Deletion of the miR-144/451 cluster aggravates lethal sepsis-induced lung epithelial oxidative stress and apoptosis.
Deletion of the miR-144/451 cluster aggravates lethal sepsis-induced lung epithelial oxidative stress and apoptosis.
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miR-144/451簇的缺失会加剧致命性脓毒症诱导的肺上皮氧化应激和细胞凋亡
DOI：
10.21037/atm-22-1024
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发表时间：
2022-05
影响因子：
--
通讯作者：
Yu, Duonan
中科院分区：
文献类型：
--
作者：
Wu, Fan;Yuan, Xiaoling;Liu, Weili;Meng, Lijun;Li, Xiuru;Gao, Xiang;Zhou, Shuting;Fang, Lei;Yu, Duonan
脓毒症与高死亡率相关。脓毒症患者死亡的主要原因是呼吸衰竭，其特征在于氧化损伤、上皮细胞凋亡和肺通透性增加。microRNA（miRs）是脓毒症进展的重要调节因子。本研究旨在探讨miR-144/451在脓毒症小鼠中的作用。通过盲肠结扎穿孔（CLP）在C57 BL/6小鼠中诱导实验性脓毒症。CLP显著诱导全身性炎症、肺通透性和肺上皮细胞凋亡，并下调抗氧化酶的信使RNA（mRNA）水平。与野生型小鼠相比，miR-144/451敲除小鼠CLP后48小时存活率较低，血浆肿瘤坏死因子α（TNF-α）和白细胞介素-6（IL-6）水平较高，肺通透性较高。CLP还显著增加了间质出血，使更多肺泡囊塌陷，并增加了miR-144/451敲除肺组织中末端脱氧核苷酸转移酶dUTP缺口末端标记（TUNEL）阳性和Bcl-2相关X（Bax）阳性细胞的数量，Bax mRNA水平升高，过氧化氢酶（Cat）和谷胱甘肽过氧化物酶1（Gpx 1）活性降低。在miR-144/451敲除肺和A549细胞系中证明，miR-451负调节14-3-3 miR表达。在脂多糖（LPS）诱导的A549细胞中，miR-451过表达显著抑制活性氧的产生，抑制细胞凋亡，并提高FoxO 3蛋白及相关酶的水平。miR-144/451簇的缺失加重脓毒症诱导的肺上皮细胞氧化损伤。
Sepsis is associated with a high mortality rate. A major cause of death in sepsis patients is respiratory failure, which is characterized by oxidative injury, epithelial apoptosis, and increased lung permeability. MicroRNAs (miRs) are important regulators of sepsis progression. This study aimed to explore the role of miR-144/451 in sepsis in mice. Experimental sepsis was induced in C57BL/6 mice by cecal ligation and puncture (CLP). CLP significantly induced systemic inflammation, lung permeability, and lung epithelial apoptosis with downregulated messenger RNA (mRNA) levels of antioxidant enzymes. The miR-144/451 knockout mice had a lower 48-hour survival rate, higher plasma tumor necrosis factor α (TNF-α) and interleukin-6 (IL-6) levels, and greater pulmonary permeability compared with wild-type mice after CLP. CLP also markedly increased interstitial hemorrhage, collapsed more alveolar sacs, and increased the number of terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL)-positive and Bcl-2-associated X (Bax)-positive cells in miR-144/451 knockout lung tissues, with elevated mRNA levels of Bax and reduced activities of catalase (Cat), glutathione peroxidase 1(Gpx1). MiR-451 negatively regulated 14-3-3ζ expression evidenced in miR-144/451 knockout lungs and the A549 cell line. In lipopolysaccharide (LPS)-induced A549 cells, miR-451 overexpression remarkably suppressed the production of reactive oxygen species, inhibited cell apoptosis, and enhanced levels of FoxO3 protein and related enzymes. Deletion of the miR-144/451 cluster aggravated sepsis-induced oxidative injury of lung epithelial cells.
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影响因子：
7.5
作者：
Li H;Shi H;Gao M;Ma N;Sun R
通讯作者：
Sun R
影响因子：
8.4
作者：
Chen, Dongqin;Huang, Jiayuan;Chen, Longbang
通讯作者：
Chen, Longbang
影响因子：
4.6
作者：
Bartel S;Schulz N;Alessandrini F;Schamberger AC;Pagel P;Theis FJ;Milger K;Noessner E;Stick SM;Kicic A;Eickelberg O;Freishtat RJ;Krauss-Etschmann S
通讯作者：
Krauss-Etschmann S
影响因子：
3.7
作者：
Hassan F;Nuovo GJ;Crawford M;Boyaka PN;Kirkby S;Nana-Sinkam SP;Cormet-Boyaka E
通讯作者：
Cormet-Boyaka E
影响因子：
5.3
作者：
Grailer JJ;Kalbitz M;Zetoune FS;Ward PA
通讯作者：
Ward PA