Department of Geriatrics, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai 200032, China.
Department of Cardiac Surgery, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai 200032, China.
Exp Gerontol. 2019 Oct 1;125:110661. doi: 10.1016/j.exger.2019.110661. Epub 2019 Jul 15.
Old people are spectacularly susceptible to acute lung injury (ALI) and the accompanying complications. An acute aggravated inflammatory response is a characteristic feature of ALI, and inflammasomes play a critical role in the inflammatory response. Metformin has been shown to be an effective anti-inflammatory agent in ALI. However, the mechanism of this regulation still remains poorly understood. In this study, 18- to 19-month-old male mice were treated by intratracheal instillation of lipopolysaccharide (LPS) or PBS with or without metformin pretreatment. We found that the metformin pretreatment alleviated the lung injury and decreased the levels of TNF-a, IL-1β and IL-6 in the bronchoalveolar lavage fluid (BALF) and in lung tissues, as well as the levels of NLRP3, NLRC4 and cleaved caspase-1 associated with LPS-induced ALI in old mice. Furthermore, the in vitro study showed metformin dose-dependently suppressed NLRC4 inflammasome expression. Metformin activated AMPK by phosphorylation; thus, we investigated the role of AMPK in NLRC4 activation. The results demonstrated that the efficacy of metformin was reduced when using the AMPK pharmacological inhibitor compound C or AMPKα expression was knocked down in RAW 264.7 cells. In conclusion, our data indicated that metformin may inhibit NLRC4 inflammasome activation in LPS-induced ALI in old mice through AMPK signaling, and further understanding of the AMPK/NLRC4 axis may provide a novel therapeutic strategy for LPS-induced ALI in the future.
老年人极易发生急性肺损伤（ALI）和随之而来的并发症。急性加重的炎症反应是 ALI 的特征，炎性小体在炎症反应中起着关键作用。二甲双胍已被证明是 ALI 的一种有效抗炎药物。然而，这种调节的机制仍知之甚少。在这项研究中，18-19 个月大的雄性小鼠通过气管内滴注脂多糖（LPS）或 PBS 并用或不用二甲双胍预处理进行处理。我们发现，二甲双胍预处理减轻了肺损伤，并降低了老年小鼠 LPS 诱导的 ALI 中支气管肺泡灌洗液（BALF）和肺组织中 TNF-a、IL-1β 和 IL-6 的水平，以及与 NLRP3、NLRC4 和切割 caspase-1 相关的水平。此外，体外研究表明二甲双胍可剂量依赖性地抑制 NLRC4 炎性小体的表达。二甲双胍通过磷酸化激活 AMPK；因此，我们研究了 AMPK 在 NLRC4 激活中的作用。结果表明，在用 AMPK 药理学抑制剂化合物 C 或在 RAW 264.7 细胞中敲低 AMPKα表达时，二甲双胍的疗效降低。总之，我们的数据表明，二甲双胍可能通过 AMPK 信号通路抑制 LPS 诱导的老年小鼠 ALI 中的 NLRC4 炎性小体激活，进一步了解 AMPK/NLRC4 轴可能为未来 LPS 诱导的 ALI 提供新的治疗策略。
