Abstract
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.
Highlights
Chronic obstructive pulmonary disease (COPD) is one of the most common respiratory diseases that threaten the lives of the patients [1]
cigarette smoke (CS) exposure was associated with the increased number of neutrophils and the quantity of neutrophil elastase (NE) in bronchoalveolar lavage fluid (BALF) from CS-exposed mice (Figure 1D and 1E), suggesting that smoke stimulation induces the lung injury and chronic obstructive pulmonary disease (COPD) accompanied with the activation of neutrophils
Higher concentration of PAF and lower activity of platelet-activating factor acetylhydrolase (PAF-AH) were detected in BALF from mice after chronic CS stimulation (Figure 1I and 1J), which may format a feedback control mechanism to keep the platelet- activating factor receptor (PAFR) signaling pathway activation [13]. These results suggest that activation of PAFR signaling in neutrophils is involved in the pathogenesis of CS-induced COPD
Summary
Chronic obstructive pulmonary disease (COPD) is one of the most common respiratory diseases that threaten the lives of the patients [1]. The immune microenvironment of the lung tissue which is maintained by neutrophils, macrophages, lymphocytes, epithelial cells and fibroblasts promotes the progression of this disease [4, 5]. Several studies demonstrated that the numbers of immune cells are increased in the airway lumen in patients with COPD [5]. CS and other inhaled insults in the airway stimulate resident macrophages and epithelial cells to release large quantity of chemokines, which recruit neutrophils, monocytes and lymphocytes into the damaged tissue [6, 7]. It has been reported that the expression of PAFR is increased in airway epithelial cells from COPD patients [11, 12], and that CS exposure can promote the production of platelet-activating factor (PAF) [13]. Whether neutrophil participates in CS-induced COPD through PAFR remains unknown
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