Bioactive 10-shogaol liposome for ameliorating endotoxemia-associated acute respiratory distress syndrome (ARDS) via restraining neutrophil extracellular trap release

Sepsis is a life-threatening condition caused by a dysregulated host response to infection, leading to organ dysfunctions. Acute respiratory distress syndrome (ARDS) is the most common complication of sepsis with high mortality and pathological characteristics of uncontrolled neutrophil extracellular trap (NET) release and excessive inflammation. However, current therapeutic strategies for sepsis-induced ARDS face limitations, including potential toxicity, suboptimal efficacy, and poor bioavailability. In this timely study, we encapsulated 10-shogaol (SA), a natural anti-inflammatory compound derived from Zingiber officinale , into liposomes to yield SA-Lipo for the treatment of endotoxemia-induced ARDS. SA-Lipo initially demonstrated stable physicochemical properties, reliable biocompatibility, and increased bioavailability. A series of in vitro experiments subsequently validated that SA-Lipo significantly inhibited inflammation, oxidative stress, and excessive NET release. The in vivo evaluation in an endotoxemia-induced ARDS mouse model further revealed that SA-Lipo attenuated pulmonary dysfunction, alleviated lung edema, reduced inflammatory mediators, and promoted repair of pulmonary pathological injury. Mechanistically, RNA sequencing of lung tissues suggested that SA-Lipo may exert its therapeutic effects by inhibiting multiple immune- and inflammation-related signaling pathways. Molecular docking, western blotting, and immunofluorescent staining supported the potential of SA-Lipo to inhibit the activation of the proinflammatory MyD88/NF-κB pathway and PAD4/Cit-H3-mediated NET release in endotoxemia-induced ARDS, although the causal relationship between these two cascades remains unclear. Taken together, our findings consolidated the availability of a new lipid-nanomedicine SA-lipo for the treatment of endotoxemia-induced ARDS via controlling NET release and excessive inflammation, hence providing a promising therapeutic strategy for acute inflammatory lung diseases.