GSDMD deficiency attenuates BPD by suppressing macrophage pyroptosis and promoting M2 polarization

Bronchopulmonary dysplasia (BPD), a frequent complication in preterm infants receiving supplemental oxygen, is characterized by hyper-activation of macrophage inflammasomes, exuberant release of pro-inflammatory cytokines such as interleukin-1β (IL-1β), and Gasdermin D (GSDMD)-driven pyroptosis. However, the precise contribution of macrophage pyroptosis to BPD pathogenesis remains incompletely defined, and effective pharmacological interventions are still lacking. Using neonatal C57BL/6 wild-type (WT) and GSDMD-knockout (GSDMD^-/-) mice, we established a hyperoxia-induced BPD model (85% FiO₂, 14 days) and administered the GSDMD inhibitor disulfiram (50 mg kg⁻¹ intraperitoneally, once daily for 7 days). In vivo, we assessed lung histopathology, IL-1β levels, alveolarization, and vascular development; ex vivo, we isolated bone-marrow-derived macrophages (BMDMs) to quantify pyroptotic markers, M1/M2 polarization, and antibacterial capacity. GSDMD deletion or disulfiram treatment significantly attenuated macrophage and neutrophil infiltration, decreased pulmonary IL-1β concentrations, improved alveolar architecture and vascular density, and reduced overall cell death. BMDMs from GSDMD^-/- mice displayed diminished M1 polarization, enhanced bacterial killing, yet unaltered zymosan phagocytosis. Collectively, these findings identify GSDMD-mediated macrophage pyroptosis as a critical driver of BPD-related lung injury. Targeted GSDMD inhibition, whether genetic or pharmacologic, alleviates experimental BPD by down-regulating IL-1β and promoting alveolar development, thereby providing a promising therapeutic avenue for this devastating neonatal disorder.