LKB1 / p53 / TIGAR /自噬依赖的VEGF表达有助于PM2.5诱导的肺部炎症反应。,Scientific Reports

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LKB1 / p53 / TIGAR /自噬依赖的VEGF表达有助于PM2.5诱导的肺部炎症反应。
Scientific Reports ( IF 3.8 ) Pub Date : 2019-11-12 , DOI: 10.1038/s41598-019-53247-6
Huan Xu _{1,

2} , Xiuduan Xu _{1,

2,

3} , Hongli Wang _{1,

4} , Aodeng Qimuge _{1,

5} , Shasha Liu _{1,

6} , Yuanlian Chen _{1,

7} , Chongchong Zhang _{1,

4} , Meiru Hu ₁ , Lun Song _{1,

2}

Affiliation

PM2.5暴露对健康的危害之一是诱发肺部炎症反应。在我们以前的研究中，我们证明了永生化和原代人支气管上皮细胞都暴露于PM2.5会导致VEGF产生显着上调，这是触发慢性气道炎症的典型信号事件。进一步的研究表明，暴露于PM2.5会强烈诱导ATR / CHK1 / p53级联激活，从而通过激活Src / STAT3途径诱导DRAM1依赖性自噬介导VEGF表达。在当前的研究中，我们进一步揭示了TIGAR是p53的另一个转录靶标，可在PM2.5暴露后触发Beas-2B细胞中的自噬和VEGF上调。此外，LKB1，而不是ATR和CHK1，通过连接至Src / STAT3信号级联，在介导p53 / TIGAR /自噬/ VEGF途径激活中也发挥了关键作用。因此，结合以前的报告，我们已经确定了ATR / CHK1 / p53 / DRAM1-和LKB1 / p53 / TIGAR依赖性自噬在PM2.5暴露下介导支气管上皮细胞中VEGF的产生。此外，体内研究进一步证实了气道中的VEGF诱导可能导致了PM2.5治疗的大鼠肺血管内皮中的炎症反应。因此，阻断VEGF表达或自噬诱导可能是缓解PM2.5引起的呼吸道损伤的有价值的策略。我们已经发现在PM2.5暴露下，ATR / CHK1 / p53 / DRAM1-和LKB1 / p53 / TIGAR依赖的自噬介导了支气管上皮细胞的VEGF产生。此外，体内研究进一步证实了气道中的VEGF诱导可能导致了PM2.5治疗的大鼠肺血管内皮中的炎症反应。因此，阻断VEGF的表达或自噬诱导可能是缓解PM2.5引起的呼吸道损伤的有价值的策略。我们已经发现在PM2.5暴露下，ATR / CHK1 / p53 / DRAM1-和LKB1 / p53 / TIGAR依赖的自噬介导了支气管上皮细胞的VEGF产生。此外，体内研究进一步证实了气道中的VEGF诱导可能导致了PM2.5治疗的大鼠肺血管内皮中的炎症反应。因此，阻断VEGF表达或自噬诱导可能是缓解PM2.5引起的呼吸道损伤的有价值的策略。

"点击查看英文标题和摘要"

LKB1/p53/TIGAR/autophagy-dependent VEGF expression contributes to PM2.5-induced pulmonary inflammatory responses.

One of the health hazards of PM2.5 exposure is to induce pulmonary inflammatory responses. In our previous study, we demonstrated that exposing both the immortalized and primary human bronchial epithelial cells to PM2.5 results in a significant upregulation of VEGF production, a typical signaling event to trigger chronic airway inflammation. Further investigations showed that PM2.5 exposure strongly induces ATR/CHK1/p53 cascade activation, leading to the induction of DRAM1-dependent autophagy to mediate VEGF expression by activating Src/STAT3 pathway. In the current study, we further revealed that TIGAR was another transcriptional target of p53 to trigger autophagy and VEGF upregulation in Beas-2B cells after PM2.5 exposure. Furthermore, LKB1, but not ATR and CHK1, played a critical role in mediating p53/TIGAR/autophagy/VEGF pathway activation also by linking to Src/STAT3 signaling cascade. Therefore, on combination of the previous report, we have identified both ATR/CHK1/p53/DRAM1- and LKB1/p53/TIGAR- dependent autophagy in mediating VEGF production in the bronchial epithelial cells under PM2.5 exposure. Moreover, the in vivo study further confirmed VEGF induction in the airway potentially contributed to the inflammatory responses in the pulmonary vascular endothelium of PM2.5-treated rats. Therefore, blocking VEGF expression or autophagy induction might be the valuable strategies to alleviating PM2.5-induced respiratory injuries.

更新日期：2019-11-13

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