Mechanosensitive ion channel Piezo1 mediates mechanical ventilation-exacerbated ARDS-associated pulmonary fibrosis.
Mechanosensitive ion channel Piezo1 mediates mechanical ventilation-exacerbated ARDS-associated pulmonary fibrosis.
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机械敏感离子通道 Piezo1 介导机械通气加剧 ARDS 相关肺纤维化。
DOI：
10.1016/j.jare.2022.12.006
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发表时间：
2023-11
影响因子：
10.7
通讯作者：
Shang, You
中科院分区：
文献类型：
--
作者：
Fang, Xiang-Zhi;Li, Min;Wang, Ya-Xin;Zhang, Pei;Sun, Miao-Miao;Xu, Jia-Xin;Yang, Yi-Yi;He, Ya-Jun;Yu, Yuan;Li, Rui-Ting;Zhou, Ting;Reng, Le-Hao;Sun, De-Yi;Shu, Hua-Qing;Yuan, Shi-Ying;Xu, Ji-Qian;Shang, You
肺纤维化是急性呼吸窘迫综合征（ARDS）预后不良的主要原因。虽然机械通气（MV）是ARDS不可或缺的救生干预措施，但它可能导致肺上皮细胞的重塑过程紊乱，加剧ARDS相关的肺纤维化。 Piezo1 是一种机械敏感离子通道，已知在调节多种生理过程中发挥作用，但 Piezo1 是否是 MV 加剧的 ARDS 相关肺纤维化所必需的仍不清楚。本研究旨在探讨 Piezo1 在 MV 加剧的 ARDS 相关肺纤维化中的作用。用盐酸 (HCl) 刺激人肺上皮细胞，然后机械拉伸 48 小时。使用酸吸入引起的小鼠肺损伤后的两次 MV 模型。 MV 14 天后处死小鼠。 Piezo1 的药理学抑制和敲除用于描述 Piezo1 在 MV 加剧的 ARDS 相关肺纤维化中的作用。在一些实验中，施用ATP或ATP水解酶腺苷三磷酸双磷酸酶。人肺上皮细胞对 HCl 的刺激会导致上皮间质转化 (EMT) 表型，而机械拉伸会增强这种表型。 MV 加剧了暴露于 HCl 的小鼠的肺纤维化。 Piezo1 的药理学抑制或敲除可在体内和体外减轻 MV 加剧的 EMT 过程和肺纤维化。从机制上讲，观察到的效应是由肺上皮细胞中 Piezo1 依赖性 Ca2+ 流入和 ATP 释放介导的。 我们的研究结果确定了 Piezo1 在 MV 加剧的 ARDS 相关肺纤维化中的关键作用，该纤维化是由肺上皮细胞中 ATP 释放增加介导的。抑制 Piezo1 可能构成治疗 MV 加剧的 ARDS 相关肺纤维化的新策略。
Pulmonary fibrosis is a major cause of the poor prognosis of acute respiratory distress syndrome (ARDS). While mechanical ventilation (MV) is an indispensable life-saving intervention for ARDS, it may cause the remodeling process in lung epithelial cells to become disorganized and exacerbate ARDS-associated pulmonary fibrosis. Piezo1 is a mechanosensitive ion channel that is known to play a role in regulating diverse physiological processes, but whether Piezo1 is necessary for MV-exacerbated ARDS-associated pulmonary fibrosis remains unknown. This study aimed to explore the role of Piezo1 in MV-exacerbated ARDS-associated pulmonary fibrosis. Human lung epithelial cells were stimulated with hydrochloric acid (HCl) followed by mechanical stretch for 48 h. A two-hit model of MV after acid aspiration-induced lung injury in mice was used. Mice were sacrificed after 14 days of MV. Pharmacological inhibition and knockout of Piezo1 were used to delineate the role of Piezo1 in MV-exacerbated ARDS-associated pulmonary fibrosis. In some experiments, ATP or the ATP-hydrolyzing enzyme apyrase was administered. The stimulation of human lung epithelial cells to HCl resulted in phenotypes of epithelial-mesenchymal transition (EMT), which were enhanced by mechanical stretching. MV exacerbated pulmonary fibrosis in mice exposed to HCl. Pharmacological inhibition or knockout of Piezo1 attenuated the MV-exacerbated EMT process and lung fibrosis in vivo and in vitro. Mechanistically, the observed effects were mediated by Piezo1-dependent Ca2+ influx and ATP release in lung epithelial cells. Our findings identify a key role for Piezo1 in MV-exacerbated ARDS-associated pulmonary fibrosis that is mediated by increased ATP release in lung epithelial cells. Inhibiting Piezo1 may constitute a novel strategy for the treatment of MV-exacerbated ARDS-associated pulmonary fibrosis.
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DOI：
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影响因子：
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