Metformin Alleviates LPS-Induced Acute Lung Injury by Regulating the SIRT1/NF-κB/NLRP3 Pathway and Inhibiting Endothelial Cell Pyroptosis.
Metformin Alleviates LPS-Induced Acute Lung Injury by Regulating the SIRT1/NF-κB/NLRP3 Pathway and Inhibiting Endothelial Cell Pyroptosis.
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二甲双胍通过调节SIRT 1/NF-κB/NLRP 3通路和抑制内皮细胞热凋亡减轻LPS诱导的急性肺损伤
DOI：
10.3389/fphar.2022.801337
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发表时间：
2022
影响因子：
5.6
通讯作者：
Wang, Yan
中科院分区：
文献类型：
--
作者：
Zhang, Yunqian;Zhang, Hui;Li, Siyuan;Huang, Kai;Jiang, Lai;Wang, Yan
急性呼吸窘迫综合征(ARDS)是一种多种疾病的破坏性并发症，通常与高死亡率有关。众所周知，内皮细胞损伤和炎症反应是ARDS发病机制中的重要环节。然而，EC损伤的机制在很大程度上是未知的。在本研究中，我们研究了上睑下垂在ARDS发病中的作用，并证明内皮下垂可能在ARDS的病理生理学中起着关键作用。二甲双胍是一种抗糖尿病药物，对脂多糖诱导的肺损伤有保护作用，我们推测它可能通过抑制内皮细胞的下垂而减轻内毒素诱导的肺损伤。在体内，雄性ICR小鼠被气管内注射脂多糖，而二甲双胍先前被注射到腹膜内。观察肺组织的形态特征。结果显示，二甲双胍可抑制NLRP3炎症小体激活和NLRP3诱导的下垂，表现为肺组织中caspase-1裂解水平、GSDMDN末端片段和IL-1β蛋白含量的降低。二甲双胍治疗后，脂多糖诱导的血管黏附分子表达也减少。在体外，肺内皮细胞暴露于脂多糖可导致NLRP3表达增加和下垂相关指标的增加。通过用NLRP3抑制剂MCC950抑制NLRP3的表达，改善了上睑下垂的相关标志物和血管黏附分子。此外，二甲双胍可显著抑制脂多糖刺激的肺组织和肺内皮细胞中的NF-κB信号转导通路和上调sirtuin1的表达。选择性SIRT1抑制剂烟酰胺能显著逆转二甲双胍对内皮细胞和急性肺损伤(ALI)的保护作用。因此，这些结果表明二甲双胍通过抑制NF-κB-NLRP3介导的内皮细胞下垂，可能是通过上调SIRT1的表达来减轻内毒素诱导的ALI。
Acute respiratory distress syndrome (ARDS), a devastating complication of numerous conditions, is often associated with high mortality. It is well known that endothelial cell (EC) damage and inflammation are vital processes in the pathogenesis of ARDS. Nevertheless, the mechanisms of EC damage are largely unknown. In the present study, we investigated the role of pyroptosis in the initiation of ARDS and demonstrated that endothelial pyroptosis might play a pivotal role in the pathophysiology of ARDS. Metformin, an antidiabetic drug, exhibited a protective effect in lipopolysaccharide (LPS)-induced lung injury, and we hypothesized that metformin alleviated LPS-induced lung injury via inhibiting ECs pyroptosis. In vivo, male ICR mice were intratracheally injected with LPS, and metformin was previously administered intraperitoneally. Morphological properties of lung tissues were detected. We showed that metformin inhibited NLRP3 inflammasome activation and NLRP3-stimulated pyroptosis induction, as shown by decreased levels of cleaved caspase-1, N-terminal fragment of GSDMD, and protein contents of IL-1β in lung tissues of mice exposed to LPS. LPS-induced expression of vascular adhesion molecules was also reduced after the treatment with metformin. In vitro, exposure of pulmonary ECs to LPS resulted in increased expression of NLRP3 and pyroptosis-associated indicators. By inhibiting the expression of NLRP3 with NLRP3 inhibitor MCC950, pyroptosis-related markers and vascular adhesion molecules were ameliorated. Moreover, metformin treatment significantly inhibited the NF-κB signaling pathway and increased the expression of sirtuin 1 (SIRT1) both in LPS-stimulated lung tissues and pulmonary ECs. Administration of the selective SIRT1 inhibitor nicotinamide significantly reversed the protective effect of metformin against endothelial pyroptosis and lung injury in LPS-treated ECs and LPS-induced acute lung injury (ALI). Thus, these findings demonstrated that metformin alleviated LPS-induced ALI by inhibiting NF-κB-NLRP3–mediated ECs pyroptosis, possibly by upregulating the expression of SIRT1.
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影响因子：
7.3
作者：
Arunachalam G;Samuel SM;Marei I;Ding H;Triggle CR
通讯作者：
Triggle CR
白藜芦醇对肺内皮屏障的保护涉及通过 Nrf2 依赖性机制抑制 HMGB1 释放和 HMGB1 诱导的线粒体氧化损伤
影响因子：
7.4
作者：
Dong, Wen-Wen;Liu, Yu-Jian;Jiang, Lai
通讯作者：
Jiang, Lai
DOI：
10.1016/j.bbi.2018.06.010
发表时间：
2018-10
期刊：
Brain, behavior, and immunity
影响因子：
--
作者：
Herman FJ;Pasinetti GM
通讯作者：
Pasinetti GM
影响因子：
8.3
作者：
Hattori, Yoshiyuki;Suzuki, Kunihiro;Kasai, Kikuo
通讯作者：
Kasai, Kikuo
DOI：
10.4049/jimmunol.1402513
发表时间：
2015-02-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Han S;Mallampalli RK
通讯作者：
Mallampalli RK