Xu Xiuduan, Wang Hongli, Liu Shasha, Xing Chen, Liu Yang, Zhou Wei, Yuan Xiaoyan, Ma Yongfu, Hu Meiru, Hu Yongliang, Zou Shuxian, Gu Ye, Peng Shuangqing, Yuan Shengtao, Li Weiping, Ma Yuanfang, Song Lun
a Department of Stress Medicine , Beijing Institute of Basic Medical Sciences , Beijing , China.
b Anhui Medical University , Hefei , China.
Autophagy. 2016 Oct 2;12(10):1832-1848. doi: 10.1080/15548627.2016.1204496. Epub 2016 Jul 27.
ABSTARCT Epidemiological and clinical studies have increasingly shown that fine particulate matter (PM2.5) is associated with a number of pathological respiratory diseases, such as bronchitis, asthma, and chronic obstructive pulmonary disease, which share the common feature of airway inflammation induced by particle exposure. Thus, understanding how PM2.5 triggers inflammatory responses in the respiratory system is crucial for the study of PM2.5 toxicity. In the current study, we found that exposing human bronchial epithelial cells (immortalized Beas-2B cells and primary cells) to PM2.5 collected in the winter in Wuhan, a city in southern China, induced a significant upregulation of VEGFA (vascular endothelial growth factor A) production, a signaling event that typically functions to control chronic airway inflammation and vascular remodeling. Further investigations showed that macroautophagy/autophagy was induced upon PM2.5 exposure and then mediated VEGFA upregulation by activating the SRC (SRC proto-oncogene, non-receptor tyrosine kinase)-STAT3 (signal transducer and activator of transcription 3) pathway in bronchial epithelial cells. By exploring the upstream signaling events responsible for autophagy induction, we revealed a requirement for TP53 (tumor protein p53) activation and the expression of its downstream target DRAM1 (DNA damage regulated autophagy modulator 1) for the induction of autophagy. These results thus extend the role of TP53-DRAM1-dependent autophagy beyond cell fate determination under genotoxic stress and to the control of proinflammatory cytokine production. Moreover, PM2.5 exposure strongly induced the activation of the ATR (ATR serine/threonine kinase)-CHEK1/CHK1 (checkpoint kinase 1) axis, which subsequently triggered TP53-dependent autophagy and VEGFA production in Beas-2B cells. Therefore, these findings suggest a novel link between processes regulating genomic integrity and airway inflammation via autophagy induction in bronchial epithelial cells under PM2.5 exposure.
摘要 流行病学和临床研究越来越多地表明，细颗粒物（PM2.5）与多种病理性呼吸系统疾病有关，如支气管炎、哮喘和慢性阻塞性肺疾病，这些疾病都具有因颗粒物暴露引起气道炎症的共同特征。因此，了解PM2.5如何触发呼吸系统中的炎症反应对于研究PM2.5毒性至关重要。在当前的研究中，我们发现将人支气管上皮细胞（永生化的Beas-2B细胞和原代细胞）暴露于中国南方城市武汉冬季采集的PM2.5中，会导致血管内皮生长因子A（VEGFA）产生显著上调，这是一个通常在控制慢性气道炎症和血管重塑中起作用的信号事件。进一步的研究表明，PM2.5暴露会诱导巨自噬/自噬，然后通过激活支气管上皮细胞中的SRC（SRC原癌基因，非受体酪氨酸激酶）-STAT3（信号转导和转录激活因子3）途径介导VEGFA上调。通过探索负责自噬诱导的上游信号事件，我们揭示了TP53（肿瘤蛋白p53）激活及其下游靶点DRAM1（DNA损伤调节自噬调节剂1）的表达对于自噬诱导的必要性。因此，这些结果将TP53-DRAM1依赖性自噬的作用扩展到了基因毒性应激下细胞命运决定之外，以及对促炎细胞因子产生的控制。此外，PM2.5暴露强烈诱导了ATR（ATR丝氨酸/苏氨酸激酶）-CHEK1/CHK1（检查点激酶1）轴的激活，随后在Beas-2B细胞中触发了TP53依赖性自噬和VEGFA产生。因此，这些发现表明在PM2.5暴露下，支气管上皮细胞中通过自噬诱导调节基因组完整性和气道炎症的过程之间存在新的联系。
