期刊
AGING AND DISEASE
卷 -, 期 -, 页码 -出版社
INT SOC AGING & DISEASE
DOI: 10.14336/AD.2021.1023
关键词
acute lung injury; miRNA; PANoptosis; N6-methyladenosine; inflammation
资金
- National Key R&D Program of China [2016YFC1304204]
- Project Program of National Clinical Research Center for Geriatric Disorders (Xiangya Hospital) [2020 LNJJ05]
- National Natural Science Foundation of China [81770080]
- China Postdoctoral Science Foundation [2020M670104ZX]
- scientific research project of Hunan Health Commission [202103020612]
- Scientific Research Foundation of Hunan Provincial Education Department [19B069]
- Project of Special Program on COVID-19 of Changsha Technology Hall [kq2001049]
The study revealed that miR-29a-3p is downregulated in ARDS patients and ALI model mice, and its regulation of inflammatory factors helps reduce lung injury by decreasing alveolar epithelial cell death, presenting a potential therapeutic target for ALI/ARDS.
Alveolar epithelial cell damage is an important determinant of the severity of acute lung injury/acute respiratory distress syndrome (ALI/ARDS). However, the molecular mechanisms of alveolar epithelial death during the development of ALI/ARDS remain unclear. In this study, we explore the role of miR29a-3p in ALI/ARDS and its molecular mechanism. Plasma samples were collected from healthy controls and ARDS patients. Mice were intratracheally instilled with lipopolysaccharide (LPS) to establish acute lung injury. N6-adenosine (m6A) quantification, RNA-binding protein immunoprecipitation, cell viability assay, quantitative real-time polymerase chain reaction, and western blotting were performed. We found that miR-29a-3p was downregulated in plasma of ARDS patients and lung tissue of ALI model mice, and miR-29a-3p agomir injection downregulated the levels of the inflammatory factors, including tumor necrosis factor-alpha (TNF-alpha), interleukin-1 beta (IL-1 beta), and interleukin-6 (IL-6) in the lungs, reducing alveolar epithelial cell PANoptosis as evaluated by the downregulation of Z-DNA binding protein 1 (ZBP1), gasdermin D (GSDMD), caspase-3, caspase-8, and mixed lineage kinase domain-like protein (MLKL), ultimately improving lung injury in the ALI model mice. Mechanism studies demonstrated that the knockout of methyltransferase 3 (N6-adenosine-methyltransferase complex catalytic subunit) removed the m6A modification of miR-29a-3p and reduced miR-29a-3p expression. Our findings suggest that miR-29a-3p is a potential target that can be manipulated for ALI/ARDS.
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