Interleukin-9 promotes EMT-mediated PM2.5-induced pulmonary fibrosis by activating the STAT3 pathway
Yuxuan Li1, Yi Zhong1, Chenwen Li1,2
1Environmental Health Effects and Risk Assessment Key Laboratory of Luzhou, School of Public Health, Southwest Medical University, Luzhou, 646000, China.
Abstract:
This study investigated the impact of PM2.5 on promoting EMT in PM2.5-induced pulmonary fibrosis (PF) development and explored molecular mechanisms of the IL-9/STAT3/Snail/TWIST1 signaling pathway in PF owing to PM2.5. Four groups of male SD rats were formed: control (0 mg/kg.bw), low (1 mg/kg.bw), medium (5 mg/kg.bw), and high-dose (25 mg/kg.bw) PM2.5 groups. Experimental rats were subjected to PM2.5 exposure via intratracheal instillation, given once weekly for 16 weeks. 24 h after the final exposure, blood, BALF, and lung tissues were collected. Pulmonary epithelial cells underwent cultivation and exposure to varying PM2.5 concentrations with/without inhibitors for 24 h, after which total protein was extracted for relevant protein assays. The findings demonstrated that PM2.5 damaged lung tissue to different degrees and led to PF in rats. Rats subjected to PM2.5 exposure exhibited elevated concentrations of IL-9 protein in both serum and BALF, and elevated levels of IL-9 and its receptor, IL-9R, in lung tissues, compared to control counterparts. Furthermore, PM2.5-exposed groups demonstrated significantly augmented protein levels of p-STAT3, Snail, TWIST1, Vimentin, COL-I, and α-SMA, while displaying notably diminished levels of E-Cadherin compared to control group. The same findings were observed in PM2.5-treated cells. In BEAS-2B cells co-treated with Stattic (STAT3 inhibitor) and PM2.5, the opposite results occurred. Similar results were obtained for cells co-treated with IL-9-neutralizing antibody and PM2.5. Our findings suggest PM2.5 mediates PF development by promoting IL-9 expression, leading to STAT3 phosphorylation and upregulation of Snail and TWIST1 expression, triggering EMT occurrence and progression in lung epithelial cells.
Insights
Fine particulate matter (PM2.5) exposure causes pulmonary fibrosis by activating the IL-9/STAT3 pathway, promoting epithelial-mesenchymal transition (EMT). This study reveals PM2.5
Area of Science:
- Environmental Health
- Pulmonary Medicine
- Molecular Biology
Background:
- Particulate matter (PM2.5) is a major air pollutant linked to respiratory diseases.
- Pulmonary fibrosis (PF) is a chronic lung disease characterized by progressive scarring.
- Epithelial-mesenchymal transition (EMT) plays a crucial role in the pathogenesis of PF.
Purpose of the Study:
- To investigate the role of PM2.5 in promoting EMT in PF development.
- To elucidate the molecular mechanisms involving the IL-9/STAT3/Snail/TWIST1 signaling pathway in PM2.5-induced PF.
Main Methods:
- Male Sprague-Dawley rats were exposed to varying doses of PM2.5 via intratracheal instillation for 16 weeks.
- Pulmonary epithelial cells were treated with PM2.5 and specific pathway inhibitors.
- Serum, bronchoalveolar lavage fluid (BALF), and lung tissues were analyzed for protein and gene expression.
Main Results:
- PM2.5 exposure led to significant lung tissue damage and PF development in rats.
- Elevated levels of IL-9, IL-9R, p-STAT3, Snail, TWIST1, Vimentin, COL-I, and α-SMA were observed in PM2.5-exposed groups.
- Decreased E-Cadherin levels and increased EMT markers were noted in PM2.5-treated cells, which were reversed by STAT3 inhibition or IL-9 neutralization.
Conclusions:
- PM2.5 induces pulmonary fibrosis by promoting IL-9 expression.
- The IL-9/STAT3 signaling pathway is critical for PM2.5-mediated EMT and PF.
- Targeting this pathway may offer therapeutic strategies for PM2.5-related lung diseases.
