Airborne fine particulate matter induces multiple cell death pathways in human lung epithelial cells
Airborne fine particulate matter induces multiple cell death pathways in human lung epithelial cells
复制标题
空气中的细颗粒物诱导人肺上皮细胞的多种细胞死亡途径
DOI：
10.1007/s10495-014-0980-5
复制
发表时间：
2014-07-01
期刊：
影响因子：
7.2
通讯作者：
Ding, Wenjun
中科院分区：
文献类型：
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作者：
Deng, Xiaobei;Zhang, Fang;Ding, Wenjun
我们小组是第一个报道空气中平均直径小于2.5微米(PM2.5)的细颗粒物(PM)可在人肺上皮A549细胞中引发自噬的报道，这可能会导致细胞死亡。在本研究中，我们进一步探讨了自噬和凋亡之间的潜在相互作用，因为PM2.5可以诱导A549细胞的凋亡。令我们惊讶的是，我们发现PM2.5暴露引起A549细胞氧化应激，导致多条细胞死亡途径的激活，即肿瘤坏死因子-α(TNF-α)诱导的途径，如肿瘤坏死因子-α(TNF-α)诱导的途径，如肿瘤坏死因子-α(TNF-α)的分泌和caspase-8和-3的激活，内在的凋亡途径，如促凋亡蛋白Bax的表达增加，抗凋亡蛋白bcl2的表达降低，线粒体膜电位的破坏，caspase-9和-3的激活，以及自噬，如双膜小泡的增加。伴随着微管相关蛋白轻链3(Lc3)的转换和点缀增加以及Beclin 1的表达。由于ROS的清除剂N-乙酰半胱氨酸预先处理几乎完全取消了TNF-α的分泌，并显著减少了凋亡和自噬细胞的数量，因此似乎ROS在所有这三个途径中都起着信号分子的作用。另一方面，用自噬特异性抑制剂3-甲基腺嘌呤抑制自噬，可增强PM2.5诱导的细胞凋亡和细胞毒性。有趣的是，用抗肿瘤坏死因子-α的特殊抗体中和肿瘤坏死因子-α，不仅取消了caspase-8的激活，还显著降低了LC3-II的转化率。因此，本研究对PM2.5暴露相关疾病的细胞毒性机制甚至发病机制提供了新的见解。
Our group was the first one reporting that autophagy could be triggered by airborne fine particulate matter (PM) with a mean diameter of less than 2.5 mu m (PM2.5) in human lung epithelial A549 cells, which could potentially lead to cell death. In the present study, we further explored the potential interactions between autophagy and apoptosis because it was well documented that PM2.5 could induce apoptosis in A549 cells. Much to our surprise, we found that PM2.5-exposure caused oxidative stress, resulting in activation of multiple cell death pathways in A549 cells, that is, the tumor necrosis factor-alpha (TNF-alpha)-induced pathway as evidenced by TNF-alpha secretion and activation of caspase-8 and -3, the intrinsic apoptosis pathway as evidenced by increased expression of pro-apoptotic protein Bax, decreased expression of anti-apoptotic protein Bcl-2, disruption of mitochondrial membrane potential, and activation of caspase-9 and -3, and autophagy as evidenced by an increased number of double-membrane vesicles, accompanied by increases of conversion and punctuation of microtubule-associated proteins light chain 3 (LC3) and expression of Beclin 1. It appears that reactive oxygen species (ROS) function as signaling molecules for all the three pathways because pretreatment with N-acetylcysteine, a scavenger of ROS, almost completely abolished TNF-alpha secretion and significantly reduced the number of apoptotic and autophagic cells. In another aspect, inhibiting autophagy with 3-methyladenine, a specific autophagy inhibitor, enhanced PM2.5-induced apoptosis and cytotoxicity. Intriguingly, neutralization of TNF-alpha with an anti-TNF-alpha special antibody not only abolished activation of caspase-8, but also drastically reduced LC3-II conversion. Thus, the present study has provided novel insights into the mechanism of cytotoxicity and even pathogenesis of diseases associated with PM2.5 exposure.