Fine-particulate matter aggravates cigarette smoke extract–induced airway inflammation via Wnt5a–ERK pathway in COPD

BACKGROUND: Exposure to environmental particulate matter (PM) ≤2.5 μm in diameter (PM(2.5)) and smoking are common contributors to COPD, and pertinent research implicates both factors in pulmonary inflammation. Using in vivo mouse and in vitro human cellular models, we investigated the joint impact of PM(2.5) pollution, and cigarette smoke (CS) in mice or cigarette-smoke extract (CSE) in cells on COPD inflammation, and explored potential mechanisms. METHODS: Tissue changes in lungs of C57BL/6 mice exposed to PM(2.5) and CS were studied by light microscopy, H&E, immunochemistry, and immunofluorescence-stained sections. Levels of inflammatory factors induced by PM(2.5)/CS in mice and PM(2.5)/CSE in 16HBE cells were also monitored by quantitative reverse-transcription (qRT)-PCR and ELISA. Expression of genes related to the Wnt5a-signaling pathway was assessed at transcriptional and protein levels using immunofluorescence, qRT-PCR, and Western blotting. RESULTS: Inflammatory response to combined exposure of PM(2.5) and CS or CSE in mouse and 16HBE cells surpassed responses incited separately. Although separate PM(2.5) and CS/CSE exposure upregulated the expression of Wnt5a (a member of the Wnt-secreted glycoprotein family), combined PM(2.5) and CS/CSE exposure produced a steeper rise in Wnt5a levels. Use of a Wnt5a antagonist (BOX5) successfully blocked related inflammatory effects. ERK phosphorylation appeared to mediate the effects of Wnt5a in the COPD model, promoting PM(2.5) aggravation of CS/CSE-induced airway inflammation. CONCLUSION: Our findings suggest that combined PM(2.5) and CS/CSE exposure induce airway inflammation and Wnt5a expression in vivo in mice and in vitro in 16HBE cells. Furthermore, PM(2.5) seems to aggravate CS/CSE-induced inflammation via the Wnt5a–ERK pathway in the context of COPD.