EGR-1 Contributes to Pulmonary Edema by Regulating the Epithelial Sodium Channel in Lipopolysaccharide-Induced Acute Lung Injury

ABSTRACTAcute lung injury (ALI) is a common lung disease with increasing morbidity and mortality rates due to the lack of specific drugs. Impaired alveolar fluid clearance (AFC) is a primary pathological feature of ALI. Epithelial sodium channel (ENaC) is a primary determinant in regulating the transport of Na+ and the clearance of alveolar edema fluid. Therefore, ENaC is an important target for the development of drugs for ALI therapy. However, the role of ENaC in the progression of ALI remains unclear. Inhibition of early growth response factor (EGR-1) expression has been reported to induce a protective effect on ALI; therefore, we evaluated whether EGR-1 participates in the progression of ALI by regulating ENaC-α in alveolar epithelium. We investigated the potential mechanism of EGR-1-mediated regulation of ENaC in ALI. We investigated whether EGR-1 aggravates the pulmonary edema response in ALI by regulating ENaC. ALI mouse models were established by intrabronchial injection of lipopolysaccharides (LPS). Lentiviruses with EGR-1 knockdown were transfected into LPS-stimulated A549 cells. We found that EGR-1 expression was upregulated in the lung tissues of ALI mice and in LPS-induced A549 cells, and was negatively correlated with ENaC-α expression. Knockdown of EGR-1 increased ENaC-α expression and relieved cellular edema in ALI. Moreover, EGR-1 regulated ENaC-α expression at the transcriptional level, and correspondingly promoted pulmonary edema and aggravated ALI symptoms. In conclusion, our study demonstrated that EGR-1 could promote pulmonary edema by downregulating ENaC-α at the transcriptional level in ALI. Our study provides a new potential therapeutic strategy for treatment of ALI.HIGHLIGHTS EGR-1 expression was increased in LPS-induced ALI mice and associated with aggravated pulmonary edemaEGR-1 induced pulmonary edema relying on regulating the expression of ENaC-α at the transcriptional level by manipulating the promoterKEYWORDS: Acute lung injuryalveolar fluid clearanceearly growth response factorepithelial sodium channeltranscription Disclosure statementNo potential conflict of interest was reported by the author(s).CRediT authorship contribution statementSong Wang, Hongwei Cai, Zhen Meng: Conceptualization, Methodology, Formal analysis, Writing-original draft. Xin Li, Xinmiao Xian, Guohao Gu, Guikun Tan: Data Collection, Software. Jing Ma, Bingwu Yang, Jianran Guo: Formal analysis and interpretation. Jing Ma, Song Wang, Bo Fu, Zhen Meng, Bingwu Yang: Conceptualization, Funding acquisition, Project administration. Song Wang, Anqi Zhang: Writing – review & editing, Resources. All the authors agreed with the final version of the manuscript.Additional informationFundingThis study was financed by a Medical and Health Science and Technology Development Plan Project of Shandong Province [Grant no. 202203020733]; Traditional Chinese Medicine Science and Technology Foundation of Shandong Province [Grant no. 2020M184]; Liaocheng Key R&D Project (Grant no. 2022YDSF35); Liaocheng Key R&D Project [Grant no. 2022YDSF31]; Natural Science Foundation of Shandong Province [Grant no. ZR2022MH272]; Natural Science Foundation of Shandong Province [Grant no. ZR2020QH216]; Medical and Health Science and Technology Development Plan Project of Shandong Province [Grant no. 2018WS415].