Background

Chronic obstructive pulmonary disease (COPD) is a chronic respiratory disease usually caused by prolonged exposure to noxious gases or particles [1]. Although cigarette smoking is an important risk factor in COPD, many patients with COPD are never-smokers [2,3,4]. Occupational exposure and biomass fuels are well-known risk factors in never-smoker COPD [5, 6]. Recent studies have linked particulate matter of diameter ≤ 2.5 μm (PM2.5) to decreased lung function, airway inflammation, and emphysematous changes in the lungs, leading to the development of COPD and increased mortality [7,8,9,10].

Both PM2.5 and smoking have been reported to promote inflammation and cell death in the lungs [11,12,13,14,15,16]. Particularly, PM2.5 is known to induce various types of cell deaths, including autophagy, necrosis, apoptosis, pyroptosis, and ferroptosis [17]. Recently, pyroptosis has been identified as a crucial process in lung injury. Pyroptosis is an inflammatory type of programmed cell death mediated by caspase-1 and activated by the inflammasome [18, 19]. The inflammasome is an intracellular multi-protein component composed primarily of nucleotide-binding oligomerization domain-like receptor (NLR) family and the pyrin and hematopoietic interferon-inducible nuclear domain protein family [20]. NLR protein-3 (NLRP3) is an important member of NLR family that recognizes and is activated by pathogen-associated molecular patterns or damage-associated molecular patterns [21, 67]. Exposure to PM2.5 was associated with systemic inflammation in patients with COPD [68], and systemic inflammation in COPD was associated with poor QOL [69, 70]. In pyroptosis, the plasma-membrane rapidly ruptures and proinflammatory intracellular contents are released, resulting in pathological inflammation [19]. Moreover, patients with stable COPD had significantly higher plasma IL-1β levels and upregulated expression of the IL1B, NLRP3, and CASP1 genes compared with that in healthy controls [71]. In our investigation, high ambient PM2.5 concentrations were linked to high SGRQ-C scores in currently smoking patients with COPD. Moreover, high SGRQ-C scores were associated with rapid lung function decline and frequent exacerbation [72,73,74]. We can conclude from this study that PM2.5 exposure aggravates smoking-induced airway inflammation and deteriorates QOL of patients with COPD, with local or systemic pyroptosis-mediated inflammation playing an important role. Furthermore, PM2.5 exposure may induce lung function decline and exacerbation in currently smoking patients with COPD.

There are some limitations in our study. First, PM2.5 exposure alone did not alter the total number or the differential proportions of cells in the BALF, nor did it induce peribronchial inflammatory cell infiltration. Second, a 1-week time interval between the last exposure to PM2.5 and euthanasia of the mice may allow clearance of PM2.5 by macrophages. Third, the synergistic effect of PM2.5 and cigarette smoke exposure was prominent in the protein composition of BALF, whereas this synergy was relatively less evident in qPCR levels of lung homogenate. Since both PM2.5 and cigarette smoke were delivered intratracheally, their impact on the alveolar space appears to be more pronounced. Additionally, the alterations observed in protein levels holds greater significance compared with those observed in mRNA. Fourth, although exposure to smoking and PM2.5 caused lung injury and cell death in our experiments, other cell death mechanisms, such as apoptosis, might be involved. Meanwhile, our results demonstrate a significant upregulation of pyroptosis-related genes and proteins, as well as restored cell viability with caspase-1 inhibition and NLRP3 silencing. Fifth, in clinical data, a larger sample size and longer study duration might show a more consistent difference in associations between current and ex-smokers. However, the correlation between SGRQ-C score and PM2.5 concentration in current smokers implies that the combined exposure to smoking and PM2.5 has an additive aggravating effect, and pyroptosis-induced systematic inflammation may be involved.

Conclusions

In conclusion, the combined exposure to PM2.5 and cigarette smoking aggravates smoking-induced airway inflammation and cell death with pyroptosis being one of the dominant mechanisms. In patients with COPD, PM2.5 aggravates the QOL caused by concurrent smoking and may deteriorate lung function and induce exacerbation. COPD is a preventable disease caused by exposure to noxious particles with various synergistic effects. Identifying these addictive effects will contribute to our understanding of the pathogenesis of COPD and the development of effective treatment options.