Evaluation and Research Center for Toxicology, Institute of Disease Control and Prevention, Academy of Military Medical Sciences, Beijing 100071, PR China.
Evaluation and Research Center for Toxicology, Institute of Disease Control and Prevention, Academy of Military Medical Sciences, Beijing 100071, PR China; Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang 110016, PR China.
Ecotoxicol Environ Saf. 2017 Nov;145:605-614. doi: 10.1016/j.ecoenv.2017.07.047. Epub 2017 Aug 9.
Severe smog/haze events accompanied by extremely high concentrations of airborne fine particulate matter (PM2.5) have emerged frequently in China and the potential health risks have attracted ever-growing attention. During these episodes, a surge in hospital visits for acute respiratory symptoms and respiratory diseases exacerbation has been reported to be associated with acute exposure to high-levels of particulate matters. To investigate cell fate determination and the underlying pathogenic mechanisms during severe haze episodes or smog events, we exposed human lung epithelial cells (BEAS-2B) to PM2.5 (0-400μg/mL) for 24h and found that high doses of PM2.5 caused cell necrosis and autophagy dysfunction, while co-treatment with the autophagy inhibitor 3-MA could partially reduce PM2.5-induced cell necrosis. Exposure to PM2.5 also increased the expression and mitochondrial transposition of heme oxygenase 1 (HO-1), which consequently reduced the release of cytochrome C from mitochondria to cytosol. Knockdown of HO-1 by siRNA attenuated the mitochondrial accumulation of HO-1, reversed HO-1-induced the reduction of cytochrome C release and promoted PM2.5-induced cell apoptosis. In contrast to necrosis, PM2.5-induced autophagy was independent of HO-1. In conclusion, our results demonstrate that acute exposure to high PM2.5 concentrations causes autophagy-related cell necrosis. The decrease in cytochrome C release and apoptosis by upregulation of HO-1 maybe assist PM2.5-induced autophagy-related cell necrosis. Further, this study reveals dual roles for HO-1 in PM2.5-induced cytotoxicity and presents a possible explanation for the onset of acute respiratory symptoms under extreme particulate air pollution.
严重的雾霾/烟雾事件伴随着极高浓度的空气细颗粒物（PM2.5）在中国频繁出现，其潜在的健康风险引起了越来越多的关注。在这些事件中，据报道，由于急性暴露于高水平的颗粒物，因急性呼吸道症状和呼吸道疾病恶化而导致的医院就诊人数激增。为了研究在严重雾霾事件或烟雾事件中细胞命运决定和潜在的发病机制，我们将人肺上皮细胞（BEAS-2B）暴露于 PM2.5（0-400μg/mL）24 小时，发现高剂量的 PM2.5 会导致细胞坏死和自噬功能障碍，而用自噬抑制剂 3-MA 共同处理可以部分减少 PM2.5 引起的细胞坏死。暴露于 PM2.5 还增加血红素加氧酶 1（HO-1）的表达和线粒体易位，从而减少细胞色素 C 从线粒体向细胞质的释放。用 siRNA 敲低 HO-1 减弱了线粒体中 HO-1 的积累，逆转了 HO-1 诱导的细胞色素 C 释放减少，并促进了 PM2.5 诱导的细胞凋亡。与坏死相反，PM2.5 诱导的自噬不依赖于 HO-1。总之，我们的结果表明，急性暴露于高浓度的 PM2.5 会导致自噬相关的细胞坏死。HO-1 的上调降低了细胞色素 C 的释放和凋亡，可能有助于 PM2.5 诱导的自噬相关细胞坏死。此外，这项研究揭示了 HO-1 在 PM2.5 诱导的细胞毒性中的双重作用，并为在极端颗粒物空气污染下出现急性呼吸道症状提供了可能的解释。
