Berberine Alleviates Lipopolysaccharide-Induced Acute Lung Injury by Modulating the AMPK-HMGB1-NF-κB Signaling Axis

The activation of adenosine-monophosphate-activated protein kinase (AMPK) by berberine (BBR) benefits various inflammatory diseases. Conversely, high mobility group box-1 (HMGB1), a prototypical damage-associated molecular pattern (DAMP), typically exerts opposing effects. This research aims to investigate the relationship between AMPK and HMGB1, elucidating the functions and underlying mechanisms by which BBR alleviates acute lung injury (ALI) caused by lipopolysaccharide (LPS).

Male C57BL/6J mice were intragastrically administered BBR twice daily for three days with a total of 25 and 100 mg/kg/day. On day four, an intraperitoneal injection of 10 mg/kg LPS was administered, and BBR was given two hours before and six hours after this injection, respectively. Eighteen hours post-LPS administration, lung tissues and serum samples were collected to assess indicators of lung tissue injury, inflammation, oxidative stress, and apoptosis. The relationship between AMPK activation, HMGB1 release, and inflammatory activation was investigated in both mice and RAW264.7 cells using protein expression analysis, AMPK silencing, and exogenous HMGB1 introduction.

Our findings demonstrate that BBR activates AMPK and inhibits HMGB1 expression, translocation, and release in LPS-induced ALI, resulting in reduced histopathological lung injuries, decreased expression of inflammatory cytokine genes, and diminished oxidative stress and apoptosis. Mechanistic studies revealed that BBR decreases extracellular HMGB1 in LPS-stimulated RAW264.7 cells and inhibits HMGB1-stimulated nuclear factor Kappa B (NF-κB) activation. Concurrently, silencing the activation of AMPK by siRNA and compound C reversed the BBR-reduced extracellular HMGB1 level in LPS-stimulated RAW264.7 cells.

Based on these findings, we conclude that BBR effectively inhibits inflammation, oxidative stress, and apoptosis in LPS-induced ALI by modulating the AMPK-HMGB1-NF-κB axis. Consequently, BBR and other AMPK activators may represent promising therapeutic options for managing systemic inflammation and injury during sepsis.