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Chronic lung inflammation and pulmonary fibrosis after multiple intranasal instillation of PM2 .5 in mice
Mengmeng Xu1,2, Xiaohui Wang3, Lu Xu2
1Department of Pulmonary and Critical Care Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China.
Abstract:
Fine particulate matter (PM2.5 ) is an important component of air pollution and can induce lung inflammation and oxidative stress. We hypothesized that PM2.5 could play a role in the induction of pulmonary fibrosis. We examined whether multiple intranasal instillation of PM2.5 can induce pulmonary fibrosis in the mouse, and also investigated the underlying pro-fibrotic signaling pathways. C57/BL6 mice were intranasally instilled with 50 μl of PM2.5 suspension (7.8 μg/g body weight) or PBS three times a week over 3 weeks, 6 weeks or 9 weeks. To observe the recovery of pulmonary fibrosis after the termination of PM2.5 exposure, 9 week-PM2.5 instilled mice were also studied at 3 weeks after termination of instillation. There were significant decreases in total lung capacity (TLC) and compliance (Cchord) in the 9-week PM2.5 -instilled mice, while there were increased histological fibrosis scores with enhanced type I collagen and hydroxyproline deposition, increased mitochondrial ROS levels and NOX activity, decreased total SOD and GSH levels, accompanied by decreased mitochondrial number and aberrant mitochondrial morphology (swelling, vacuolization, cristal disruption, reduced matrix density) in PM2.5 -instilled mice. Multiple PM2.5 instillation resulted in increased expression of TGFβ1, increases of N-Cadherin and Vimentin and a decrease of E-Cadherin. It also led to decreases in OPA1 and MFN2, and increases in Parkin, SQSTM1/p62, the ratio of light china (LC) 3B II to LC3B I, PI3k/Akt phosphorylation, and NLRP3 expression. Intranasal instillation of PM2.5 for 9 weeks induced lung inflammation and pulmonary fibrosis, which was linked with aberrant epithelial-mesenchymal transition, oxidative stress, mitochondrial damage and mitophagy, as well as activation of TGFβ1-PI3K/Akt, TGFβ1- NOX and TGFβ1-NLRP3 pathways.
Insights
Fine particulate matter (PM2.5) exposure causes lung inflammation and fibrosis in mice. This study reveals PM2.5 induces pulmonary fibrosis through oxidative stress, mitochondrial damage, and specific signaling pathways.
Area of Science:
- Environmental Health
- Toxicology
- Pulmonology
Background:
- Fine particulate matter (PM2.5) is a major air pollutant linked to respiratory issues.
- PM2.5 is known to cause lung inflammation and oxidative stress.
- Its role in inducing pulmonary fibrosis requires further investigation.
Purpose of the Study:
- To investigate if repeated intranasal instillation of PM2.5 induces pulmonary fibrosis in mice.
- To explore the underlying pro-fibrotic signaling pathways involved in PM2.5-induced lung damage.
Main Methods:
- C57/BL6 mice were exposed to PM2.5 via intranasal instillation three times weekly for 3, 6, or 9 weeks.
- Lung function (TLC, Cchord), histological fibrosis, collagen deposition, oxidative stress markers, mitochondrial function, and key signaling pathways (TGFβ1, epithelial-mesenchymal transition, mitophagy, NLRP3) were assessed.
- Recovery was studied 3 weeks after 9-week exposure cessation.
Main Results:
- Nine weeks of PM2.5 instillation significantly reduced lung capacity and compliance, increased fibrosis scores, collagen, and hydroxyproline deposition.
- PM2.5 exposure led to increased mitochondrial ROS, NOX activity, and NLRP3 expression, alongside decreased SOD and GSH.
- Aberrant mitochondrial morphology, decreased mitochondrial numbers, epithelial-mesenchymal transition, and activation of TGFβ1-PI3K/Akt, TGFβ1-NOX, and TGFβ1-NLRP3 pathways were observed.
Conclusions:
- Repeated intranasal PM2.5 instillation for 9 weeks induces lung inflammation and pulmonary fibrosis in mice.
- The fibrosis is associated with epithelial-mesenchymal transition, oxidative stress, mitochondrial damage, mitophagy, and activation of specific pro-fibrotic signaling pathways.
- These findings highlight PM2.5 as a potential inducer of pulmonary fibrosis and elucidate key molecular mechanisms.
