Effects of Real-Ambient PM2.5 Exposure on Lung Damage Modulated by Nrf2−/−

Abstract

Previous studies have shown that long-term exposure to fine particulate matter (PM2.5) increases the morbidity and mortality of pulmonary diseases such as asthma, chronic obstructive pulmonary disease and pulmonary emphysema. Oxidative stress and inflammation play key roles in pulmonary damage caused by PM2.5. Nuclear factor erythroid 2-related factor 2 (Nrf2) could regulate the expression of antioxidant and anti-inflammatory genes and is pivotal for protection against PM2.5-induced oxidative stress. In this study, a real-ambient exposure system was constructed with the outdoor ambient air in north China. Wild-type (WT) and Nrf2−/− (KO) mice were exposed to the real-ambient system for six weeks. After PM2.5 exposure, our data showed that the levels of inflammatory factors and malondialdehyde were significantly increased in WT and KO mice. Moreover, the lung function and pathological phenotype of the WT mice were altered but there was no obvious change in the Nrf2−/− mice. To further explore the potential molecular mechanisms, we performed RNA-sequencing. The RNA-sequence analysis results showed that the CYP450 pathway in the first ten pathways of KEGG was related to the metabolism of PM2.5. In WT and KO mice, the expression of CYP2E1 in the CYP450 pathway showed opposite trends after PM2.5 exposure. The data showed that the expression of the CYP2E1 gene in WT-PM mice increased while it decreased in KO-PM; the expression of the CYP2E1 protein showed a similar trend. CYP2E1 is primarily distributed in the endoplasmic reticulum (ER) where it could metabolize various exogenous substances attached to PM2.5 and produce highly toxic oxidation products closely related to ER stress. Consistently, the expression level of GRP94, a biomarker of ER stress, was increased in WT mice and reduced in KO mice under PM2.5 exposure. Persistent ER stress is a mechanism that causes lung damage under PM2.5 exposure. Nrf2 facilitates lung injury during PM2.5 exposure and CYP2E1 metabolism is involved in this process.

Nrf2−/− regulated lung DNA demethylation and CYP2E1 DNA methylation under PM2.5 exposure

“…In short, the IVC exposure system consists of a control and exposure chamber, which is connected to a three-layer HEPA filter to produce filtered air (FA), and an exposure chamber which is connected to unfiltered air (PM). The factors (temperature, airflow, humidity, pressure, ventilation frequency, air flow rate, and noise) in both chambers are consistent (Ding et al, 2021). Eight-week-old Nrf2 Knockout mice and WT mice were placed in FA and PM chambers (10 mice per group), and the mice were given food and water freely in a circulating chamber with 12 h light and 12 dark.…”

“…Shijiazhuang City in Hebei Province experiences some of the most severe PM 2.5 pollution in China. The city's main sources of PM 2.5 are industrial emissions, vehicle exhaust, and coal burning (Zhang et al, 2021). Because of its severe pollution, we selected this city for our study.…”

“…CYP2E1, CYP1A1, and CYP2S1 are the key metabolic enzymes in phase I and are mainly located in the membrane of the endoplasmic reticulum (ER) and mitochondrion ( Mittal et al, 2015 ; Popescu et al, 2021 ). PM 2.5 exposure increases the expression of CYP2E1, which leads to lung injury via endoplasmic reticulum stress ( Ding et al, 2021 ). Exogenous chemicals in PM 2.5 can be metabolized by CYP1A1 to induce oxidative stress and inflammation, which lead to human lung cell injury ( Abbas et al, 2019 ).…”

Endoplasmic Reticulum Stress in Chronic Obstructive Pulmonary Disease: Mechanisms and Future Perspectives

“…These results suggest that the upregulation of NRF2 expression may help prevent oxidative stress-related COPD progression. Interestingly, recent studies have shown that NRF2-deficient mice that were chronically exposed to particulate matter 2.5 had elevated oxidative stress and depressed ER stress levels but did not show obvious emphysema [ 144 ]. This may be attributed to the fact that the NRF2 deficiency reduces the expression of cytochrome P450 family 2 subfamily E member 1, thereby diminishing the cellular damage resulting from the metabolism of exogenous compounds [ 144 , 145 ].…”

Multi-omics reveals hypertrophy of adipose tissue and lipid metabolism disorder via mitochondria in young mice under real-ambient exposure to air pollution

“…The real-ambient exposure system that was previously established in Shijiazhuang city was applied in this study ( Jiang et al, 2020 ; Ding et al, 2021 ). Compared to the concentrated ambient particle (CAP) exposure system, our system maintains the original chemical characteristics of PM2.5 and a concentration of PM2.5 similar to that of ambient PM2.5.…”