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Transcriptome-wide profiling discover: PM2.5 aggravates airway dysfunction through epithelial barrier damage
Lei Zhang1, Xiang He1, Ying Xiong2
1Laboratory of Allergy and Precision Medicine, Chengdu Institute of Respiratory Health, the Third People's Hospital of Chengdu, Chengdu 610031, China; Department of Pulmonary and Critical Care Medicine, Chengdu Third People's Hospital Branch of National Clinical Research Center for Respiratory Disease, Affiliated Hospital of ChongQing Medical University, Chengdu 610031, China.
Background:
Epidemiologic evidence suggests that PM2.5 exposure aggravates asthma, but the molecular mechanisms are not fully discovered.
Methods:
Ovalbumin (OVA)-induced mice exposed to PM2.5 were constructed. Pathological staining and immunofluorescence were performed in in vivo study. Gene set enrichment analysis (GSEA) was performed to identify the pathway involved in asthma severity by using U-BIOPRED data (human bronchial biopsies) and RNA-seq data (Beas-2B cells treated with PM2.5). Lentiviruses transfection, Real-time qPCR, immunofluorescence staining and trans-epithelial electrical resistance (TEER) measurement were performed for mechanism exploration in vitro.
Results:
PM2.5 exposure aggravated airway inflammation and mucus secretion in OVA-induced mice. Based on transcriptome analysis of mild-to-severe asthma from human bronchial biopsies, gene set enrichment analysis (GSEA) showed that up-regulated reactive oxygen species (ROS) pathway gene set and down-regulated apical junction gene set correlated with asthma severity. Consistent with the analysis of mild-to-severe asthma, after PM2.5 exposure, the ROS pathway in Beas-2B cells was up-regulated with the down-regulation of apical junction. The expression levels of genes involved in the specific gene sets were validated by using qPCR. The mRNA levels of junction genes, ZO-1, E-cadherin and Occludin, were significantly decreased in cells exposed to PM2.5. Moreover, it confirmed that inhibition of ROS recovered the expression levels of E-cadherin, Occludin and ZO-1, and ameliorated inflammation and mucus secretion in airway in OVA-induced mice exposed to PM2.5. Meanwhile, ROS level was elevated by PM2.5. By checking trans-epithelial electrical resistance (TEER) value, we also found that epithelial barrier was damaged after PM2.5 exposure. Importantly, Stanniocalcin 2 (STC2) was identified as a key gene in regulation of epithelial barrier. It showed that STC2 expression was up-regulated by PM2.5, which was recovered by NAC as well. Over-expression of STC2 could decrease the expression levels of ZO-1, Occludin and E-cadherin. Contrarily, suppression of STC2 could increase the expression levels of ZO-1, Occludin and E-cadherin reduced by PM2.5.
Conclusions:
By using transcriptome analysis, we revealed that STC2 played a key role in PM2.5 aggravated airway dysfunction through regulation of epithelial barrier in OVA-induced mice.
Insights
Particulate matter (PM2.5) exposure worsens asthma by damaging the airway epithelial barrier. Stanniocalcin 2 (STC2) is identified as a key regulator in this process, offering potential therapeutic targets for PM2.5-induced airway dysfunction.
Area of Science:
- Environmental Health
- Pulmonology
- Molecular Biology
Background:
- Epidemiological studies link fine particulate matter (PM2.5) exposure to aggravated asthma.
- The precise molecular mechanisms underlying PM2.5-induced asthma exacerbation remain incompletely understood.
- Airway epithelial barrier integrity is crucial for respiratory health and is implicated in asthma pathogenesis.
Purpose of the Study:
- To elucidate the molecular mechanisms by which PM2.5 exposure exacerbates asthma.
- To investigate the role of reactive oxygen species (ROS) and epithelial barrier dysfunction in PM2.5-induced airway inflammation.
- To identify key regulatory genes involved in PM2.5-mediated airway dysfunction.
Main Methods:
- Established a mouse model of ovalbumin (OVA)-induced asthma exposed to PM2.5.
- Utilized transcriptomic analysis (RNA-seq) and Gene Set Enrichment Analysis (GSEA) on human bronchial biopsies and cell lines.
- Performed in vivo and in vitro experiments including gene expression analysis (qPCR), immunofluorescence, and measurement of epithelial barrier function (TEER).
Main Results:
- PM2.5 exposure worsened airway inflammation and mucus production in OVA-induced mice.
- Transcriptome analysis revealed up-regulation of the reactive oxygen species (ROS) pathway and down-regulation of apical junction genes, correlating with asthma severity.
- Stanniocalcin 2 (STC2) was identified as a key mediator, with its up-regulation by PM2.5 impairing epithelial barrier function (reduced ZO-1, E-cadherin, Occludin) and exacerbating inflammation; inhibition of ROS and STC2 ameliorated these effects.
Conclusions:
- PM2.5 exposure exacerbates asthma by disrupting the airway epithelial barrier, partly through ROS-mediated pathways.
- Stanniocalcin 2 (STC2) plays a critical role in PM2.5-induced airway dysfunction by regulating epithelial barrier integrity.
- Targeting STC2 and ROS may represent a therapeutic strategy for mitigating PM2.5-aggravated asthma.
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