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Heterozygous SOD2 deletion deteriorated chronic intermittent hypoxia-induced lung inflammation and vascular remodeling through mtROS-NLRP3 signaling pathway.
Acta Pharmacologica Sinica ( IF 8.2 ) Pub Date : 2020-02-17 , DOI: 10.1038/s41401-019-0349-y
Jie-Qiong Song 1, 2 , Li-Yan Jiang 1 , Cui-Ping Fu 1 , Xu Wu 1 , Zi-Long Liu 1 , Liang Xie 1, 3 , Xiao-Dan Wu 1, 3 , Sheng-Yu Hao 1, 3 , Shan-Qun Li 1, 3
Affiliation  

Oxidative stress caused by chronic intermittent hypoxia (CIH) is the hallmark of obstructive sleep apnea (OSA). Among the first line of defense against oxidative stress is the dismutation of superoxide radicals, which in the mitochondria is carried out by manganese superoxide dismutase (SOD2). In this study, wild-type (WT) and SOD2-heterozygous knockout (SOD2+/-) mice were exposed to CIH or normoxic (Nor) conditions. After 4 weeks, pulmonary artery pressure was measured, and the mice were processed to harvest either serum for cytokine assays or lungs for flow cytometry and histopathological studies. Herein, we showed that heterozygous deletion of SOD2 markedly deteriorated pulmonary remodeling and increased the oxidative stress, especially promoted the infiltration of macrophages in the lungs of CIH mouse. Moreover, in the intermittent hypoxia (IH)-treated RAW264.7 cells, SOD2 knockdown increased the nucleotide-binding domain-like receptor protein 3 (NLRP3) inflammasome activation accompanied with the IL-1β elevation and caspase-1 activity. Additionally, mitochondrial ROS (mtROS) scavenger mito-TEMPO abolished NLRP3 inflammasome activation in IH-treated RAW264.7 cells. Collectively, our results supported that SOD2 contributed to the pathogenesis of CIH-induced lung remodeling. Meanwhile, SOD2 knockdown exacerbates oxidative damage through assembly and activation of NLRP3 inflammasome in macrophages. SOD2 may be a novel therapeutic target for CIH-induced pulmonary inflammation and arteriole remodeling.

中文翻译:

杂合SOD2缺失通过mtROS-NLRP3信号通路恶化了慢性间歇性缺氧诱导的肺部炎症和血管重塑。

慢性间歇性缺氧(CIH)引起的氧化应激是阻塞性睡眠呼吸暂停(OSA)的标志。抵御氧化应激的第一道防线是超氧化物自由基的歧化,其在线粒体中是通过锰超氧化物歧化酶(SOD2)进行的。在这项研究中,野生型(WT)和SOD2杂合敲除(SOD2 +/-)小鼠暴露于CIH或常氧(Nor)条件下。4周后,测量肺动脉压,处理小鼠以收集血清用于细胞因子测定,或收集肺用于流式细胞术和组织病理学研究。在这里,我们表明,SOD2的杂合缺失显着恶化了肺重构并增加了氧化应激,特别是促进了CIH小鼠肺中巨噬细胞的浸润。此外,在间歇性缺氧(IH)处理的RAW264.7细胞中,SOD2敲低增加了核苷酸结合域样受体蛋白3(NLRP3)炎性小体的激活,并伴有IL-1β升高和caspase-1活性。此外,线粒体ROS(mtROS)清除剂mito-TEMPO消除了IH处理的RAW264.7细胞中的NLRP3炎性体激活。总体而言,我们的研究结果支持SOD2有助于CIH诱导的肺重构的发病机理。同时,SOD2的敲低通过巨噬细胞中NLRP3炎性小体的组装和激活加剧了氧化损伤。SOD2可能是CIH诱导的肺部炎症和小动脉重构的新型治疗靶标。SOD2敲低增加了核苷酸结合域样受体蛋白3(NLRP3)炎性小体的激活,并伴有IL-1β升高和caspase-1活性。此外,线粒体ROS(mtROS)清除剂mito-TEMPO消除了IH处理的RAW264.7细胞中的NLRP3炎性体激活。总体而言,我们的研究结果支持SOD2有助于CIH诱导的肺重构的发病机理。同时,SOD2的敲低通过巨噬细胞中NLRP3炎性小体的组装和激活加剧了氧化损伤。SOD2可能是CIH诱导的肺部炎症和小动脉重构的新型治疗靶标。SOD2敲低增加了核苷酸结合域样受体蛋白3(NLRP3)炎性小体的激活,并伴有IL-1β升高和caspase-1活性。此外,线粒体ROS(mtROS)清除剂mito-TEMPO消除了IH处理的RAW264.7细胞中的NLRP3炎性体激活。总体而言,我们的研究结果支持SOD2有助于CIH诱导的肺重构的发病机理。同时,SOD2的敲低通过巨噬细胞中NLRP3炎性小体的组装和激活加剧了氧化损伤。SOD2可能是CIH诱导的肺部炎症和小动脉重构的新型治疗靶标。我们的结果支持SOD2促进CIH诱导的肺重构的发病机理。同时,SOD2的敲低通过巨噬细胞中NLRP3炎性小体的组装和激活加剧了氧化损伤。SOD2可能是CIH诱导的肺部炎症和小动脉重构的新型治疗靶标。我们的结果支持SOD2促进CIH诱导的肺重构的发病机理。同时,SOD2的敲低通过巨噬细胞中NLRP3炎性小体的组装和激活加剧了氧化损伤。SOD2可能是CIH诱导的肺部炎症和小动脉重构的新型治疗靶标。
更新日期:2020-02-17
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