通过调节线粒体裂变和融合减轻 PM2.5 诱导的肺泡上皮细胞和肺损伤。

IF 7.2 1区 医学 Q1 TOXICOLOGY Particle and Fibre Toxicology Pub Date : 2023-07-18 DOI:10.1186/s12989-023-00534-w
Qi Liu, Jiali Weng, Chenfei Li, Yi Feng, Meiqin Xie, Xiaohui Wang, Qing Chang, Mengnan Li, Kian Fan Chung, Ian M Adcock, Yan Huang, Hai Zhang, Feng Li
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引用次数: 2

摘要

背景:暴露于空气动力学直径小于 2.5 μm 的颗粒物(PM)(PM2.5)是罹患肺部疾病和现有疾病恶化的风险因素。线粒体裂变和融合是健康和疾病中线粒体平衡的基本过程。我们研究了线粒体裂变和融合在 PM2.5 诱导的肺泡上皮细胞损伤和肺损伤中的作用。这些过程中的关键基因分别包括肌营养不良相关蛋白 1(DRP1)和视神经萎缩 1(OPA1):方法:肺泡上皮细胞(A549)在Mdivi-1(10µM,DRP1抑制剂)或BGP-15(10µM,OPA1激活剂)存在或不存在的情况下接受PM2.5(32 µg/ml)处理。结果通过 DRP1 敲除(KD)和 OPA1 外显(OE)进行了验证。小鼠腹腔注射 Mdivi-1(20 毫克/千克)、BGP-15(20 毫克/千克)或蒸馏水(对照组)一小时后,鼻腔注射 PM2.5(7.8 毫克/千克)或蒸馏水,连续两天:结果:暴露于PM2.5的A549细胞会导致氧化应激、炎症加剧、坏死、有丝分裂和线粒体功能障碍,表现为线粒体形态异常、线粒体膜电位(ΔΨm)降低、线粒体呼吸减少以及线粒体分裂和融合紊乱。利用 Mdivi-1 和 BGP-15 对线粒体裂变和融合进行药理学调控,以及利用 DRP1-KD 和 OPA1-OE 对线粒体裂变和融合进行基因调控,可防止 PM2.5 诱导的 A549 细胞的细胞损伤。Mdivi-1和BGP-15减轻了PM2.5诱导的小鼠急性肺损伤:结论:线粒体裂变增加和线粒体融合减少可能是 PM2.5 在体外诱导肺泡上皮细胞损伤和在体内诱导肺损伤的原因。
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Attenuation of PM2.5-induced alveolar epithelial cells and lung injury through regulation of mitochondrial fission and fusion.

Background: Exposure to particulate matter (PM) with an aerodynamic diameter less than 2.5 μm (PM2.5) is a risk factor for developing pulmonary diseases and the worsening of ongoing disease. Mitochondrial fission and fusion are essential processes underlying mitochondrial homeostasis in health and disease. We examined the role of mitochondrial fission and fusion in PM2.5-induced alveolar epithelial cell damage and lung injury. Key genes in these processes include dystrophin-related protein 1 (DRP1) and optic atrophy 1 (OPA1) respectively.

Methods: Alveolar epithelial (A549) cells were treated with PM2.5 (32 µg/ml) in the presence and absence of Mdivi-1 (10µM, a DRP1 inhibitor) or BGP-15 (10µM, an OPA1 activator). Results were validated using DRP1-knockdown (KD) and OPA1-overexpression (OE). Mice were injected intraperitoneally with Mdivi-1 (20 mg/kg), BGP-15 (20 mg/kg) or distilled water (control) one hour before intranasal instillation of PM2.5 (7.8 mg/kg) or distilled water for two consecutive days.

Results: PM2.5 exposure of A549 cells caused oxidative stress, enhanced inflammation, necroptosis, mitophagy and mitochondrial dysfunction indicated by abnormal mitochondrial morphology, decreased mitochondrial membrane potential (ΔΨm), reduced mitochondrial respiration and disrupted mitochondrial fission and fusion. Regulating mitochondrial fission and fusion pharmacologically using Mdivi-1 and BGP-15 and genetically using DRP1-KD and OPA1-OE prevented PM2.5-induced celluar damage in A549 cells. Mdivi-1 and BGP-15 attenuated PM2.5-induced acute lung injury in mice.

Conclusion: Increased mitochondrial fission and decreased mitochondrial fusion may underlie PM2.5-induced alveolar epithelial cell damage in vitro and lung injury in vivo.

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来源期刊
CiteScore
15.90
自引率
4.00%
发文量
69
审稿时长
6 months
期刊介绍: Particle and Fibre Toxicology is an online journal that is open access and peer-reviewed. It covers a range of disciplines such as material science, biomaterials, and nanomedicine, focusing on the toxicological effects of particles and fibres. The journal serves as a platform for scientific debate and communication among toxicologists and scientists from different fields who work with particle and fibre materials. The main objective of the journal is to deepen our understanding of the physico-chemical properties of particles, their potential for human exposure, and the resulting biological effects. It also addresses regulatory issues related to particle exposure in workplaces and the general environment. Moreover, the journal recognizes that there are various situations where particles can pose a toxicological threat, such as the use of old materials in new applications or the introduction of new materials altogether. By encompassing all these disciplines, Particle and Fibre Toxicology provides a comprehensive source for research in this field.
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