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

中文翻译：

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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

暴露于空气动力学直径小于 2.5 μm 的颗粒物 (PM2.5) 是发生肺部疾病和现有疾病恶化的危险因素。线粒体裂变和融合是健康和疾病中线粒体稳态的重要过程。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蛋白相关蛋白 1 (DRP1) 和视神经萎缩 1 (OPA1)。在存在和不存在 Mdivi-1（10μM，DRP1 抑制剂）或 BGP-15（10μM，OPA1 激活剂）的情况下，用 PM2.5 (32 µg/ml) 处理肺泡上皮 (A549) 细胞。使用 DRP1 敲低 (KD) 和 OPA1 过表达 (OE) 验证结果。小鼠腹腔注射Mdivi-1（20 mg/kg）、BGP-15（20 mg/kg）或蒸馏水（对照），然后鼻内滴注PM2.5（7.8 mg/kg）或蒸馏水2次。连续多日。A549 细胞暴露于 PM2.5 会导致氧化应激、炎症增强、坏死性凋亡、线粒体自噬和线粒体功能障碍，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裂变和融合破坏。使用 Mdivi-1 和 BGP-15 从药理学上调节线粒体裂变和融合，并使用 DRP1-KD 和 OPA1-OE 从遗传学上调节线粒体裂变和融合，可防止 A549 细胞中 PM2.5 诱导的细胞损伤。Mdivi-1 和 BGP-15 可减轻 PM2.5 诱导的小鼠急性肺损伤。线粒体分裂增加和线粒体融合减少可能是 PM2.5 诱导的体外肺泡上皮细胞损伤和体内肺损伤的基础。