GRP78 在香烟烟雾诱导的气道上皮细胞炎症反应中介导线粒体融合和分裂。

IF 2 4区 医学 Q4 TOXICOLOGY
Inhalation Toxicology Pub Date : 2024-10-01 Epub Date: 2024-11-20 DOI:10.1080/08958378.2024.2428163
Yong Wang, Ya-Jing Li, Chen-Chen Li, Li Pu, Wan-Li Geng, Fei Gao, Qing Zhang
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引用次数: 0

摘要

目的:慢性阻塞性肺病(COPD)的特点是持续的气道炎症,香烟烟雾是造成上皮损伤的主要因素。最近的研究表明,线粒体功能异常与气道炎症的发生和发展密切相关。材料与方法:将人支气管上皮细胞(HBE)暴露于香烟烟雾提取物(CSE)中,评估线粒体融合标志物 MFN2 和 OPA1、裂变标志物 DRP1 以及葡萄糖调控蛋白 GRP78 的表达。研究人员采用了针对 DRP1、MFN2 和 GRP78 的 siRNA 和药物。对细胞和上清液进行了炎症因子水平及相关信号通路的分析:结果:在这项研究中,暴露于 CSE 的 HBE 细胞显示出 MFN2 和 OPA1 蛋白的显著减少以及 DRP1 蛋白的增加。抑制 DRP1 的表达可减轻炎症,而沉默 MFN2 则会加剧炎症。使用 DRP1 抑制剂 mdivi-1 和 MFN2 激活剂来氟米特也同样证实了这一点。此外,我们还证明了 GRP78 作为一种重要的内质网蛋白发挥着重要的调节作用,它能调节线粒体的融合/分裂过程,进而激活 NF-κB 通路以调节气道炎症:综上所述,这些结果表明 GRP78 介导的线粒体融合和裂变过程在香烟烟雾诱导的气道炎症中发挥了重要作用,并可能成为这方面的潜在治疗靶点。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
GRP78 mediates mitochondrial fusion and fission in cigarette smoke-induced inflammatory responses in airway epithelial cells.

Objective: Chronic obstructive pulmonary disease (COPD) is characterized by persistent airway inflammation, with cigarette smoke being a major contributor to epithelial injury. Recent studies have shown that abnormal mitochondrial function is closely linked to the onset and progression of airway inflammation. This study aims to explore the role and underlying molecular mechanisms of mitochondrial dynamics in cigarette smoke-induced airway inflammation.

Materials and methods: Human bronchial epithelial (HBE) cells were exposed to cigarette smoke extract (CSE) to assess the expression of mitochondrial fusion markers MFN2 and OPA1, the fission marker DRP1, and the glucose-regulated protein GRP78. The siRNA and pharmaceutics targeting DRP1, MFN2, and GRP78 were employed. Both cells and supernatants were analyzed for inflammatory factor levels and the related signaling pathways.

Results: In this study, HBE cells exposed to CSE showed a significant decrease in the proteins MFN2 and OPA1 and an increase in DRP1. The inhibition of DRP1 expression mitigated inflammation while silencing MFN2 exacerbated it. This was similarly corroborated by the use of the DRP1 inhibitor mdivi-1 and the MFN2 activator leflunomide. Additionally, we proved that GRP78 played an important regulatory role as an essential endoplasmic reticulum protein, regulating the mitochondrial fusion/fission process and subsequently activating the NF-κB pathway to regulate airway inflammation.

Discussion and conclusion: Taken together, these results suggested that the GRP78-mediated mitochondrial fusion and fission process played a vital role in cigarette smoke-induced airway inflammation and might be a potential therapeutic target in this regard.

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来源期刊
Inhalation Toxicology
Inhalation Toxicology 医学-毒理学
CiteScore
4.10
自引率
4.80%
发文量
38
审稿时长
6-12 weeks
期刊介绍: Inhalation Toxicology is a peer-reviewed publication providing a key forum for the latest accomplishments and advancements in concepts, approaches, and procedures presently being used to evaluate the health risk associated with airborne chemicals. The journal publishes original research, reviews, symposia, and workshop topics involving the respiratory system’s functions in health and disease, the pathogenesis and mechanism of injury, the extrapolation of animal data to humans, the effects of inhaled substances on extra-pulmonary systems, as well as reliable and innovative models for predicting human disease.
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