International Journal of COPD (Oct 2021)

GLIPR1 Protects Against Cigarette Smoke-Induced Airway Inflammation via PLAU/EGFR Signaling

  • Peng W,
  • Wu Y,
  • Zhang G,
  • Zhu W,
  • Chang M,
  • Rouzi A,
  • Jiang W,
  • Tong L,
  • Wang Q,
  • Liu J,
  • Song Y,
  • Li H,
  • Li K,
  • Zhou J

Journal volume & issue
Vol. Volume 16
pp. 2817 – 2832

Abstract

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Wenjun Peng,1,* Yuanyuan Wu,1,* Ge Zhang,1,* Wensi Zhu,1,* Meijia Chang,1 Ainiwaer Rouzi,1 Weipeng Jiang,1 Lin Tong,1 Qin Wang,1 Jie Liu,1 Yuanlin Song,1– 4 Huayin Li,1 Ka Li,5 Jian Zhou1– 4 1Department of Pulmonary and Critical Care Medicine, Shanghai Respiratory Research Institute, Zhongshan Hospital, Fudan University, Shanghai, 200032, People’s Republic of China; 2Center of Emergency & Intensive Care Unit, Jinshan Hospital, Fudan University, Shanghai, 200540, People’s Republic of China; 3Shanghai Key Laboratory of Lung Inflammation and Injury, Shanghai, 200032, People’s Republic of China; 4Shanghai Engineering Research Center of Internet of Things for Respiratory Medicine, Shanghai, 200032, People’s Republic of China; 5Institute of Clinical Science, Zhongshan Hospital, Fudan University, Shanghai, 200032, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jian ZhouDepartment of Pulmonary and Critical Care Medicine, Shanghai Respiratory Research Institute, Zhongshan Hospital, Fudan University, Shanghai, 200032, People’s Republic of ChinaEmail [email protected] LiInstitute of Clinical Science, Zhongshan Hospital, Fudan University, Shanghai, 200032, People’s Republic of ChinaEmail [email protected]: Chronic obstructive pulmonary disease (COPD) is a major health problem associated with high mortality worldwide. Cigarette smoke (CS) exposure is the main cause of COPD. Glioma pathogenesis-related protein 1 (GLIPR1) plays a key role in cell growth, proliferation, and invasion; however, the role of GLIPR1 in COPD remains unclear.Methods: To clarify the involvement of GLIPR1 in COPD pathogenesis, Glipr1 knockout (Glipr1-/-) mice were generated. Wild-type (WT) and Glipr1-/- mice were challenged with CS for 3 months. To illustrate how GLIPR1 regulates CS-induced airway damage, knockdown experiments targeting GLIPR1 and PLAU, as well as overexpression experiments of PLAU, were performed with human bronchial epithelial cells.Results: Compared with WT mice, Glipr1-/- mice showed exacerbated CS-induced airway damage including lung inflammation, airway wall thickening, and alveolar destruction. After CS exposure, total proteins, total white cells, neutrophils, lymphocytes, IL-6, and matrix metalloproteinase-9 increased significantly in lung of Glipr1-/- mice than those in lung of WT mice. Furthermore, in vivo and in vitro experiments demonstrated that silencing of GLIPR1 inactivated PLAU/EGFR signaling and promoted caspase-1-dependent pyroptosis (a mode of inflammatory cell death) induced by CS and CS extract exposure, respectively. In vitro experiments further revealed the interaction between GLIPR1 and PLAU, and silencing of PLAU blocked EGFR signaling and promoted pyroptosis, while overexpression of PLAU activated EGFR signaling and reversed pyroptosis.Conclusion: To conclude, GLIPR1 played a pivotal role in COPD pathogenesis and protected against CS-induced inflammatory response and airway damage, including cell pyroptosis, through the PLAU/EGFR signaling. Thus, GLIPR1 may play a potential role in COPD treatment.Keywords: chronic obstructive pulmonary disease, cigarette smoke, GLIPR1, PLAU, pyroptosis

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