• Yaxin Wang, Xiangzhi Fang, Yiyi Yang, Lin Chen, Wei Xiong, Limin Song, Bo Li, Ting Zhou, Yuan Yu, Xiaobo Yang, Huaqing Shu, Shiying Yuan, Shanglong Yao, and You Shang.
• Department of Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
• Shock. 2022 Jan 1; 57 (1): 140150140-150.

ObjectivesMechanical stretch-induced alveolar epithelial cell (AEC) apoptosis participates in the onset of ventilator-induced lung injury (VILI). In this study, we explored whether death-associated protein kinase 1 (DAPK1) mediated cyclic stretch (CS)-induced AEC apoptosis and VILI though P53 pathway.Materials And MethodsAEC apoptosis was induced by CS using the FX-5000T Flexercell Tension Plus system. C57BL/6 mouse received high tidal volume ventilation to build VILI model. DAPK1 inhibitor, P53 inhibitor, or DAPK1 plasmid was used to regulate the expression of DAPK1 and P53, respectively. Flow cytometery was performed to assay cell apoptosis and the changes of mitochondrial membrane potential (MMP); immunoblotting was adopted to analyze related protein expression. The binding of related proteins was detected by coimmunoprecipitation; AEC apoptosis in vivo was determined by immunohistochemistry assay.ResultsCS promoted AEC apoptosis, increased DAPK1 and P53 expression, and induced the binding of DAPK1 and P53; inhibition of DAPK1 or P53 reduced CS-induced AEC apoptosis, suppressed the expression of Bax, increased Bcl-2 level, and stabilized MMP; AEC apoptosis and the level of P53 were both increased after overexpressing of DAPK1. Moreover, DAPK1 plasmid transfection also promoted the expression of Bax and the change of MMP, but decreased the level of Bcl-2. Inhibition of DAPK1 or P53 in vivo alleviated high tidal volume ventilation-induced AEC apoptosis and lung injury.ConclusionsDAPK1 contributes to AEC apoptosis and the onset of VILI though P53 and its intrinsic pro-apoptotic pathway. Inhibition of DAPK1 or P53 alleviates high tidal volume ventilation-induced lung injury and AEC apoptosis.Copyright © 2021 by the Shock Society.

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