Research Papers:

Cigarette smoke promotes COPD by activating platelet-activating factor receptor and inducing neutrophil autophagic death in mice

Xiao-Xi Lv, Shan-Shan Liu, Ke Li, Bing Cui, Chang Liu and Zhuo-Wei Hu _

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Oncotarget. 2017; 8:74720-74735. https://doi.org/10.18632/oncotarget.20353

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Xiao-Xi Lv1,*, Shan-Shan Liu1,*, Ke Li2, Bing Cui1, Chang Liu1 and Zhuo-Wei Hu1

1Immunology and Cancer Pharmacology Group, State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100050, P.R. China

2Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100050, P.R. China

*These authors have contributed equally to this work

Correspondence to:

Zhuo-Wei Hu, email: [email protected]

Keywords: autophagy, elastase, emphysema, inflammation, PAF

Received: May 31, 2017    Accepted: July 13, 2017    Published: August 18, 2017


Neutrophils are the most important effector cells during the development of chronic obstructive pulmonary disease (COPD). Although neutrophil elastase is critical in cigarette smoke (CS)-induced lung parenchyma, the mechanism by which CS triggers elastase release from neutrophils remains unclear. Here we report that CS induction of autophagy in neutrophils by activating platelet- activating factor receptor (PAFR) promotes COPD progression in mouse. We found that the dead neutrophils were increased in bronchoalveolar lavage fluid from CS-exposed mice. Blocking PAFR suppressed the CS-induced autophagy in neutrophils, protected neutrophils from death, and reduced elastase release. Mechanistically, CS enhanced ROS production and High mobility group box 1 (HMGB1) expression through activation of PAFR. The elevated HMGB1 interacted with beclin1, which promoted the dissociation of Bcl-2 from beclin1 and the assembly of autophagy core complex. Moreover, the antagonism of PAFR by rupatadine, a prescription PAFR inhibitor, protected against the development of emphysema, and reduced the autophagic death of neutrophils after CS exposure. These results suggest that CS contributes to the pathogenesis of COPD partly by inducing a PAFR-dependent autophagic death of neutrophils. Therefore, PAFR may be a therapeutic target for COPD and inhibition of PAFR may provide potential therapeutic benefits in the treatment of patients with COPD.

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