Dahuang-mudanpi decoction mitigates ALI/ARDS pulmonary inflammation via multi-target regulation of HMGB1

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are severe inflammatory conditions with high mortality and limited treatment options. Targeting pulmonary inflammation is a critical strategy for improving clinical outcomes. This study was performed to investigate the therapeutic effects and underlying mechanisms of Dahuang-Mudanpi Decoction (DMD), specifically focusing on its active ingredients, paeonol (PAE) and emodin (EMO), and their regulatory role in high mobility group box 1 (HMGB1)-mediated inflammation in ALI/ARDS.

The therapeutic efficacy of DMD was evaluated using a lipopolysaccharide (LPS)-induced ALI mouse model (n = 8 per group for the DMD dose-screening experiment and n = 6 per group for the component-comparison experiment). High-performance liquid chromatography (HPLC) was employed to quantify the active compounds within DMD. The protective effects were comprehensively assessed by analyzing body weight changes, lung wet/dry (W/D) ratios, and histopathological lung injury scores. Additionally, systemic and localized inflammatory responses were evaluated by measuring hematological parameters and the levels of key inflammatory cytokines, including interleukin-1 beta (IL-1β), tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and HMGB1. Data were analyzed using one-way analysis of variance (ANOVA) or nonparametric tests, as appropriate.

DMD administration significantly mitigated LPS-induced pulmonary inflammation and attenuated lung injury in the mouse model. Mechanistic evaluations revealed distinct, complementary roles for DMD's active components, with molecular docking providing supportive structural evidence rather than definitive proof of direct molecular binding. Specifically, PAE was predicted to interact with the first nuclear localization signal (NLS1) region of HMGB1 (Vina score: -4.7 kcal/mol), which corresponded to its observed ability to effectively inhibit the nuclear translocation of HMGB1 and reduce its extracellular release. Conversely, EMO was predicted to bind near the receptor-binding region of HMGB1 (Vina score: -6.3 kcal/mol), suppressing the pro-inflammatory function of extracellular HMGB1.

These findings demonstrate the multi-target regulatory effects of DMD in mitigating ALI-associated inflammation, highlighting PAE and EMO as promising therapeutic agents for ALI/ARDS. The mechanistic insights provide novel perspectives on HMGB1-targeted treatments, suggesting that further optimization of this compound combination could yield advanced therapeutic strategies for severe pulmonary inflammation.