Melatonin alleviates sepsis-induced acute lung injury by inhibiting necroptosis via reducing circulating mtDNA release.

IF 6 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Yuce Peng, Jia Xu, Lingyu Wei, Minghao Luo, Shenglong Chen, Xuebiao Wei, Suxin Luo, Zedazhong Su, Zhonghua Wang
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引用次数: 0

Abstract

Background: Sepsis is a life-threatening condition that often leads to severe complications, including acute lung injury (ALI), which carries high morbidity and mortality in critically ill patients. Melatonin (Mel) has shown significant protective effects against sepsis-induced ALI, but its precise mechanism remains unclear.

Methods: A cecal ligation and puncture (CLP) model was used to induce sepsis in male C57BL/6 mice, which were divided into four groups: Control, Sham, CLP, and CLP + Mel. ALI severity was evaluated via hematoxylin and eosin (H&E) staining, lung wet/dry ratio, and serum biomarkers (SP-D, sRAGE). Inflammatory cytokines (IL-1β, IL-6, TNF-α) were measured in serum and bronchoalveolar lavage fluid using ELISA. Circulating mitochondrial DNA (mtDNA) subtypes (D-loop, mt-CO1, mMito) were quantified by real-time PCR. TUNEL staining was performed to assess lung cell apoptosis. Necroptosis and STING pathway activation were analyzed via Western blot and immunofluorescence.

Results: Sepsis led to increased circulating mtDNA levels and activation of necroptosis signaling pathways. Melatonin treatment alleviated sepsis-induced ALI, improving survival, reducing inflammatory cytokines and mtDNA release, and suppressing necroptosis. Intraperitoneal injection of mtDNA in mice activated necroptosis, while RIP1 inhibitor Nec-1 counteracted mtDNA-induced lung damage and necroptosis in sepsis-induced ALI. Additionally, melatonin significantly inhibited STING pathway activation. Further experiments revealed that STING modulation influenced necroptosis protein expression and mediated melatonin's protective effects in sepsis-induced ALI.

Conclusion: Melatonin mitigates sepsis-induced ALI by suppressing necroptosis through inhibition of STING activation and reduction of mtDNA release. These findings suggest melatonin as a potential therapeutic strategy for sepsis-induced ALI.

褪黑素通过减少循环mtDNA释放抑制坏死下垂,减轻败血症引起的急性肺损伤。
背景:脓毒症是一种危及生命的疾病,经常导致严重的并发症,包括急性肺损伤(ALI),在危重患者中具有很高的发病率和死亡率。褪黑素(Mel)对脓毒症引起的ALI具有显著的保护作用,但其确切机制尚不清楚。方法:采用盲肠结扎穿刺(CLP)模型诱导雄性C57BL/6小鼠脓毒症,将其分为对照组、假手术组、CLP组和CLP + Mel组。通过苏木精和伊红(H&E)染色、肺湿/干比和血清生物标志物(SP-D, sRAGE)评估ALI严重程度。采用ELISA法检测血清和支气管肺泡灌洗液中炎症因子(IL-1β、IL-6、TNF-α)的含量。实时荧光定量PCR检测循环线粒体DNA (mtDNA)亚型(D-loop、mt-CO1、mMito)。TUNEL染色观察肺细胞凋亡情况。Western blot和免疫荧光分析坏死下垂和STING通路激活情况。结果:脓毒症导致循环mtDNA水平升高和坏死坏死信号通路的激活。褪黑素治疗可减轻脓毒症引起的ALI,提高生存率,减少炎症细胞因子和mtDNA释放,抑制坏死下垂。小鼠腹腔注射mtDNA可激活坏死性上睑下垂,而RIP1抑制剂Nec-1可抵消mtDNA诱导的脓毒症ALI肺损伤和坏死性上睑下垂。此外,褪黑素显著抑制STING通路的激活。进一步的实验表明,STING调节影响坏死性上睑下垂蛋白的表达,并介导褪黑素在脓毒症诱导的ALI中的保护作用。结论:褪黑素通过抑制STING激活和减少mtDNA释放来抑制坏死下垂,从而减轻败血症诱导的ALI。这些发现提示褪黑素是脓毒症诱发ALI的潜在治疗策略。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Molecular Medicine
Molecular Medicine 医学-生化与分子生物学
CiteScore
8.60
自引率
0.00%
发文量
137
审稿时长
1 months
期刊介绍: Molecular Medicine is an open access journal that focuses on publishing recent findings related to disease pathogenesis at the molecular or physiological level. These insights can potentially contribute to the development of specific tools for disease diagnosis, treatment, or prevention. The journal considers manuscripts that present material pertinent to the genetic, molecular, or cellular underpinnings of critical physiological or disease processes. Submissions to Molecular Medicine are expected to elucidate the broader implications of the research findings for human disease and medicine in a manner that is accessible to a wide audience.
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