Interferon regulatory factor 1 (IRF1) inhibits lung endothelial regeneration following inflammation-induced acute lung injury

作者全名："Chen, Xiaorui; Qi, Di; Fan, Shulei; He, Yirui; Jing, Hekun; Wang, Daoxin"

作者地址："[Chen, Xiaorui; Qi, Di; Fan, Shulei; Jing, Hekun; Wang, Daoxin] Chongqing Med Univ, Affiliated Hosp 2, Dept Resp & Crit Care Med, Chongqing, Peoples R China; [He, Yirui] Chongqing Med Univ, Affiliated Hosp 2, Dept Endocrinol, Chongqing, Peoples R China"

通信作者："Chen, XR; Wang, DX (通讯作者)，Chongqing Med Univ, Affiliated Hosp 2, Dept Resp & Crit Care Med, Chongqing, Peoples R China."

来源：CLINICAL SCIENCE

ESI学科分类：CLINICAL MEDICINE

WOS号：WOS:000977320500002

JCR分区：Q1

影响因子：6.7

年份：2023

卷号：137

期号：5

开始页：367

结束页：383

文献类型：Article

关键词：　

摘要："Background: Acute respiratory distress syndrome (ARDS) is a respiratory condition caused by severe endothelial barrier dysfunction within the lung. In ARDS, excessive inflammation, tissue edema, and immune cell influx prevents endothelial cell regeneration that is crucial in repairing the endothelial barrier. However, little is known about the molecular mechanism that underpin endothelial cell regeneration in ARDS.Methods: R-based bioinformatics tools were used to analyze microarray-derived tran-scription profiles in human lung microvascular endothelial cells (HLMVECs) subjected to non-treatment or lipopolysaccharide (LPS) exposure. We generated endothelial cell-specific interferon regulatory factor 1 (Irf1) knockout (Irf1EC-/-) and Irf1fl/fl control mice for use in an endotoxemic murine model of acute lung injury (ALI). In vitro studies (qPCR, immunoblotting, and ChIP-qPCR) were conducted in mouse lung endothelial cells (MLECs) and HLMVECs. Dual-luciferase promoter reporter assays were performed in HLMVECs.Results: Bioinformatics analyses identified IRF1 as a key up-regulated gene in HLMVECs post-LPS exposure. Endothelial-specific knockout of Irf1 in ALI mice resulted in enhanced regeneration of lung endothelium, while liposomal delivery of endothelial-specific Irf1 to wild-type ALI mice inhibited lung endothelial regeneration in a leukemia inhibitory factor (Lif)-dependent manner. Mechanistically, we demonstrated that LPS-induced Stat1Ser727 phosphorylation promotes Irf1 transactivation, resulting in downstream up-regulation of Lif that inhibits endothelial cell proliferation.Conclusions: These results demonstrate the existence of a p-Stat1Ser727-Irf1-Lif axis that inhibits lung endothelial cell regeneration post-LPS injury. Thus, direct inhibition of IRF1 or LIF may be a promising strategy for enhancing endothelial cell regeneration and improving clinical outcomes in ARDS patients."

基金机构：National Natural Science Foundation of China [81670071]

基金资助正文：Funding This work was supported by the National Natural Science Foundation of China [grant number 81670071 (to Daoxin Wang) ] .