Chronic lung inflammation and pulmonary fibrosis after multiple intranasal instillation of PM2.5 in mice

Abstract

Background: Fine particulate matter (PM 2.5 ) is an important component of air pollution and can induce lung inflammation and oxidative stress. We hypothesised that PM 2.5 could play a role in the induction of pulmonary fibrosis. We examined whether multiple intranasal instillation of PM 2.5 can induce pulmonary fibrosis in the mouse, and also investigated the underlying pro-fibrotic signaling pathways.Methods: C57/BL6 mice were intranasally instilled with 50 μl of PM 2.5 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 PM 2.5 exposure, 9 week-PM 2.5 instilled mice were also studied at 3 weeks after termination of instillation.Results: There were significant decreases in total lung capacity (TLC) and compliance (Cchord) in the 9-week PM 2.5 -instilled mice, while there was an increase in total cell counts in bronchoalveolar fluid and lung section in 3-week, 6-week and 9-week PM 2.5 -instilled mice and 9 week-PM 2.5 instilled-3 week-air exposed mice. There were increased histological fibrosis scores with enhanced type I collagen and hydroxyproline deposition in lung tissue in 6-week and 9-week PM 2.5 -instilled mice and 9-week-PM 2.5 instilled-3-week-air-exposed mice. Multiple PM 2.5 instillation resulted in increased expression of TGFβ1, increases of N-Cadherin and Vimentin and 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, NOX4 and NLRP3 expression.Conclusions: The intranasal instillation of PM 2.5 for 9 weeks induced lung inflammation and pulmonary fibrosis, which was linked with aberrant epithelial-mesenchymal transition, mitochondrial damage and mitophagy, as well as activation of TGFβ1-PI3K/Akt and TGFβ1-NOX4 -NLRP3 pathways.

Epigallocatechin Gallate Relieved PM2.5-Induced Lung Fibrosis by Inhibiting Oxidative Damage and Epithelial-Mesenchymal Transition through AKT/mTOR Pathway

“…Fibrosis is one of the most important features of PM2.5-induced lung injury [ 28 ]. Hence, we also observed the effects of EG on lung fibrosis of mice challenged with PM2.5.…”

The Physiological Effects of Air Pollution: Particulate Matter, Physiology and Disease

“…Mechanisms by which PM may induce fibrosis include increased intracellular edema, microvilli density, lamellar bodies and the density of macrophages containing endocytosed PM ( 40 ). In mice, PM2.5 exposure reduced mitochondrial density, increased NADPH oxidase 2 expression, significantly reduced total lung capacity, inspiratory capacity, and lung compliance ( 48 ). This same study found that PM2.5 exposure increased lung epithelia expression of N-Cadherin and reduced that of E-Cadherin; markers of epithelial-mesenchymal transition, a process common to cancer metastasis ( 48 ).…”

Remarkable contribution of particulate matter-induced macrophage ferroptosis to the pathology of pulmonary fibrosis

“…Experimental data in animals have indicated that pulmonary fibrosis is closely associated with PM exposure 23,24 . Previous studies have revealed that diffuse interstitial pulmonary fibrosis causes compromised pulmonary compliance and capillary bed, leading to severe respiratory dysfunction 25,26 .…”