Endothelial PPARδ Ablation Exacerbates Vascular Hyperpermeability via STAT1/CXCL10 Signaling in Acute Lung Injury

作者：Huiling Hong, Yalan Wu, Yangxian Li, Yumeng Han, Xiaoyun Cao, Vivian Wei Yan Wu, Thomas Ting Hei Chan, Jingying Zhou, Qin Cao, Kathy O. Lui, Chun Kwok Wong, Zhiyu Dai, Xiao Yu Tian · 发表于：Circulation Research · 年份：2025 · DOI：10.1161/circresaha.124.325855 · 被引用次数：21 · 研究领域：Cardiac Fibrosis and Remodeling、Peroxisome Proliferator-Activated Receptors、Immune cells in cancer

BACKGROUND: Vascular hyperpermeability is one of the hallmarks of acute lung injury, contributing to excessive inflammation and respiratory failure. The PPARδ (peroxisome proliferator-activated receptor delta) is an anti-inflammatory transcription factor, although its role in endothelial barrier function remains unclear. Here, we studied the essential role of PPARδ in maintaining vascular endothelial barrier integrity during lung inflammation and investigated the underlying mechanisms. METHODS: Endothelial cell (EC)–selective PPARδ knockout mice (Ppard EC-KO ) and littermate control mice (Ppard EC-WT ) received lipopolysaccharide injection to induce acute lung injury. Lung inflammation, pulmonary vascular leakage, and mouse mortality were monitored. Single-cell RNA sequencing was performed on sorted mouse lung ECs. RESULTS: Ppard EC-KO mice exhibited aggravated lung inflammation, characterized by increased leukocyte infiltration, elevated production of proinflammatory cytokines, and higher mortality rates. The enhanced inflammatory responses were associated with increased protein leakage, interstitial edema, and impaired endothelial barrier structure, leading to vascular hyperpermeability in Ppard EC-KO mice. Mechanistically, with single-cell RNA sequencing, we identified the emergence of an interferon-activated capillary EC population marked by CXCL10 (C-X-C motif chemokine 10) expression following lipopolysaccharide challenge. PPARδ silencing significantly increased CXCL10 ...