Sivelestat sodium mitigates lung injury post-acute pulmonary embolism by inhibiting NE-SPP1 neutrophil recruitment and restoring redox balance.

Acute pulmonary embolism (APE) is a major cardiovascular cause of death, characterized by inflammation and oxidative lung injury, for which targeted therapies are lacking. This study investigated the therapeutic potential of Sivelestat sodium, a neutrophil elastase (NE) inhibitor, in a rabbit APE model. APE rabbits were treated with Sivelestat sodium. Cardiopulmonary function was assessed via echocardiography and blood gas analysis. Histopathology, molecular assays (Western blot, RT-qPCR, immunofluorescence), and bioinformatics analysis were used to evaluate injury, inflammation, fibrosis, and the role of secreted phosphoprotein 1 (SPP1). Sivelestat sodium significantly improved cardiopulmonary function and reduced lung damage, neutrophil infiltration, and NETosis. It decreased levels of NE, proinflammatory cytokines (IL-1β, TNF-α, IL-6, IL-8), and markers of coagulation. Treatment also attenuated fibrosis and endothelial barrier injury. Bioinformatics identified SPP1 as a key ECM-related gene. Sivelestat inhibited NE-mediated upregulation of SPP1, subsequently restoring the expression of antioxidant genes (GSTM2, GCLC, GPX1, GPX7) and reducing oxidative stress and collagen deposition. Sivelestat sodium alleviates APE by inhibiting the NE-SPP1 axis, thereby reducing inflammation, oxidative stress, fibrosis, and endothelial injury. This identifies SPP1 as a novel therapeutic target for APE treatment.