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<p>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<sup>−/−</sup>) 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<sup>−/−</sup> 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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月4日

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  • Xinyi Yang,
  • Xinru Wang,
  • Yihang Yang,
  • Yue Ma,
  • Xinli Liu,
  • Dandan Mo,
  • Chunbao Guo,
  • Wenli Han

摘要

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.