[1]蒋贝,江雨昕,杜彦君,等.Mito TEMPO通过STING/NF-κB信号通路抑制急性肺损伤肺泡巨噬细胞M1极化的研究[J].医学研究与战创伤救治(原医学研究生学报),2026,39(01):10-17.[doi:10.16571/j.cnki.20972768.2026.01.002]
　JIANG Bei,JIANG Yuxin,DU Yanjun,et al.Mito TEMPO inhibits M1 polarization of alveolar macrophages in acute lung injury via the STING/NF-κB signaling pathway[J].JOURNAL OF MEDICALRESEARCH —COMBAT TRAUMA CARE,2026,39(01):10-17.[doi:10.16571/j.cnki.20972768.2026.01.002]
点击复制

Mito TEMPO通过STING/NF-κB信号通路抑制急性肺损伤肺泡巨噬细胞M1极化的研究()

《医学研究与战创伤救治》（原医学研究生学报）[ISSN:1672-271X/CN:32-1713/R]

卷:
第39卷
期数:
2026年01期
页码:
10-17
栏目:
基础研究
出版日期:
2026-01-20

文章信息/Info

Title:
Mito TEMPO inhibits M1 polarization of alveolar macrophages in acute lung injury via the STING/NF-κB signaling pathway
作者:
蒋贝1; 江雨昕2; 杜彦君3; 徐秋丽2; 金佳佳4; 朱素华4; 张方1; 4
南京中医药大学金陵临床医学院（东部战区总医院）呼吸与危重症医学科，江苏南京 210002
Author(s):
JIANG Bei1;  JIANG Yuxin2;  DU Yanjun3;  XU Qiuli2;  JIN Jiajia4;  ZHU Suhua4;  ZHANG Fang1; 4
Department of Respiratory and Critical Care Medicine, Jinling Clinical Medical College, Nanjing University of Chinese Medicine/General Hospital of Eastern Theater Command, PLA, Nanjing 210002, Jiangsu, China
关键词:
急性肺损伤; 巨噬细胞; Mito TEMPO; cGASSTING; 核因子κB
Keywords:
acute lung injury;  macrophages;  Mito TEMPO;  cGASSTING;  nuclear factor kappa-B
分类号:
R563
DOI:
10.16571/j.cnki.20972768.2026.01.002
文献标志码:
A
摘要:
目的探讨Mito TEMPO在急性肺损伤（ALI）中的作用及其机制，为ALI治疗提供新理论依据。方法通过体内外双模型探讨Mito TEMPO对LPS诱导急性肺损伤的保护效应。体内实验：6～8周龄雄性C57BL/6小鼠完全随机原则，分为Ctrl组、LPS组、LPS+MT组，每组4只。腹腔注射LPS前1 h予Mito TEMPO预处理，12 h后采集标本。ELISA测定支气管肺泡灌洗液IL6、TNFα、IL1β水平；HE染色评估肺组织病理损伤；流式细胞术检测肺单细胞悬液中中性粒细胞浸润及M1型巨噬细胞比例；Western blot分析肺组织cGASSTING/NFκB通路关键蛋白（pSTING、pTBK1、pp65）表达。体外实验：检测各组肺泡巨噬细胞MHS细胞内活性氧、线粒体膜电位（JC1）及细胞外mtDNA含量。结果与LPS组相比，Mito TEMPO干预显著抑制BALF中IL6、TNFα及IL1β的升高（P<0.05），并下调肺组织cGASSTING/NFκB轴关键蛋白（pSTING、pTBK1、pp65）的磷酸化水平（P<0.05）。流式细胞术显示，肺内中性粒细胞浸润及M1型巨噬细胞比例显著降低（P<0.05），肺组织病理损伤明显减轻（P<0.05）。体外实验进一步证实，MitoTEMPO 可显著抑制 LPS 诱导的活性氧过量生成及线粒体 DNA 泄漏（P<0.05），恢复线粒体膜电位（P<0.05），并降低 MHS 细胞培养上清中 IL6 与 TNFα 的水平（P<0.05）。结论Mito TEMPO通过抑制cGASSTING/NFκB通路，调控巨噬细胞极化，减轻ALI炎症反应，为ALI治疗提供了潜在靶点。
Abstract:
ObjectiveTo investigate the role and mechanism of MitoTEMPO in acute lung injury (ALI) and to provide new theoretical basis for ALI treatment.MethodsThe protective effect of MitoTEMPO on LPSinduced acute lung injury was explored through both in vivo and in vitro models. In vivo experiment: Male C57BL/6 mice aged 68 weeks were randomly divided into Ctrl group, LPS group, and LPS + MT group, with 4 mice in each group. MitoTEMPO was pretreated 1 hour before intraperitoneal injection of LPS, and samples were collected 12 hours later. ELISA was used to determine the levels of IL6, TNFα, and IL1β in bronchoalveolar lavage fluid; HE staining was used to evaluate lung tissue pathological damage; flow cytometry was used to detect the infiltration of neutrophils and the proportion of M1type macrophages in the lung singlecell suspension; Western blot was used to analyze the expression of key proteins (pSTING, pTBK1, pp65) of the cGASSTING/NFκB pathway in lung tissue. In vitro experiment: The intracellular reactive oxygen species, mitochondrial membrane potential (JC1), and extracellular mtDNA content of MHS cells in alveolar macrophages of each group were detected.ResultsCompared with the LPS group, MitoTEMPO intervention significantly inhibited the increase of IL6, TNFα, and IL1β in BALF (P<0.05), and downregulated the phosphorylation levels of key proteins (pSTING, pTBK1, pp65) of the cGASSTING/NFκB axis in lung tissue (P<0.05). Flow cytometry showed that the infiltration of neutrophils in the lung and the proportion of M1type macrophages were significantly reduced (P<0.05), and the lung tissue pathological damage was significantly alleviated (P<0.05). The in vitro experiment further confirmed that MitoTEMPO could significantly inhibit the excessive generation of reactive oxygen species and the leakage of mitochondrial DNA induced by LPS (P<0.05), restore mitochondrial membrane potential (P<0.05), and reduce the levels of IL6 and TNFα in the supernatant of MHS cell culture (P<0.05).ConclusionMitoTEMPO may alleviate ALI by inhibiting the cGASSTING/NFκB pathway and regulating macrophage polarization, thereby reducing the inflammatory response. Meanwhile, it can provide a potential target for ALI treatment.

参考文献/References:

[1]Bos LDJ, Ware LB. Acute respiratory distress syndrome: causes, pathophysiology, and phenotypes[J]. Lancet, 2022, 400(10358): 11451156.[2]Matthay MA, Arabi YM, Siegel ER, et al. Phenotypes and personalized medicine in the acute respiratory distress syndrome[J]. Intensive Care Med, 2020, 46(12): 21362152.[3]Meyer NJ, Gattinoni L, Calfee CS. Acute respiratory distress syndrome[J]. Lancet, 2021, 398(10300): 622637.[4]Long ME, Mallampalli RK, Horowitz JC. Pathogenesis of pneumonia and acute lung injury[J]. Clin Sci (Lond), 2022, 136(10): 747769.[5]Matthay MA, Ware LB, Zimmerman GA. The acute respiratory distress syndrome[J]. J Clin Invest, 2012, 122(8): 27312740.[6]Hopfner KP, Hornung V. Molecular mechanisms and cellular functions of cGASSTING signalling[J]. Nat Rev Mol Cell Biol, 2020, 21(9): 501521.[7]Schmitz CRR, Maurmann RM, Guma F, et al. cGASSTING pathway as a potential trigger of immunosenescence and inflammaging[J]. Front Immunol, 2023, 14: 1132653.[8]Nathan C, Ding A. Nonresolving inflammation[J]. Cell, 2010, 140(6): 871882.[9]Attiq A, Yao LJ, Afzal S, et al. The triumvirate of NFκB, inflammation and cytokine storm in COVID19[J]. Int Immunopharmacol, 2021, 101(Pt B): 108255.[10]Locati M, Curtale G, Mantovani A. Diversity, Mechanisms, and Significance of Macrophage Plasticity[J]. Annu Rev Pathol, 2020, 15: 123147.[11]Luo M, Zhao F, Cheng H, et al. Macrophage polarization: an important role in inflammatory diseases[J]. Front Immunol, 2024, 15: 1352946.[12]Zhang W, Huang X. Targeting cGASSTING pathway for reprogramming tumorassociated macrophages to enhance antitumor immunotherapy[J]. Biomark Res, 2025, 13(1): 43.[13]Wang L, Wang D, Zhang T, et al. The role of immunometabolism in macrophage polarization and its impact on acute lung injury/acute respiratory distress syndrome[J]. Front Immunol, 2023, 14: 1117548.[14]Zhao M, Wang Y, Li L, et al. Mitochondrial ROS promote mitochondrial dysfunction and inflammation in ischemic acute kidney injury by disrupting TFAMmediated mtDNA maintenance[J]. Theranostics, 2021, 11(4): 18451863.[15]He J, Liu X, Su C, et al. Inhibition of Mitochondrial Oxidative Damage Improves Reendothelialization Capacity of Endothelial Progenitor Cells via SIRT3 (Sirtuin 3)Enhanced SOD2 (Superoxide Dismutase 2) Deacetylation in Hypertension[J]. Arterioscler Thromb Vasc Biol, 2019, 39(8): 16821698.[16]Han YK, Kim JS, Lee GB, et al. Oxidative stress following acute kidney injury causes disruption of lung cell cilia and their release into the bronchoaveolar lavage fluid and lung injury, which are exacerbated by Idh2 deletion[J]. Redox Biol, 2021, 46: 102077.[17]Wei S, Qiu T, Yao X, et al. Arsenic induces pancreatic dysfunction and ferroptosis via mitochondrial ROSautophagylysosomal pathway[J]. J Hazard Mater, 2020, 384: 121390.[18]Saaoud F, Liu L, Xu K, et al. Aorta and livergenerated TMAO enhances trained immunity for increased inflammation via ER stress/mitochondrial ROS/glycolysis pathways[J]. JCI Insight, 2023, 8(1): e158183.[19]Han YK, Kim JS, Jang G, et al. Cisplatin induces lung cell cilia disruption and lung damage via oxidative stress[J]. Free Radic Biol Med, 2021, 177: 270277.[20]Jiaqi L, Siqing H, Qin W, et al. Andrographolide promoted ferroptosis to repress the development of nonsmall cell lung cancer through activation of the mitochondrial dysfunction[J]. Phytomedicine, 2023, 109: 154601.[21]Weidinger A, Birgisdóttir L, Schffer J, et al. Systemic Effects of mitoTEMPO upon Lipopolysaccharide Challenge Are Due to Its Antioxidant Part, While Local Effects in the Lung Are Due to Triphenylphosphonium[J]. Antioxidants (Basel), 2022, 11(2): 323.[22]Fu P, Epshtein Y, Ramchandran R, et al. Essential role for paxillin tyrosine phosphorylation in LPSinduced mitochondrial fission, ROS generation and lung endothelial barrier loss[J]. Sci Rep, 2021, 11(1): 17546.[23]Gu Y, Lv L, Jin J, et al. STING mediates LPSinduced acute lung injury by regulating ferroptosis[J]. Exp Cell Res, 2024, 438(2): 114039.[24]Wu B, Xu MM, Fan C, et al. STING inhibitor ameliorates LPSinduced ALI by preventing vascular endothelial cellsmediated immune cells chemotaxis and adhesion[J]. Acta Pharmacol Sin, 2022, 43(8): 20552066.[25]Ning L, Wei W, Wenyang J, et al. Cytosolic DNASTINGNLRP3 axis is involved in murine acute lung injury induced by lipopolysaccharide[J]. Clin Transl Med, 2020, 10(7): e228.[26]Malainou C, Abdin SM, Lachmann N, et al. Alveolar macrophages in tissue homeostasis, inflammation, and infection: evolving concepts of therapeutic targeting[J]. J Clin Invest, 2023, 133(19): e170501.[27]Shapourimoghaddam A, Mohammadian S, Vazini H, et al. Macrophage plasticity, polarization, and function in health and disease[J]. J Cell Physiol, 2018, 233(9): 64256440.[28]Hussell T, Bell TJ. Alveolar macrophages: plasticity in a tissuespecific context[J]. Nat Rev Immunol, 2014, 14(2): 8193.[29]欧阳倪冰, 张冉阳, 王鹏, 等. 肺泡巨噬细胞在急性肺损伤中的作用[J]. 免疫学杂志, 2024, 40(6): 551554.[30]Wynn TA, Vannella KM. Macrophages in Tissue Repair, Regeneration, and Fibrosis[J]. Immunity, 2016, 44(3): 450462.[31]Lawrence T, Natoli G. Transcriptional regulation of macrophage polarization: enabling diversity with identity[J]. Nat Rev Immunol, 2011, 11(11): 750761.[32]Sica A, Mantovani A. Macrophage plasticity and polarization: in vivo veritas[J]. J Clin Invest, 2012, 122(3): 787795.[33]Wang N, Liang H, Zen K. Molecular mechanisms that influence the macrophage m1m2 polarization balance[J]. Front Immunol, 2014, 5: 614.[34]Liu T, Zhang L, Joo D, et al. NFκB signaling in inflammation[J]. Signal Transduct Target Ther, 2017, 2: 17023.[35]Luo J, Wang J, Zhang J, et al. Nrf2 Deficiency Exacerbated CLPInduced Pulmonary Injury and Inflammation through Autophagy and NFκB/PPARγMediated Macrophage Polarization[J]. Cells, 2022, 11(23):3927[36]Zhang S, Xu P, Zhu Z, et al. Acetylation of p65(Lys310) by p300 in macrophages mediates antiinflammatory property of berberine[J]. Redox Biol, 2023, 62: 102704.[37]虞秋艳,尹安琪,张利东. 氢气在脓毒症相关性脑病中作用的研究进展[J]. 医学研究与战创伤救治, 2024, 37(11): 12061209. [38]刘海波,张敬敏,刘秀兰,等. 不同潮气量机械通气对急性呼吸窘迫综合征大鼠肺纤维化的作用机制[J]. 医学研究与战创伤救治, 2023, 36(10): 10221028.

相似文献/References:

[1]吴勇,叶芬,葛轶睿,等.SN50对缺血再灌注损伤中TNF-α影响的实验研究[J].医学研究与战创伤救治(原医学研究生学报),2014,16(05):453.[doi:10.3969/j.issn.1672-271X.2014.05.002]
　WU Yong,YE Fen,GE Yi-rui,et al.Experimental study of SN50 on TNF-α effects in ischemia-reperfusion injury[J].JOURNAL OF MEDICALRESEARCH —COMBAT TRAUMA CARE,2014,16(01):453.[doi:10.3969/j.issn.1672-271X.2014.05.002]
[2]徐晓峰,许秀娟,郝建,等.高温气体吸入致豚鼠急性肺损伤动物模型制备的实验研究[J].医学研究与战创伤救治(原医学研究生学报),2017,19(05):449.[doi:10.3969/j.issn.1672-271X.2017.05.001]
　XU Xiao-feng,XU Xiu-juan,HAO Jian,et al.An experimental study of acute lung injury in guinea pigs induced by high temperature gas[J].JOURNAL OF MEDICALRESEARCH —COMBAT TRAUMA CARE,2017,19(01):449.[doi:10.3969/j.issn.1672-271X.2017.05.001]
[3]张少波,温春虹,何杰综述,等.巨噬细胞极化分型与创伤修复的研究进展[J].医学研究与战创伤救治(原医学研究生学报),2018,20(04):390.[doi:10.3969/j.issn.1672-271X.2018.04.014]
[4]孔凯文,孟岩,邓小明.Nrf2/HO-1信号通路在急性肺损伤中的研究进展[J].医学研究与战创伤救治(原医学研究生学报),2022,24(6):646.[doi:10.3969/j.issn.1672-271X.2022.06.017]
　KONG Kai-wen,MENG Yan,DENG Xiao-ming.Research progress of Nrf2/HO-1 signaling pathway in acute lung injury[J].JOURNAL OF MEDICALRESEARCH —COMBAT TRAUMA CARE,2022,24(01):646.[doi:10.3969/j.issn.1672-271X.2022.06.017]
[5]房智超,李佳敏,王树楷综述,等.组织驻留巨噬细胞在急性胰腺炎中的作用及靶向干预研究进展[J].医学研究与战创伤救治(原医学研究生学报),2023,25(3):301.[doi:10.3969/j.issn.1672-271X.2023.03.016]
　FANG Zhichao,LI Jiamin,WANG Shukai,et al.Advances in the role of tissue-resident macrophages in acute pancreatitis and targeted intervention[J].JOURNAL OF MEDICALRESEARCH —COMBAT TRAUMA CARE,2023,25(01):301.[doi:10.3969/j.issn.1672-271X.2023.03.016]

备注/Memo

备注/Memo:
基金项目：国家自然科学基金（82100095）
更新日期/Last Update: 2026-03-02