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MiR-29a-3p Improves Acute Lung Injury by Reducing Alveolar Epithelial Cell PANoptosis. 2022

Yanhui Cui, and Xueqin Wang, and Fengyu Lin, and Wen Li, and Yuhao Zhao, and Fei Zhu, and Hang Yang, and Mingjun Rao, and Yi Li, and Huaying Liang, and Minhui Dai, and Ben Liu, and Lingli Chen, and Duoduo Han, and Rongli Lu, and Wenzhong Peng, and Yan Zhang, and Chao Song, and Yanwei Luo, and Pinhua Pan

1Respiratory and critical care medicine, Xiangya Hospital, Central South University, Hunan 410000, China.

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 miR-29a-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 down-regulated in plasma of ARDS patients and lung tissue of ALI model mice, and miR-29a-3p agomir injection down-regulated the levels of the inflammatory factors, including tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), 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.