Compound Yujie decoction ameliorates LPS-induced acute lung injury by suppressing NLRP3 inflammasome-mediated...

Compound Yujie decoction (CYD) is a clinically used Chinese medicine against sepsis-induced acute lung injury (ALI), but its active components and their underlying anti-ALI mechanisms have not been elucidated.

This study aims to identify key active components and molecular mechanisms of CYD for alleviating lipopolysaccharide (LPS)-induced ALI, via integrating in vivo tests, serum pharmacology, transcriptomics, and network pharmacology.

To evaluate the in vivo therapeutic efficacy of CYD, a mouse model of lipopolysaccharide (LPS)-induced ALI was established via intraperitoneal injection. Histopathological and serum biochemical analyses were conducted after successive oral administration of CYD for 14 days to test its safety profile. The anti-inflammatory effects of CYD-containing serum (CYDS) was tested in bone marrow-derived macrophages (BMDMs). Phytochemicals in CYD and the absorbed components of this Chinese medicine were identified using ultra-high-performance liquid chromatography coupled with quadrupole-Orbitrap high-resolution mass spectrometry (UHPLC-Q-Exactive Orbitrap HRMS). Key active constituents and potential targets were further predicted through transcriptomics and network pharmacology. Finally, the key active components and potential mechanisms were validated in vitro using BMDMs.

CYD significantly alleviated LPS-induced ALI in mice, reducing lung inflammation, oxidative stress, and histopathological damage. Toxicological assessments demonstrated that CYD showed favorable safety profiles in healthy mice. CYDS significantly suppressed the levels of pro-inflammatory cytokine factors and mitochondrial reactive oxygen species (mtROS) in LPS- and ATP-challenged BMDMs. Transcriptomic analysis revealed that CYD markedly modulated inflammation-related genes and pathways. Further investigations demonstrated that CYD dose-dependently suppressed NLRP3 inflammasome activation both in vitro and in vivo, suggesting a key mechanism for its protective effects against sepsis-induced ALI. Network pharmacology highlighted seven key active compounds in CYD. Among these, baicalin showed the most potent protective effects against LPS- and ATP-induced injury in BMDMs, suppressing cytokine storm and macrophage pyroptosis via supressing NLRP3 inflammasome activation.

CYD significantly ameliorates LPS-induced ALI by suppressing NLRP3 inflammasome-mediated macrophage pyroptosis and this Chinese medicine also shows high safety profile, making it a promising therapeutic for the treatment of LPS-induced ALI.