Endoplasmic reticulum stress is involved in ventilator-induced lung injury in mice via the IRE1α-TRAF2-NF-κB pathway

Liu, Ye; Zeng, Qi; Dai, Huijun; Zhang, Weikang; Wang, Xiaoxia; Ma, Riliang; Hong, Xueqi; Zhao, Chen; Pan, Linghui

doi:10.1016/j.intimp.2019.106069

Cited by 26 publications

(22 citation statements)

References 36 publications

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“…And the ER stress was also increased in WT-PM mice compared with WT-FA mice. Previous study has shown that ER stress is involved in ventilator-induced lung injury in mice via the IRE1α-TRAF2-NF-κB pathway (Ye et al, 2020). Therefore, the lung function and pathology showed significant changes in WT mice after exposure to PM 2.5 .…”

Section: Discussionmentioning

confidence: 92%

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

Ding

Jiang

et al. 2021

Front. Pharmacol.

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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.

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Section: Discussionmentioning

confidence: 92%

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

Ding

Jiang

et al. 2021

Front. Pharmacol.

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“…However, excessive ventilation can exacerbate pre-existing lung damage and damage healthy lungs, this process is known as Vili (22,23). The mechanisms of Vili involve atelectrauma, barotrauma, biotrauma and volutrauma (24), although there are numerous factors that have been considered as possible triggers for VILI. Based on a previous study (20), a rat Vili model using the HVT-MV method was successfully established in the present study.…”

Section: Discussionmentioning

confidence: 99%

Dexmedetomidine reduces ventilator-induced lung injury via ERK1/2 pathway activation

Zhu

Ben-qing

et al. 2020

Mol Med Rep

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Mechanical ventilation (MV) can contribute to ventilator-induced lung injury (Vili); dexmedetomidine (dex) treatment attenuates MV-related pulmonary inflammation, but the mechanisms remain unclear. Therefore, the present study aimed to explore the protective effect and the possible molecular mechanisms of dex in a Vili rodent model. adult male Sprague-dawley rats were randomly assigned to one of seven groups (n=24 rats/group). rats were euthanized after 4 h of continuous MV, and pathological changes, lung wet/dry (W/D) weight ratio, the levels of inflammatory cytokines (il-1β, TnF-α and il-6) in the bronchoalveolar lavage fluid (BALF), and the expression levels of Bcl-2 homologous antagonist/killer (Bak), Bcl-2, pro-caspase-3, cleaved caspase-3 and the phosphorylation of erK1/2 in the lung tissues were measured. Propidium iodide uptake and Tunel staining were used to detect epithelial cell death. The dex pretreatment group exhibited fewer pathological changes, lower W/d ratios and lower expression levels of inflammatory cytokines in BALF compared with the VILI group. Dex significantly attenuated the ratio of Bak/Bcl-2, cleaved caspase-3 expression levels and epithelial cell death, and increased the expression of phosphorylated erK1/2. The protective effects of dex could be partially reversed by Pd98059, which is a mitogen-activated protein kinase (upstream of erK1/2) inhibitor. overall, dexmedetomidine was found to reduce the inflammatory response and epithelial cell death caused by Vili, via the activation of the erK1/2 signaling pathway.

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“…CHOP is a proapoptotic transcription factor which was activated via three pathways, including protein kinase RNA-(PKR-) like/pancreatic ER kinase (PERK), activating transcription factor 6 (ATF-6), and inositol-requiring enzyme 1 (IRE-1) pathways [51]. In addition to inducing apoptosis, CHOP also plays an important role in modulating NF-κB signaling [52] which is a major regulator to modulate the expression of TSP-1 [21]. Furthermore, an increase in ROS production under ER stress could also activate multiple proinflammatory cytokines, including NF-κB [53].…”

Section: Endoplasmic Reticulum (Er)mentioning

confidence: 99%

Thrombospondin-1: A Key Protein That Induces Fibrosis in Diabetic Complications

Zhang

Chen

et al. 2020

Journal of Diabetes Research

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Fibrosis accompanies most common pathophysiological features of diabetes complications in different organs. It is characterized by an excessive accumulation of extracellular matrix (ECM) components, the response to which contributes to inevitable organ injury. The extracellular protein thrombospondin-1 (TSP-1), a kind of extracellular glycoprotein, is upregulated by the increased activity of some transcription factors and results in fibrosis by activating multiple pathways in diabetes. The results of studies from our team and other colleagues indicate that TSP-1 is associated with the pathological process leading to diabetic complications and is considered to be the most important factor in fibrosis. This review summarizes the molecular mechanism of increased TSP-1 induced by hyperglycemia and the role of TSP-1 in fibrosis during the development of diabetes complications.

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Endoplasmic reticulum stress is involved in ventilator-induced lung injury in mice via the IRE1α-TRAF2-NF-κB pathway

Cited by 26 publications

References 36 publications

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

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

Dexmedetomidine reduces ventilator-induced lung injury via ERK1/2 pathway activation

Thrombospondin-1: A Key Protein That Induces Fibrosis in Diabetic Complications

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