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

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

  • Sci Rep. 2019 Nov 12;9(1):16600. 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 8 9
Affiliations

Affiliations

  • 1 Institute of Military Cognitive and Brain Sciences, 27 Taiping Road, Beijing, 100850, People's Republic of China.
  • 2 Anhui Medical University, 81 Meishan Road, Hefei, 230032, People's Republic of China.
  • 3 School of Life Sciences, Tsinghua University, Beijing, China.
  • 4 Laboratory of Cellular and Molecular Immunology, School of Medicine, Henan University, 357 Ximen Road, Kaifeng, 475004, People's Republic of China.
  • 5 Department of New Drug Screening Center, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, 210009, People's Republic of China.
  • 6 Department of Pathology, School of Basic Medical Sciences, Lanzhou University, Tianshui South Road, Lanzhou, 730000, People's Republic of China.
  • 7 Guiin Medical University, 1 Zhiyuan Road, Guilin, 541100, P.R. China.
  • 8 Institute of Military Cognitive and Brain Sciences, 27 Taiping Road, Beijing, 100850, People's Republic of China. lunsong0752@163.com.
  • 9 Anhui Medical University, 81 Meishan Road, Hefei, 230032, People's Republic of China. lunsong0752@163.com.
Abstract

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.

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