Sulodexide attenuates sepsis-induced lung injury in neonatal rats via TNF-α pathway

BACKGROUND: Neonatal sepsis is a leading cause of morbidity and mortality, often complicated by acute lung injury (ALI). Current treatments lack targeted anti-inflammatory or antioxidant strategies. Sulodexide (SDX), a glycosaminoglycan with endothelial-protective, anti-inflammatory, and antioxidant properties, may offer therapeutic benefit. METHODS: A lipopolysaccharide (LPS)-induced neonatal rat model was used to evaluate the effects of SDX. Following LPS injection, neonatal rats received SDX at different doses. Survival, lung histopathology, wet-to-dry lung weight ratios, and serum procalcitonin levels were assessed. Endothelial glycocalyx integrity was examined by transmission electron microscopy. Cytokines and oxidative stress markers were measured by western blotting and antioxidant assays. Transcriptomic changes were analyzed by RNA sequencing and validated by quantitative real-time polymerase chain reaction (qRT-PCR). RESULTS: SDX improved survival, reduced pulmonary edema, and alleviated histopathological lung damage. Endothelial glycocalyx structure was partially preserved. SDX reduced levels of interleukin-1β (IL-1β), interferon-γ (IFN-γ), and tumor necrosis factor-α (TNF-α), and increased total antioxidant capacity. Transcriptome analysis identified the TNF signaling pathway as a key target, with downregulation of suppressor of cytokine signaling 3 (SOCS3), phosphorylated c-Jun N-terminal kinase (p-JNK), and nuclear factor kappa B (NF-κB), and upregulation of mitogen-activated protein kinase phosphatase 1 (MKP1). CONCLUSION: SDX attenuates LPS-induced ALI in neonatal rats by modulating inflammation, particularly through the TNF-α signaling pathway. These findings suggest the potential of SDX as a therapeutic agent for neonatal sepsis-associated ALI. IMPACT: Sulodexide, a drug that has been used clinically for nearly four decades primarily in the management of adult vascular disorders, demonstrates both safety and therapeutic efficacy in a neonatal rat model of sepsis. This study provides the first experimental evidence supporting the repurposing of sulodexide for neonatal sepsis-associated acute lung injury. Sulodexide significantly attenuates inflammatory lung injury by modulating TNF-α pathway. These findings highlight sulodexide as a promising and readily translatable anti-inflammatory therapy for neonatal sepsis.