundation
Tien Le: the Perinatal Institute of Cincinnati Children’s Research Foundation
David Milewski: the Perinatal Institute of Cincinnati Children’s Research Foundation
Matthew Bacchetta: Vanderbilt University Medical Center
Ahmed Emad Hozain: State University of New York Downstate Medical Center
Yuliya Tipograf: State University of New York Downstate Medical Center
Ya-Wen Chen: Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai
Yan Xu: the Perinatal Institute of Cincinnati Children’s Research Foundation
Donglu Shi: College of Engineering and Applied Science, University of Cincinnati
Vladimir V. Kalinichenko: the Perinatal Institute of Cincinnati Children’s Research Foundation
Tanya V. Kalin: the Perinatal Institute of Cincinnati Children’s Research Foundation

Nature Communications, 2023, vol. 14, issue 1, 1-20

Abstract: Abstract 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.

Date: 2023
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DOI: 10.1038/s41467-023-38177-2

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