Sirtuin 3 deficiency exacerbates emphysema and lung inflammation in a murine model of chronic obstructive pulmonary disease.

IF 3.6 2区 医学 Q1 PHYSIOLOGY
Taro Ishimori, Minako Saito, Masaaki Yuki, Mototaka Hattori, Masahiro Shuzui, Saki Nagoshi, Shiho Kono, Hideaki Isago, Hiroyuki Tamiya, Naoya Miyashita, Takashi Ishii, Yu Mikami, Takahide Nagase, Yasuhiro Terasaki, Yoichi Shinozaki, Akihisa Mitani
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引用次数: 0

Abstract

Chronic obstructive pulmonary disease (COPD) is a progressive lung disease caused mainly by cigarette smoke-mediated induction of oxidative stress. Sirtuin 3 (SIRT3) regulates reactive oxygen species levels, but there are no definitive reports on its role in COPD pathogenesis. We hypothesized that SIRT3 plays a protective role in COPD. First, we observed significantly reduced SIRT3 expression in COPD lungs and identified smoking as a suppressive factor for SIRT3 expression in the airway epithelium. Next, we analyzed the lung phenotypes of SIRT3 knockout (KO) mice and SIRT3-overexpressing transgenic (OE) mice, and induced a COPD model in these mice using elastase and lipopolysaccharide. We subsequently investigated the effects of SIRT3 on cytokine production, oxidative stress, and apoptosis in airway epithelial cells in vitro. SIRT3 knockout mice exhibited increased expression of apoptosis markers, and aged SIRT3 KO mice and SIRT3 KO COPD model mice exhibited a worsened emphysematous phenotype. By contrast, this effect was mitigated in SIRT3 OE COPD model mice. In vitro studies revealed that SIRT3 deficiency exacerbated inflammation, oxidative stress, and apoptosis in airway epithelial cells. We concluded that SIRT3 plays a vital role in COPD pathogenesis and could be a novel therapeutic target.NEW & NOTEWORTHY Our study is the first to elucidate the protective role of SIRT3 in the pathogenesis of COPD by modulating inflammatory responses and apoptosis. We have demonstrated that SIRT3 knockout mice spontaneously develop emphysema, and SIRT3 overexpression reduced elastase and LPS-induced emphysematous changes. In vitro studies have shown that SIRT3 deficiency leads to increased inflammation, oxidative stress, and apoptosis in airway and alveolar epithelium, contributing to the formation and exacerbation of emphysema.

Sirtuin 3缺乏在慢性阻塞性肺疾病小鼠模型中加重肺气肿和肺部炎症
慢性阻塞性肺疾病(COPD)是一种主要由吸烟介导的氧化应激引起的进行性肺部疾病。Sirtuin 3 (SIRT3)调节活性氧水平,但其在COPD发病机制中的作用尚无明确的报道。我们假设SIRT3在COPD中起保护作用。首先,我们观察到SIRT3在COPD肺中的表达显著降低,并确定吸烟是气道上皮中SIRT3表达的抑制因素。接下来,我们分析了SIRT3敲除(KO)小鼠和SIRT3过表达转基因(OE)小鼠的肺表型,并在这些小鼠中使用弹性蛋白酶和LPS诱导COPD模型。随后,我们在体外研究了SIRT3对气道上皮细胞细胞因子产生、氧化应激和凋亡的影响。SIRT3敲除小鼠表现出凋亡标志物的表达增加,老年SIRT3 KO小鼠和SIRT3 KO COPD模型小鼠表现出恶化的肺气肿表型。相比之下,这种影响在SIRT3 OE COPD模型小鼠中减轻。体外研究显示SIRT3缺乏会加重气道上皮细胞的炎症、氧化应激和凋亡。我们得出结论,SIRT3在COPD发病机制中起着至关重要的作用,可能是一个新的治疗靶点。
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来源期刊
CiteScore
9.20
自引率
4.10%
发文量
146
审稿时长
2 months
期刊介绍: The American Journal of Physiology-Lung Cellular and Molecular Physiology publishes original research covering the broad scope of molecular, cellular, and integrative aspects of normal and abnormal function of cells and components of the respiratory system. Areas of interest include conducting airways, pulmonary circulation, lung endothelial and epithelial cells, the pleura, neuroendocrine and immunologic cells in the lung, neural cells involved in control of breathing, and cells of the diaphragm and thoracic muscles. The processes to be covered in the Journal include gas-exchange, metabolic control at the cellular level, intracellular signaling, gene expression, genomics, macromolecules and their turnover, cell-cell and cell-matrix interactions, cell motility, secretory mechanisms, membrane function, surfactant, matrix components, mucus and lining materials, lung defenses, macrophage function, transport of salt, water and protein, development and differentiation of the respiratory system, and response to the environment.
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