辣椒素通过 SIRT3 依赖性机制抑制铁变态反应和维持线粒体氧化还原平衡,从而减轻呼吸机诱发的肺损伤

IF 6 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Jinyuan Lin, Huajin Ou, Bijun Luo, Maoyao Ling, Fei Lin, Liming Cen, Zhaokun Hu, Liu Ye, Linghui Pan
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引用次数: 0

摘要

呼吸机诱发的肺损伤(VILI)是临床上与机械通气(MV)有关的严重并发症之一。辣椒素(CAP)具有抗炎和抑制氧化应激的作用,而氧化应激是导致细胞铁氧化的重要因素。然而,CAP 在 VILI 中调节铁细胞凋亡的具体作用和潜在机理途径仍未确定。VILI 在体内建立,循环拉伸(CS)诱导的肺上皮细胞损伤模型在体外建立。小鼠和细胞均以 CAP 进行预处理。采用透射电子显微镜、ELISA、Western印迹、免疫荧光、RT-PCR、荧光探针等实验方法,阐明了肺泡上皮细胞铁死亡与VILI之间的关系,以及辣椒素是否通过抑制铁死亡来缓解VILI及其具体机制。通过利用体内模型,研究发现铁的蜕变与 VILI 有关。辣椒素抑制铁凋亡,减轻了VILI的肺损伤和炎症反应,而辣椒素的这种保护作用依赖于通过SITR3信号维持线粒体氧化还原系统。在CS引起的肺上皮细胞损伤模型中,CAP可减少CS引起的病理性铁蛋白沉积和细胞损伤。敲除 SIRT3 逆转了 CAP 在病理 CS 下维持线粒体功能障碍的作用,并消除了其随后对过度伸展细胞的铁突变的有利影响。研究结果表明,CAP可通过提高SITR3的活性来抑制线粒体氧化损伤和维持线粒体氧化还原平衡,从而缓解VILI中的铁卟啉沉积,这说明它有可能成为VILI的一种新型治疗目标。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Capsaicin mitigates ventilator-induced lung injury by suppressing ferroptosis and maintaining mitochondrial redox homeostasis through SIRT3-dependent mechanisms
Ventilator-induced lung injury (VILI) is one of the severe complications in the clinic concerning mechanical ventilation (MV). Capsaicin (CAP) has anti-inflammatory and inhibitory effects on oxidative stress, which is a significant element causing cellular ferroptosis. Nevertheless, the specific role and potential mechanistic pathways through which CAP modulates ferroptosis in VILI remain elusive. VILI was established in vivo, and the pulmonary epithelial cell injury model induced by circulation stretching (CS) was established in vitro. Both mice and cells were pretreated with CAP. Transmission electron microscopy, ELISA, Western blot, immunofluorescence, RT-PCR, fluorescent probes, and other experimental methods were used to clarify the relationship between iron death and VILI in alveolar epithelial cells, and whether capsaicin alleviates VILI by inhibiting iron death and its specific mechanism. Ferroptosis was involved in VILI by utilizing in vivo models. CAP inhibited ferroptosis and alleviated VILI's lung damage and inflammation, and this protective effect of CAP was dependent on maintaining mitochondrial redox system through SITR3 signaling. In the CS-caused lung epithelial cell injury models, CAP reduced pathological CS-caused ferroptosis and cell injury. Knockdown SIRT3 reversed the role of CAP on the maintaining mitochondria dysfunction under pathological CS and eliminated its subsequent advantageous impacts for ferroptosis against overstretching cells. The outcomes showed that CAP alleviated ferroptosis in VILI via improving the activity of SITR3 to suppressing mitochondrial oxidative damage and maintaining mitochondrial redox homeostasis, illustrating its possibility as a novel therapeutic goal for VILI.
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来源期刊
Molecular Medicine
Molecular Medicine 医学-生化与分子生物学
CiteScore
8.60
自引率
0.00%
发文量
137
审稿时长
1 months
期刊介绍: Molecular Medicine is an open access journal that focuses on publishing recent findings related to disease pathogenesis at the molecular or physiological level. These insights can potentially contribute to the development of specific tools for disease diagnosis, treatment, or prevention. The journal considers manuscripts that present material pertinent to the genetic, molecular, or cellular underpinnings of critical physiological or disease processes. Submissions to Molecular Medicine are expected to elucidate the broader implications of the research findings for human disease and medicine in a manner that is accessible to a wide audience.
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