Role of PM2.5 in the development and progression of COPD and its mechanisms

Abstract

Background: A multitude of epidemiological studies have shown that ambient fine particulate matter 2.5 (diameter < 2.5um; PM_2.5) was associated with increased morbidity and mortality of chronic obstructive pulmonary disease (COPD). However, the underlying associated mechanisms have not yet been elucidated. We conducted this study to investigate the role of PM_2.5 in the development of COPD and associated mechanisms.

Methods: We firstly conducted a cross-sectional study in Chinese han population to observe PM_2.5 effects on COPD morbidity. Then, in vitro, we incubated human bronchial epithelial cells to different concentrations of PM_2.5 for 24 h. The expression levels of IL-6 and IL-8 were detected by ELISA and the levels of MMPs, TGF-β1, fibronectin and collagen was determined by immunoblotting. In vivo, we subjected C57BL/6 mice to chronic prolonged exposure to PM_2.5 for 48 weeks to study the influence of PM_2.5 exposure on lung function, pulmonary structure and inflammation.

Results: We found that the effect of PM_2.5 on COPD morbidity was associated with its levels and that PM_2.5 and cigarette smoke could have a synergistic impact on COPD development and progression. Both vitro and vivo studies demonstrated that PM_2.5 exposure could induce pulmonary inflammation, decrease lung function, and cause emphysematous changes. Furthermore, PM_2.5 could markedly aggravated cigarette smoke-induced changes.

Conclusions: In short, we found that prolonged chronic exposure to PM_2.5 resulted in decreased lung function, emphysematous lesions and airway inflammation. Most importantly, long-term PM_2.5 exposure exacerbateed cigarette smoke-induced changes in COPD.

Keywords: Airway inflammation; Ambient fine particulate matter; Chronic obstructive pulmonary disease; Emphysematous lesions; Lung function.

Fig. 1

The association of PM_2.5 with COPD incidence in the population study. a The levels of PM_2.5 in urban and rural settings; b COPD incidence among different groups based on smoking-pack-years

Fig. 2

Effects of PM_2.5 on the cytokines release of IL-6 and IL-8 in HBEs. HBEs were, respectively, incubated with CSE (25 μg/ml) or 25 μg/ml to 200 μg/ml PM_2.5 for 24 h to examine the levels of pro-inflammatory cytokines by ELISA. a IL-6, b IL-8. HBEs were co-stimulated with CSE and different concentrations of PM_2.5 for 24 h to examine the levels of proinflammatory cytokines by ELISA. c IL-6, d IL-8.The results are mean ± SD of three independent experiments. *P < 0.05, ** P < 0.01, *** P < 0.001 vs control group; ^#P < 0.05, ^## P < 0.01, ^### P < 0.001 vs CSE group

Fig. 3

Effects of PM_2.5 on the protein expression levels of MMPs, TGF-β1, fibronectin and collagen proteins. HBEs were incubated with PM_2.5 with or without CSE for 24 h. The protein expression levels of MMPs, TGF-β1, fibronectin and collagens were detected by WB. a The protein expression of MMPs, TGF-β1, fibronectin and collagen induced by PM_2.5 /CSE. b The protein expression levels of MMPs, TGF-β1, fibronectin and collagens induced by PM_2.5 + CSE. * P < 0.05, ** P < 0.01, *** P < 0.001 vs control group; ^#P < 0.05, ^## P < 0.01, ^### P < 0.001 vs CSE group

Fig. 4

Morphological and pathological changes of lung tissue in mouse model. The representative micrographs of H&E-stained lung tissue of long-term exposure to PM_2.5 with or without CS for 48 weeks (a-d) (200x). a control group; b CS-exposed group; c PM_2.5-exposed group; d PM_2.5 + CS -exposed group. e Quantitative morphometric measurements of MLI. ** P < 0.01, *** P < 0.001 vs control group

Fig. 5

Effect of PM_2.5 and cigarette smoke exposure on pulmonary inflammation. The representative changes of pulmonary inflammation after long-term exposure to PM_2.5 with or without CS for 48 weeks (a-d) (200x). a control group; b CS-exposed group; c PM_2.5-exposed group; d PM_2.5 + CS -exposed group. The levels of inflammatory cytokines IL-6 and KC (mouse IL-8) in BAL were detected by ELISA; e the level of IL-8 in BAL and f the level of IL-6 in BAL. Data are presented as mean ± SD (n = 6). * P < 0.05, ** P < 0.01 vs control group

Fig. 6

Immunohistochemical staining of MMP9, MMP12, and TGF-β1 in lungs sections induced by PM_2.5 exposure (400x) (a) and semiquantitative assessment of MMP9, MMP12, and TGF-β1 protein expression using Image-Pro Plus (b). Data are presented as mean ± SD (n = 6). *P < 0.05, ** P < 0.01, *** P < 0.001 vs control group; ^#P < 0.05, ^## P < 0.01, ^### P < 0.001 vs PM_2.5 + CSE-exposed group

Fig. 7

Western blot examination for MMP9, MMP12, and TGF-β1 protein levels expression in lungs sections induced by PM_2.5/CS exposure. The expressions of MMP9, MMP12, and TGF-β1 were analyzed with western blotting (a) and (b-d) the proteins expression were evaluated. Data are expressed as mean ± SD (n = 6). *P < 0.05, ** P < 0.01, *** P < 0.001 vs control group; ^#P < 0.05, ^## P < 0.01, ^### P < 0.001 vs PM_2.5 + CSE-exposed group

Fig. 8

Effect of PM_2.5 and cigarette smoke exposure on airway wall remodeling. a Photomicrographs of peribronchial collagen and fibronectin deposition in lung tissue induced by chronic exposure to PM_2.5 with or without CS (200X). b The assessment of peribronchial collagen deposition in lung tissue induced by chronic exposure to PM_2.5 with or without CS. c Semiquantitative assessment of fibronectin protein expression using Image-Pro Plus. Results were expressed as means± SD (n = 6). *P < 0.05, ** P < 0.01, *** P < 0.001 vs control group; ^#P < 0.05, ^## P < 0.01, ^### P < 0.001 vs PM_2.5 + CSE-exposed group