Recent evidence from omic analysis for redox signalling and mitochondrial oxidative stress in COPD.
Journal of inflammation (London, England)
COPD is driven by exogenous and endogenous oxidative stress derived from inhaled cigarette smoke, air pollution and reactive oxygen species from dysregulated mitochondria in activated inflammatory cells within the airway and lung. This is compounded by the loss in antioxidant defences including FOXO and NRF2 and other antioxidant transcription factors together with various key enzymes that attenuate oxidant effects. Oxidative stress enhances inflammation; airway remodelling including fibrosis and emphysema; post-translational protein modifications leading to autoantibody generation; DNA damage and cellular senescence. Recent studies using various omics technologies in the airways, lungs and blood of COPD patients has emphasised the importance of oxidative stress, particularly that derived from dysfunctional mitochondria in COPD and its role in immunity, inflammation, mucosal barrier function and infection. Therapeutic interventions targeting oxidative stress should overcome the deleterious pathologic effects of COPD if targeted to the lung. We require novel, more efficacious antioxidant COPD treatments among which mitochondria-targeted antioxidants and Nrf2 activators are promising.
10.1186/s12950-022-00308-9
NRF2 activates macropinocytosis upon autophagy inhibition.
Mondal Gourish,Debnath Jayanta
Cancer cell
Su et al. demonstrate that upon inhibiting autophagy, an intracellular nutrient recycling pathway, pancreatic ductal adenocarcinoma cells upregulate NRF2-mediated transcription of macropinocytosis pathway components, thereby triggering an alternate route for tumors to scavenge nutrients from extracellular sources. Accordingly, the combined inhibition of autophagy and macropinocytosis may improve cancer treatment.
10.1016/j.ccell.2021.03.011
PM Exacerbates Oxidative Stress and Inflammatory Response through the Nrf2/NF-κB Signaling Pathway in OVA-Induced Allergic Rhinitis Mouse Model.
Piao Chun Hua,Fan Yanjing,Nguyen Thi Van,Shin Hee Soon,Kim Hyoung Tae,Song Chang Ho,Chai Ok Hee
International journal of molecular sciences
Air pollution-related particulate matter (PM) exposure reportedly enhances allergic airway inflammation. Some studies have shown an association between PM exposure and a risk for allergic rhinitis (AR). However, the effect of PM for AR is not fully understood. An AR mouse model was developed by intranasal administration of 100 μg/mouse PM with a less than or equal to 2.5 μm in aerodynamic diameter (PM) solution, and then by intraperitoneal injection of ovalbumin (OVA) with alum and intranasal challenging with 10 mg/mL OVA. The effects of PM on oxidative stress and inflammatory response via the Nrf2/NF-κB signaling pathway in mice with or without AR indicating by histological, serum, and protein analyses were examined. PM administration enhanced allergic inflammatory cell expression in the nasal mucosa through increasing the expression of inflammatory cytokine and reducing the release of Treg cytokine in OVA-induced AR mice, although PM exposure itself induced neither allergic responses nor damage to nasal and lung tissues. Notably, repeated OVA-immunization markedly impaired the nasal mucosa in the septum region. Moreover, AR with PM exposure reinforced this impairment in OVA-induced AR mice. Long-term PM exposure strengthened allergic reactions by inducing the oxidative through malondialdehyde production. The present study also provided evidence, for the first time, that activity of the Nrf2 signaling pathway is inhibited in PM exposed AR mice. Furthermore, PM exposure increased the histopathological changes of nasal and lung tissues and related the inflammatory cytokine, and clearly enhanced PM phagocytosis by alveolar macrophages via activating the NF-κB signaling pathway. These obtained results suggest that AR patients may experience exacerbation of allergic responses in areas with prolonged PM exposure.
10.3390/ijms22158173
Inhibition of nuclear thioredoxin aggregation attenuates PM-induced NF-κB activation and pro-inflammatory responses.
Zhu Zhonghui,Chen Xiaowei,Sun Jingping,Li Qiuyue,Lian Ximeng,Li Siling,Wang Yan,Tian Lin
Free radical biology & medicine
Exposure to fine particulate matter (PM) can induce oxidative stress and proinflammatory cytokine production, which are central for the induction of PM-mediated adverse effects on public health. Nuclear factor kappa B (NF-κB) signaling is essential for inflammation. The subcellular distribution of thioredoxin (Trx) is related to the activation of NF-κB, but the mechanism involved is unclear. In the current study, we focused on the relationship between the antioxidant Trx and NF-κB in human bronchial epithelial cells (BEAS-2B) after PM exposure. We inhibited the nuclear translocation of Trx by cHCEU (4-cyclohexyl-[3-(2-chloroethyl)ureido]benzene) and subsequently increased the transcriptional activity of Nrf2 to upregulate the expression of Trx by t-BHQ. Our data suggest that PM exposure induces the activation of NF-κB and the expression of the downstream proinflammatory cytokines IL-1, IL-6, IL-8 and TNF-α in BEAS-2B cells. CHCEU alleviates inflammatory cytokines by blocking Trx nuclear translocation and inhibits the DNA binding activity of NF-κB. T-BHQ could promote the transcriptional activity of Nrf2 but failed to alleviate the production of inflammatory cytokines. Furthermore, the synergistic effect of t-BHQ and cHCEU on alleviating PM-induced inflammation is more effective than the use of cHCEU alone. Our findings characterize the underlying molecular mechanisms of proinflammatory responses induced by PM and show that the nuclear translocation and accumulation of Trx in nuclei play important roles in PM-induced NF-κB activation and proinflammatory responses.
10.1016/j.freeradbiomed.2018.10.438
Acute exposure to PM triggers lung inflammatory response and apoptosis in rat.
Li Yang,Batibawa Josevata Werelagi,Du Zhou,Liang Shuang,Duan Junchao,Sun Zhiwei
Ecotoxicology and environmental safety
Severe haze events, especially with high concentration of fine particulate matter (PM), are frequent in China, which have gained increasing attention among public. The purpose of our study was explored the toxic effects and potential damage mechanisms about PM acute exposure. Here, the diverse dosages of PM were used to treat SD rats and human bronchial epithelial cell (BEAS-2B) for 24 h, and then the bioassays were performed at the end of exposure. The results show that acute exposure to diverse dosages of PM could trigger the inflammatory response and apoptosis. The severely oxidative stress may contribute to the apoptosis. Also, the activation of Nrf2-ARE pathway was an important compensatory process of antioxidant damage during the early stage of acute exposure to PM. Furthermore, the HO-1 was suppression by siRNA that promoted cell apoptosis triggered by PM. In other words, enhancing the expression of HO-1 may mitigate the cell apoptosis caused by acute exposure to PM. In summary, our findings present the first time that prevent or mitigate the damage triggered by PM through antioxidant approaches was a promising strategy.
10.1016/j.ecoenv.2021.112526
[Recent advances in the study of Nrf2 and inflammatory respiratory diseases].
Xie Jian-lin,Lin Ming-bao,Hou Qi
Yao xue xue bao = Acta pharmaceutica Sinica
Nuclear factor-erythroid 2 related factor 2 (Nrf2) is an ubiquitous and important transcription factor. It regulates antioxidant response elements (AREs)-mediated expression of antioxidant enzyme and cytoprotective proteins. A large body of research showed that Nrf2-Keap1 (Kelch-like ECH-associated protein 1, Keap 1)-ARE signaling pathway is involved in the endogenous antioxidant defense mechanisms. Nrf2 increases the expression of a number of cytoprotective genes, protects cells and tissues from the injury of a variety of toxicants and carcinogens. As a result, Nrf2 enhances the expression of glutathione and antioxidants such as superoxide dismutase and glutathione S-transferase, and subsequently scavenging free radicals. Air pollution especially from PM2.5 particles, is associated with an increasing morbidity of inflammatory pulmonary diseases and their deterioration. More and more studies demonstrated that Nrf2 was a novel signaling molecule in the modulation of inflammatory responses in these inflammatory respiratory diseases, such as asthma, acute lung injury (ALI) and COPD. Therefore, Nrf2 targeting might be a therapeutic target, which will provide clinical benefit by reducing both oxidative stress and inflammation in asthma, acute lung injury (ALI) and COPD. This review focused on the relationship between Nrf2 and inflammatory respiratory diseases and oxidative stress.