Abstract
Background
Exposure to noxious particles, including cigarette smoke and fine particulate matter (PM2.5), is a risk factor for chronic obstructive pulmonary disease (COPD) and promotes inflammation and cell death in the lungs. We investigated the combined effects of cigarette smoking and PM2.5 exposure in patients with COPD, mice, and human bronchial epithelial cells.
Methods
The relationship between PM2.5 exposure and clinical parameters was investigated in patients with COPD based on smoking status. Alveolar destruction, inflammatory cell infiltration, and pro-inflammatory cytokines were monitored in the smoking-exposed emphysema mouse model. To investigate the mechanisms, cell viability and death and pyroptosis-related changes in BEAS-2B cells were assessed following the exposure to cigarette smoke extract (CSE) and PM2.5.
Results
High levels of ambient PM2.5 were more strongly associated with high Saint George’s respiratory questionnaire specific for COPD (SGRQ-C) scores in currently smoking patients with COPD. Combined exposure to cigarette smoke and PM2.5 increased mean linear intercept and TUNEL-positive cells in lung tissue, which was associated with increased inflammatory cell infiltration and inflammatory cytokine release in mice. Exposure to a combination of CSE and PM2.5 reduced cell viability and upregulated NLRP3, caspase-1, IL-1β, and IL-18 transcription in BEAS-2B cells. NLRP3 silencing with siRNA reduced pyroptosis and restored cell viability.
Conclusions
PM2.5 aggravates smoking-induced airway inflammation and cell death via pyroptosis. Clinically, PM2.5 deteriorates quality of life and may worsen prognosis in currently smoking patients with COPD.
Graphical Abstract
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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.
Data availability
The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.
Abbreviations
- BALF:
-
Bronchoalveolar lavage fluid
- COPD:
-
Chronic obstructive pulmonary disease
- CSE:
-
Cigarette smoke extract
- DMSO:
-
Dimethyl sulfoxide
- ELISA:
-
Enzyme-linked immunosorbent assay
- GADPH:
-
Glyceraldehyde 3-phosphate dehydrogenase
- H&E:
-
Hematoxylin and eosin
- IFN:
-
Interferon, IL: Interleukin
- LDH:
-
Lactate dehydrogenase
- MLI:
-
Mean linear intercept
- MTT:
-
3-[4,5-imethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide
- NLR:
-
Nucleotide-binding oligomerization domain-like receptor
- NLRP3:
-
NLR protein-3
- PBS:
-
Phosphate-buffered saline
- PM2.5 :
-
Particulate matter of diameter ≤ 2.5 μm
- PMSF:
-
Phenylmethylsulfonyl fluoride
- QOL:
-
Quality of life
- qRT-PCR:
-
Quantitative real-time polymerase chain reaction
- SGRQ-C:
-
Saint George’s respiratory questionnaire specific for COPD
- TUNEL:
-
Terminal deoxynucleotidyl transferase dUTP nick end labeling
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Acknowledgements
We thank Sun-Hee Heo (Asan Medical Center), Shinhee Park (Gangneung Asan Hospital), Seung Won Ra (Ulsan University Hospital), and Sung-Yoon Kang (Gachon University Gil Medical Center) for their help with data collection.
Funding
This study was supported by grants from the research of the Korea Centers for Disease Control and Prevention [No. 2019ER671100 and 01, and 2021ER120900], the Korea Research Institute of Bioscience and Biotechnology (KRIBB) Research Initiative Program (YJP & SJL), the National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIT) (No. 2023R1A2C2006688 and RS-2023-00222687, SWL), the Bio & Medical Technology Development Program of the National Research Foundation (NRF) funded by the Korean government (MSIT) (No. 2022M3A9G8017220), Republic of Korea, and Medical Research Promotion Program through the Gangneung Asan Hospital funded by the Asan Foundation (2023II0003). The funder did not have any role in the design of the study and did not have any role in collection, analysis, and interpretation of data and in writing the manuscript.
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CC, SYP, and SWL conceived and designed the study. SYP, J-YH, NHK, CHS, EYO, Y-JP, S-JL, and H-CK performed experiments and collected the data. CC, SYP, J-YH, and SWL analyzed data and drafted the manuscript. All authors revised and approved the final manuscript. All authors accept responsibility for the accuracy of the content of the final manuscript.
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All animal care and experimental procedures were approved by Institutional Animal Care and Use Committee of Asan Medical Center (approval number 2020-12-342). The previous clinical study was individually approved by the Institutional Review Boards as follows: Asan Medical Center (2019 − 0479), Gangneung Asan Hospital (2019-06-049), Ulsan University Hospital (2019-07-049), and Gachon University Gil Medical Center (GBirb2019-290). All participants were given detailed information about the study and provided written informed consent. The study is registered at ClinicalTrials.gov (Registration No. NCT04020237). The present study adhered to the Declaration of Helsinki and the ARRIVE guidelines, and all procedures were carried out in accordance with the relevant guidelines.
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Chung, C., Park, S.Y., Huh, JY. et al. Fine particulate matter aggravates smoking induced lung injury via NLRP3/caspase-1 pathway in COPD. J Inflamm 21, 13 (2024). https://doi.org/10.1186/s12950-024-00384-z
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DOI: https://doi.org/10.1186/s12950-024-00384-z