Xuebijing injection attenuates sepsis-associated acute respiratory distress syndrome through PLTP-mediated regulation of macrophage JNK/c-JUN signaling

Uncontrolled macrophage activation drives excessive inflammation in sepsis-associated acute respiratory distress syndrome (ARDS). Xuebijing (XBJ) injection has been widely used as an adjunctive therapy for sepsis, but the molecular mechanisms underlying its protective effects remain unclear. To investigate the molecular mechanisms underlying the protective effects of XBJ in sepsis-associated ARDS, with particular emphasis on phospholipid transfer protein (PLTP). Plasma samples from patients with sepsis-associated ARDS, an LPS-induced mouse model, and LPS-stimulated RAW264.7 macrophages were used to evaluate the effects of XBJ. Histopathology, immunofluorescence, ELISA, RT-PCR, Western blotting, transcriptomic sequencing, and functional gain- and loss-of-function experiments were performed to investigate the role of PLTP and downstream signaling. XBJ restored PLTP expression in patients, septic mice, and macrophages. Transcriptomic analysis identified PLTP as a candidate molecular mediator associated with the protective effects of XBJ. XBJ alleviated lung injury, reduced inflammatory cytokine production, suppressed macrophage apoptosis and oxidative stress, and improved survival in septic mice. Mechanistically, XBJ-mediated inhibition of JNK/c-JUN and NF-κB signaling was partially attenuated by PLTP knockdown, whereas PLTP overexpression enhanced the anti-inflammatory effects of XBJ. Furthermore, PLTP deficiency attenuated the inhibitory effects of XBJ on inflammatory signaling in vivo. XBJ protects against sepsis-associated ARDS by suppressing macrophage inflammatory activation through a PLTP-mediated mechanism involving the JNK/c-JUN and NF-κB signaling pathways. These findings provide mechanistic insights into the protective actions of XBJ and suggest that PLTP contributes to its anti-inflammatory effects.