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Critical role of mitochondrial oxidative stress in acid aspiration induced ALI in mice.
线粒体氧化应激在酸吸入诱导的小鼠 ALI 中的关键作用。
- 影响因子:2.32
- DOI:10.1080/15376516.2019.1710888
- 作者列表:"Puri G","Naura AS
- 发表时间:2020-01-16
Abstract
:Acute lung injury (ALI) is a pulmonary inflammatory disorder which causes significant mortality in critically ill patients. Intracellular oxidative stress has been considered to be the major component in the pathogenesis of ALI but exact source of intracellular ROS is not clearly known. The present study has been designed to elucidate the role of NADPH oxidase system and/or mitochondrial oxidative stress and its downstream pathway NLRP3 inflammasomes in mouse model of acid aspiration mediated ALI. Our data showed that acid aspiration induced lung inflammation was associated with enhanced oxidative stress as evident by data on MDA levels, nitrite levels and redox imbalance. Further acid aspiration resulted in elevation of expression of NADPH oxidase subunits (gp91 phox/p22 phox/p67 phox) as well as mitochondrial oxidative stress as reflected by aconitase activity, mitochondrial ROS levels. Interestingly, NADPH oxidase inhibitor, apocynin did not alter lung inflammation upon HCl instillation. Conversely, mitochondrial antioxidant mito-tempo resulted in significant amelioration of lung inflammation as indicated by suppression of pulmonary neutrophils and inflammatory cytokines namely IL-1β, TNF-α, IL-6 in BALF. Analysis of mitochondrial enzymes aconitase/mitochondrial ROS/Mn-SOD confirmed that reduction in lung inflammation by mito-tempo was associated with normalization of oxidative stress in mitochondria. Further, mito-tempo administration blunted phosphorylation of p65- NF-κB at Ser 536. Finally, mito-tempo downregulated HCl-induced NF-κB-dependent pro-inflammatory cytokines (IL-1β, TNF-α, IL-6) drastically at mRNA levels. Overall, our data support that mitochondrial oxidative stress is crucial in modulating the HCl induced lung inflammation and identifies mitochondrial-targeted antioxidant as a potential therapeutic agent.
摘要
急性肺损伤 (ALI) 是一种肺部炎症性疾病,可导致危重患者的严重死亡。细胞内氧化应激已被认为是 ALI 发病机制中的主要成分,但细胞内 ROS 的确切来源尚不清楚。本研究旨在阐明 NADPH 氧化酶系统和/或线粒体氧化应激及其下游通路 NLRP3 炎症小体在酸吸入介导的 ALI 小鼠模型中的作用。我们的数据表明,酸吸入诱导的肺部炎症与氧化应激增强有关,从 MDA 水平、亚硝酸盐水平和氧化还原失衡的数据可以明显看出。进一步的酸抽吸导致 NADPH 氧化酶亚单位 (gp91 phox/p22 phox/p67 phox) 的表达升高,以及由乌头酸酶活性、线粒体 ROS 水平反映的线粒体氧化应激。有趣的是,NADPH 氧化酶抑制剂 apocynin 在 HCl 滴注后没有改变肺部炎症。相反,线粒体抗氧化剂 mito-tempo 可显著改善肺部炎症,表现为抑制肺中性粒细胞和 BALF 中的炎性细胞因子,即 il-1 β 、 TNF-α 、 IL-6。线粒体酶乌头酸酶/线粒体 ROS/Mn-SOD 的分析证实,mito-tempo 减少肺部炎症与线粒体氧化应激正常化相关。此外,mito-tempo 给药在 Ser 536 时钝化了 p65-NF-κ b 的磷酸化。最后,mito-tempo 在 mRNA 水平显著下调 HCl 诱导的 NF-κ b 依赖性促炎细胞因子 (il-1 β 、 TNF-α 、 IL-6)。总的来说,我们的数据支持线粒体氧化应激在调节 HCl 诱导的肺部炎症中至关重要,并确定线粒体靶向抗氧化剂是一种潜在的治疗药物。
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