Protectin conjugates in tissue regeneration 1 alleviates sepsis-induced acute lung injury by inhibiting ferroptosis.
Protectin conjugates in tissue regeneration 1 alleviates sepsis-induced acute lung injury by inhibiting ferroptosis.
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DOI：
10.1186/s12967-023-04111-9
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发表时间：
2023-04-30
影响因子：
7.4
通讯作者：
Gao, Ye
中科院分区：
文献类型：
--
作者：
Lv, Ya;Chen, Deming;Tian, Xinyi;Xiao, Ji;Xu, Congcong;Du, Linan;Li, Jiacong;Zhou, Siyu;Chen, Yuxiang;Zhuang, Rong;Gong, Yuqiang;Ying, Binyu;Gao-Smith, Fang;Jin, Shengwei;Gao, Ye
急性肺损伤是脓毒症常见的严重并发症，死亡率高。铁下垂，被归类为程序性细胞死亡，有助于肺损伤的发展。保护蛋白偶联组织再生1 （PCTR1）是一种内源性脂质介质，对多器官损伤具有保护作用。然而，PCTR1在脓毒症相关ALI的铁下垂中的作用尚不清楚。体外和体内分别建立了肺上皮细胞系和脂多糖刺激小鼠ALI模型。采用相关检测试剂盒评估铁下垂生物标志物，包括铁（Fe2+）、谷胱甘肽（GSH）、丙二醛（MDA）和4-羟基壬烯醛（4-HNE）。western blotting检测谷胱甘肽过氧化物酶4 （GPX4）和前列腺素内过氧化物合成酶2 （PTGS2）蛋白水平。用荧光显微镜和流式细胞术检测脂质过氧化物。采用CCK-8检测试剂盒检测细胞活力。透射电镜观察线粒体超微结构。形态学和炎性细胞因子水平预测肺损伤的严重程度。随后，利用相关抑制剂探索PCTR1调控铁下垂的潜在机制。PCTR1处理对lps诱导的小鼠肺损伤有保护作用，这与铁下垂抑制剂铁抑素-1的作用一致。PCTR1处理降低了Fe2+、PTGS2和脂质活性氧（ROS）含量，增加了GSH和GPX4水平，改善了线粒体超微结构损伤。LPS或铁下垂激动剂RSL3导致细胞活力降低，PCTR1挽救了细胞活力。机制上，抑制PCTR1受体脂素A4 （ALX）、蛋白激酶A （PKA）和转录因子camp反应元件结合蛋白（CREB）部分降低PCTR1上调GPX4表达，CREB抑制剂阻断PCTR1对铁上吊抑制和肺保护的作用。本研究提示PCTR1通过ALX/PKA/CREB信号通路抑制lps诱导的铁下垂，可能为败血症相关性ALI的治疗提供了良好的前景。在线版本包含补充材料，可在10.1186/s12967-023-04111-9获得。
Acute lung injury (ALI) is a common and serious complication of sepsis with high mortality. Ferroptosis, categorized as programmed cell death, contributes to the development of lung injury. Protectin conjugates in tissue regeneration 1 (PCTR1) is an endogenous lipid mediator that exerts protective effects against multiorgan injury. However, the role of PCTR1 in the ferroptosis of sepsis-related ALI remains unknown. A pulmonary epithelial cell line and a mouse model of ALI stimulated with lipopolysaccharide (LPS) were established in vitro and in vivo. Ferroptosis biomarkers, including ferrous (Fe2+), glutathione (GSH), malondialdehyde (MDA) and 4-Hydroxynonenal (4-HNE), were assessed by relevant assay kits. Glutathione peroxidase 4 (GPX4) and prostaglandin-endoperoxide synthase 2 (PTGS2) protein levels were determined by western blotting. Lipid peroxides were examined by fluorescence microscopy and flow cytometry. Cell viability was determined by a CCK-8 assay kit. The ultrastructure of mitochondria was observed with transmission electron microscopy. Morphology and inflammatory cytokine levels predicted the severity of lung injury. Afterward, related inhibitors were used to explore the potential mechanism by which PCTR1 regulates ferroptosis. PCTR1 treatment protected mice from LPS-induced lung injury, which was consistent with the effect of the ferroptosis inhibitor ferrostatin-1. PCTR1 treatment decreased Fe2+, PTGS2 and lipid reactive oxygen species (ROS) contents, increased GSH and GPX4 levels and ameliorated mitochondrial ultrastructural injury. Administration of LPS or the ferroptosis agonist RSL3 resulted in reduced cell viability, which was rescued by PCTR1. Mechanistically, inhibition of the PCTR1 receptor lipoxin A4 (ALX), protein kinase A (PKA) and transcription factor cAMP-response element binding protein (CREB) partly decreased PCTR1 upregulated GPX4 expression and a CREB inhibitor blocked the effects ofPCTR1 on ferroptosis inhibition and lung protection. This study suggests that PCTR1 suppresses LPS-induced ferroptosis via the ALX/PKA/CREB signaling pathway, which may offer promising therapeutic prospects in sepsis-related ALI. The online version contains supplementary material available at 10.1186/s12967-023-04111-9.
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影响因子：
14.8
作者：
Kagan VE;Mao G;Qu F;Angeli JP;Doll S;Croix CS;Dar HH;Liu B;Tyurin VA;Ritov VB;Kapralov AA;Amoscato AA;Jiang J;Anthonymuthu T;Mohammadyani D;Yang Q;Proneth B;Klein-Seetharaman J;Watkins S;Bahar I;Greenberger J;Mallampalli RK;Stockwell BR;Tyurina YY;Conrad M;Bayır H
通讯作者：
Bayır H
影响因子：
64.5
作者：
Dixon SJ;Lemberg KM;Lamprecht MR;Skouta R;Zaitsev EM;Gleason CE;Patel DN;Bauer AJ;Cantley AM;Yang WS;Morrison B 3rd;Stockwell BR
通讯作者：
Stockwell BR
第3组先天淋巴样细胞和免疫反应PCTR1的迷走神经调节可控制感染。
影响因子：
32.4
作者：
Dalli J;Colas RA;Arnardottir H;Serhan CN
通讯作者：
Serhan CN
影响因子：
--
作者：
Ayala A;Muñoz MF;Argüelles S
通讯作者：
Argüelles S
影响因子：
81.5
作者：
Matthay, Michael A.;Zemans, Rachel L.;Calfee, Carolyn S.
通讯作者：
Calfee, Carolyn S.