Buformin alleviates sepsis-induced acute lung injury via inhibiting NLRP3-mediated pyroptosis through an AMPK-dependent pathway

Background: NOD-like Receptor family pyrin domain containing 3 (NLRP3)-mediated macrophage Pyroptosis plays an important role in sepsis-induced acute lung injury (ALI). Inhibition of Pyroptosis may be a way to alleviate inflammation as well as tissue damage triggered after lipopolysaccharide (LPS) stimulation. The aim of the present study was to explore whether buformin (BF), a hypoglycemic agent, could alleviate sepsis-induced ALI by inhibiting Pyroptosis.

Methods: Wildtype C57BL/6 mice were randomly divided into control group, BF group, LPS group and LPS+BF group. BF group and LPS+BF group were pretreated with BF at a dose of 25 mg/kg, and the changes were observed. In addition, BF was used to interfere with THP-1 cells. The therapeutic effect of BF has been verified by intraperitoneal injection of BF in vivo after LPS stimulation.

Results: Inflammation and injury was significantly reduced in BF pretreated mice, and the indexes related to Pyroptosis were suppressed. The phosphorylation of AMP-activated protein kinase (AMPK) in lung tissues of mice in the BF and LPS+BF groups was significantly higher. In THP-1 cells, the AMPK Inhibitor, Compound C was added to demonstrate that BF worked via AMPK to inhibit NLRP3 inflammasome. It was further demonstrated that BF up-regulated Autophagy, which in turn promoted NLRP3 inflammasome degradation. On the Other hand, BF decreased NLRP3 mRNA level by increasing nuclear factor-erythroid 2 related factor 2 (Nrf2). And BF showed a therapeutic effect after LPS challenge.

Conclusion: Our study confirmed that BF inhibited NLRP3-mediated Pyroptosis in sepsis-induced ALI by up-regulating Autophagy and Nrf2 protein level through an AMPK-dependent pathway. This provides a new strategy for clinical mitigation of sepsis-induced ALI.