Impacts of combined exposure to formaldehyde and PM2.5 at ambient concentrations on airway inflammation in mice☆
Graphical abstract
Introduction
Asthma is a chronic respiratory disease characterized by airway inflammation. As estimated by WHO, 235 million people globally suffer from asthma currently (Lozano et al., 2012). Around 250,000 people die prematurely from asthma each year (D'Amato et al., 2016). Both genetic and environmental factors can increase the risk of asthma (Toskala and Kennedy, 2015). However, the well-documented, rapid increase in the prevalence of allergic diseases like asthma cannot be attributed to genetic alterations (Tagiyeva and Sheikh, 2014). Scientists consider it highly likely that environmental factors such as fine particulate matter (Prunicki et al., 2018), and allergens (Jie et al., 2013) are likely to play a critical role in the etiology of these diseases.
Formaldehyde (FA) and PM2.5 are the most common indoor and outdoor air pollutants in China. The exposure of Chinese urban residents to FA is very high, and the health risks posed by FA are severe (Du et al., 2014). The global burden of disease in 2010 indicated that exposure to the fine particulate matter had become the fourth leading cause of death in China. Increasing evidence shows that exposure to either FA or PM2.5 is closely related to the occurrence of asthma (Kim et al., 2015; Yao et al., 2015). Research published in the Environmental Health Perspectives in 2016, warned that more attention should be paid to the hazards of pollutants at ambient concentrations (Mirabelli et al., 2016). Recent toxicological studies have demonstrated that PM2.5 not only caused acute oxidative stress and inflammation in the lungs of healthy mice (Riva et al., 2011) but also exacerbated the severity of asthma in sensitized mice at lower concentrations (Zhang et al., 2015). Similarly, ambient concentrations of FA also caused significant up-regulation of eosinophils in the lungs of asthmatic model mice (Liu et al., 2011). Unfortunately, the above studies only focused on the effects of exposure to either FA or PM2.5 on the respiratory system, while in reality, the actual environment in which people live almost always contains both FA and PM2.5. There are very few studies looking at the impact of exposure to these pollutants simultaneously. We have identified only one study that looked at the combined exposure of FA and PM2.5, in which they found that the combined exposure exacerbated allergic asthma (Song et al., 2017), however, the concentrations that the study focused on were relatively high. We, therefore, investigate the effect of simultaneous exposure to FA and PM2.5 at more ambient concentrations on airway inflammation in asthmatic mice, and also the possible mechanism responsible for these effects.
Oxidative stress (Lee and Yang, 2012), Th1/Th2 (Wardhana et al., 2013) and Treg/Th17 immune imbalance (Wardhana et al., 2013) is the most studied pathogeneses of allergic asthma that are associated with the development of allergic asthma symptoms such as elevated IgE, airway hyperresponsiveness (AHR), excessive airway mucus secretion, tissue remodeling and airway inflammation. The p38 MAPK pathway can be activated by oxidative stress, and then act on downstream kinases and transcription factors, to regulate cell proliferation, differentiation, apoptosis and secretion of inflammatory cytokines (Zhao et al., 2013). Studies have indicated that the activation of p38 MAPK may be involved in the regulation of the Th1/Th2 cytokine balance (Wancket et al., 2012). It is also essential in the production of IL-17A (Tang et al., 2016). Inhibiting p38 MAPK activity can improve allergen-induced infiltration of eosinophils, excessive mucus secretion and AHR (Chung, 2011). Lim et al. (2010) reported that FA can induce apoptosis of human lung epithelial cells through the p38 MAPK pathway, whereas Wang et al. (2017) found that PM can significantly enhance airway inflammation by activating NF-κB via the reactive oxygen species (ROS)-mediated MAPK pathway. Two other studies found that activation of the p38 MAPK signaling pathway is involved in ozone and diisodecyl phthalate (DIDP) induced aggravation of allergic asthma, and they showed that this aggravation could be significantly reduced by inhibiting the p38 MAPK signaling (Bao et al., 2017; Qin et al., 2018). We wondered whether p38 MAPK signaling also has a key role in the aggravation of allergic asthma when asthmatic mice are exposed to both FA and PM2.5 simultaneously.
In this study, an allergic asthma mouse model was established, and these mice were then exposed to FA and/or PM2.5 at ambient concentrations. We measured pulmonary function, examined histopathological sections, and evaluated inflammatory cytokines, oxidative stress and the activation of the p38 MAPK pathway and its downstream NF-κB, to investigate the effects of combined exposure on asthmatic mice. SB203580, a p38 MAPK specific inhibitor, was used to confirm the role played by the p38 MAPK pathway in aggravated asthma.
Section snippets
Animals
5-week-old (18–20g) specific pathogen-free male Balb/c mice were purchased from Hubei Province Experimental Animal Center. These mice were acclimatized for 7 days in pathogen-free cages at 20–25 °C and 50–70% relative humidity with a 12 h light-dark cycle. The Institutional Animal Care and Use Committee of Central China Normal University approved the experimental design on March 15, 2019 (Ratification ID: CCNU-IACUC-2019-009).
Main reagents and kits
Ovalbumin (>98%, OVA) and formalin solution (10%) were purchased from
Airway remodeling of lung tissue
As Fig. 1A shows, compared with the control group, the airway wall is thicker in the OVA-sensitized group, and fibrosis was observed around the airway. The airway wall of the 1FA + OVA group had wrinkles. The OVA group, 1PM2.5+OVA group and 0.5FA+0.5PM2.5+OVA group had more obvious inflammatory cell infiltration. Compared with the OVA group, the thickening of the airway, inflammatory cell infiltration, and airway fibrosis were only slightly, and not significantly, exacerbated in the FA or PM2.5
Discussion
At present, non-occupational exposure to FA is primarily via the respiratory route. Previous surveys of indoor FA concentrations showed that the average FA concentrations in Beijing and Shanghai were 210 μg/m3 and 205 μg/m3 respectively. Similar levels were found in Tianjin, Xi'an and some other cities in China (Huang et al., 2017) We therefore based our dosage calculations on an exposure concentration of 200 μg/m3. Since people spend about 90% of their lives indoors on average, the FA
Conclusion
In this study, the results suggest that exposure to a combination of FA and PM2.5 at ambient concentrations can synergistically aggravate airway inflammation, promote airway remodeling, further damage lung function, eventually resulting in the exacerbation of allergic asthma. The p38 MAPK pathway has an important role in the aggravation of asthma, and SB203580, an antagonist of p38 MAPK, can effectively block this damage.
CRediT authors statement
Xianxian Lu: Investigation; Methodology; Data curation; Visualization; Writing – original draft; Writing – review & editing. Cunyi Gong: Investigation; Methodology; Data curation; Visualization; Writing – original draft; Writing – review & editing. Ke Lv: Resources; Investigation; Methodology; Data curation. Lifang Zheng: Investigation; Methodology; Writing - editing. Beibei Li: Writing - editing. Yuanteng Zhao: Methodology; Data curation. Haonan Lu: Investigation; Methodology. Tingting Wei:
Declaration of competing interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgments
This research is financially supported by the National Natural Science Foundation of China (42077403) and self-determined research funds of CCNU from the colleges' basic research and operation of MOE (CCNU18JCXK07 and CCNU19TS066).
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This paper has been recommended for acceptance by Wen Chen.
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Xianxian Lu and Cunyi Gong contributed equally to this work.