美国加州大学圣地亚哥分校Michael Karin课题组的最新研究表明，二甲双胍通过抑制线粒体ATP和DNA合成从而阻碍NLRP3炎症小体的激活和肺部炎症。相关论文于2021年6月9日在线发表于国际学术期刊《免疫学》杂志。

通过对COVID-19死亡患者肺部炎症小体组装的检测，研究人员探究了二甲双胍是否以及如何在发挥其抗炎作用的同时抑制炎症小体激活。研究表明，二甲双胍通过抑制培养巨噬细胞和肺泡巨噬细胞中NLRP3炎症小体的激活和白细胞介素 (IL)-1β的产生，以及炎症小体非依赖性IL-6的分泌，减轻了脂多糖(LPS)和SARS-CoV-2诱导的急性呼吸窘迫综合征(ARDS)。

通过靶向电子传递链复合体1且AMP 活化蛋白激酶 (AMPK) 或 NF-κB非依赖途径，二甲双胍阻断LPS诱导的ATP依赖性线粒体 (mt) DNA 合成和氧化mtDNA（一种 NLRP3 配体）的产生。骨髓特异性缺失LPS 诱导胞苷单磷酸激酶 2 (CMPK2) 可降低 ARDS 的严重程度，而对IL-6产生没有直接影响， CMPK2是mtDNA 合成的限速酶。因此，抑制 ATP 和 mtDNA 合成足以改善 ARDS。

研究人员表示，ARDS是一种死亡率很高的炎症性疾病，在严重性COVID-19患者中很常见，二甲双胍而非其他抗糖尿病药物可降低其风险。

附：英文原文

Title: Metformin inhibition of mitochondrial ATP and DNA synthesis abrogates NLRP3 inflammasome activation and pulmonary inflammation

Author: Hongxu Xian, Yuan Liu, Alexandra Rundberg Nilsson, Raphaella Gatchalian, Timothy R. Crother, Warren G. Tourtellotte, Yi Zhang, German R. Aleman-Muench, Gavin Lewis, Weixuan Chen, Sarah Kang, Melissa Luevanos, Dorit Trudler, Stuart A. Lipton, Pejman Soroosh, John Teijaro, Juan Carlos de la Torre, Moshe Arditi, Michael Karin, Elsa Sanchez-Lopez

Issue&Volume: 2021-06-09

Abstract: Acute respiratory distress syndrome (ARDS), an inflammatory condition with high mortality rates, is common in severe COVID-19, whose risk is reduced by metformin rather than other anti-diabetic medications. Detecting of inflammasome assembly in post-mortem COVID-19 lungs, we asked whether and how metformin inhibits inflammasome activation while exerting its anti-inflammatory effect. We show that metformin inhibited NLRP3 inflammasome activation and interleukin (IL)-1β production in cultured and alveolar macrophages along with inflammasome-independent IL-6 secretion, thus attenuating lipopolysaccharide (LPS)- and SARS-CoV-2-induced ARDS. By targeting electron transport chain complex 1 and independently of AMP-activated protein kinase (AMPK) or NF-κB, metformin blocked LPS-induced and ATP-dependent mitochondrial (mt) DNA synthesis and generation of oxidized mtDNA, an NLRP3 ligand. Myeloid-specific ablation of LPS-induced cytidine monophosphate kinase 2 (CMPK2), which is rate limiting for mtDNA synthesis, reduced ARDS severity without a direct effect on IL-6. Thus, inhibition of ATP and mtDNA synthesis is sufficient for ARDS amelioration.

DOI: 10.1016/j.immuni.2021.05.004

Source: https://www.cell.com/immunity/fulltext/S1074-7613(21)00210-7