WOFAPS 2025 8th World Congress of Pediatric Surgery

Yue Ma, Chunbao Guo

chongqing health center for women and children

This study investigates the role of gasdermin D (GSDMD) in platelet pyroptosis and its impact on neutrophil extracellular trap (NET) formation in necrotizing enterocolitis (NEC), a severe gastrointestinal emergency in neonates. The research aims to explore the mechanisms underlying GSDMD-dependent platelet pyroptosis and its contribution to excessive NET formation and associated inflammation in NEC.

Research Background

NEC is a leading cause of gastrointestinal emergencies in neonatal intensive care units, characterized by intestinal inflammation and necrosis. Despite advancements in medical treatment, the incidence and mortality rates of NEC have remained largely unchanged. Platelets play a significant role in inflammation and sepsis, and recent evidence suggests that platelet-derived exosomes may contribute to NET formation, which exacerbates inflammation. This study hypothesizes that GSDMD-dependent platelet pyroptosis is associated with the release of exosomes that induce excessive NET formation and subsequent intestinal damage in NEC.

Methods

The study retrospectively reviewed clinical data from preterm infants diagnosed with NEC and found elevated inflammatory markers and platelet pyroptosis. Platelet-derived exosomes were characterized using transmission electron microscopy and western blotting. Animal models of NEC were used to evaluate the effects of platelet depletion and pharmacological inhibition of GSDMD with disulfiram on NET levels, exosome release, and intestinal damage.

Results

Clinical data analysis revealed elevated inflammatory markers and platelet pyroptosis in NEC patients. Platelet-derived exosomes promoted NET formation, characterized by increased levels of MPO-DNA and dsDNA complexes. Platelet depletion reduced NET levels and exosome release, while pharmacological inhibition of GSDMD with disulfiram mitigated intestinal damage and improved survival rates. Mechanistically, mitochondrial ROS and oxidized mitochondrial DNA (ox-mtDNA) were identified as key mediators linking platelet pyroptosis to NET formation.

Conclusions

The study demonstrates that GSDMD-dependent platelet pyroptosis and the subsequent release of exosomes play a critical role in promoting NET formation and exacerbating inflammation in NEC. Targeting GSDMD with disulfiram could be a potential therapeutic strategy to reduce excessive NET formation and associated inflammation, thereby improving outcomes in NEC. Future research should focus on further elucidating the mechanisms underlying platelet pyroptosis and NET formation in NEC and exploring the clinical applications of targeting GSDMD in neonatal intensive care.