The combination of paeoniflorin and hydroxysafflor yellow A alleviated pulmonary thrombosis by inhibiting platelet-neutrophil interaction via the P-selectin-PSGL-1 signaling axis

Sepsis is a life-threatening syndrome characterized by an inflammatory cytokine storm and disseminated intravascular coagulation (DIC). The interplay between platelets and neutrophils is a key driver of the thrombosis-inflammation vicious cycle in sepsis, contributing to a detrimental feedback loop that exacerbates DIC and amplifies inflammatory cytokine storm. However, limited approaches are available for specifically targeting platelet-neutrophil crosstalk in sepsis. Xuebijing injection (XBJ), clinically used as an add-on for sepsis treatment, has been shown to reduce inflammatory cytokines release and alleviate microcirculation disturbances. In this study, we formulated a novel pharmaceutical composition (C0127-2) by combining paeoniflorin and hydroxysafflor yellow A according to their contents in XBJ (the two components with the highest content), demonstrating that C0127-2 effectively prevented sepsis-induced acute lung injury (ALI) and pulmonary thrombosis. We further verified this protection was achieved by disrupting the aggregates between platelets and neutrophils. Mechanistically, C0127-2 exerted its anti-crosstalk effects between platelet and neutrophil by inhibiting the P-selectin-PSGL-1 signaling axis, a core signaling axis to mediate platelet-neutrophil interaction. Collectively, we identified the key active constituents of XBJ, paving the way for developing a novel multi-component drug with specific ingredients for sepsis treatment. And we underscored a promising therapeutic strategy for sepsis that combining anti-inflammation and anti-coagulation effects, offering a potential management for improving patient outcomes.