Aucubin protects against lipopolysaccharide-induced acute pulmonary injury through regulating Nrf2 and AMPK pathways

Aucubin (Ai), a natural compound isolated from plants, including Aucuba japonica and Eucommia ulmoides, shows significant anti-inflammatory and anti-oxidative bioactivities. Here, we attempted to explore the protect effects of Ai on LPS-induced acute lung injury (ALI). Our results indicated that Ai increased the survival rate and ameliorated pathogenic processes in lipopolysaccharide (LPS)-induced mice. However, nuclear factor erythroid 2-related factor 2 (Nrf2) deletion may impede protective effect of Ai. Additionally, Ai reduced oxidative stress by down-regulating malondialdehyde (MDA) and O₂· activity, and enhancing Nrf2-targeted signals, including heme oxygenase-1 (HO-1) and quinone oxidoreductase-1 (NQO-1). Also, Ai inhibited pro-inflammatory cytokines and phosphorylated-nuclear factor-κB (NF-κB) expression in LPS-administrated mice. However, these protective effects of Ai were suppressed in Nrf2-knockout mice. Importantly, Nrf2-deficiency showed no effects on phosphorylated AMP-activated protein kinase (p-AMPK) expression in mice treated with LPS and Ai. Similarly, in LPS-induced macrophages, Ai reduced reactive oxygen species (ROS) generation, elevated NQO-1 and HO-1 expression. LPS-stimulated pro-inflammatory cytokines and p-NF-κB were reversed by Ai. Of note, we found that Ai-induced Nrf2 activation was dependent on AMPK activation. Suppression of AMPK levels may inhibit Nrf2 activation, finally leading to up regulation of inflammatory response and oxidative stress. Thus, our findings indicated the crosstalk between Nrf2 and AMPK signaling pathways, and the interaction was essential for the anti-oxidant and anti-inflammatory effects of Ai in LPS-induced macrophages, which might be beneficial for finding new treatments against ALI.