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<p>Immune checkpoint inhibitors (ICIs) have significant therapeutic effects but can also cause fatal lung injury. However, the lack of mouse animal models of ICI-related lung injury (ICI-LI) has limited the in-depth exploration of its pathogenesis. In clinical practice, underlying lung diseases increase the risk of lung injury. Thus, we used a mouse model of lung injury induced by bleomycin (BLM) and then administered anti-programmed cell death 1 (aPD-1) antibodies to induce ICI-LI. Compared with the BLM group, the aPD-1 + BLM group presented more significant weight loss, greater levels of lung inflammation and fibrosis, and decreased lung function. In this ICI-LI model, high levels of caspase-3/gasdermin E (GSDME) were detected in the lung tissue of mice, and the JNK inhibitor SP600125 mitigated lung damage by inhibiting GSDME-mediated pyroptosis. Consistent with the findings in the animal model, immunofluorescence and RNA sequencing of lung tissue from ICI-LI patients revealed upregulation of the expression of genes related to the GSDME-related pyroptosis pathway. Our results suggest that GSDME-mediated pyroptosis may be associated with the pathogenesis of ICI-LI, indicating that targeting GSDME could be a potential therapeutic strategy for treating ICI-LI.</p>

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Anti-PD-1 exacerbates bleomycin-induced lung injury in mice via Caspase-3/GSDME-mediated pyroptosis

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年1月6日

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  • Fei Wang,
  • Haiyi Deng,
  • Maolin Zhou,
  • Yilin Yang,
  • Jiankui Zhou,
  • Yansheng Wang,
  • Xiaohong Xie,
  • Xinqing Lin,
  • Ming Liu,
  • Gengyun Sun,
  • Chengzhi Zhou

摘要

Immune checkpoint inhibitors (ICIs) have significant therapeutic effects but can also cause fatal lung injury. However, the lack of mouse animal models of ICI-related lung injury (ICI-LI) has limited the in-depth exploration of its pathogenesis. In clinical practice, underlying lung diseases increase the risk of lung injury. Thus, we used a mouse model of lung injury induced by bleomycin (BLM) and then administered anti-programmed cell death 1 (aPD-1) antibodies to induce ICI-LI. Compared with the BLM group, the aPD-1 + BLM group presented more significant weight loss, greater levels of lung inflammation and fibrosis, and decreased lung function. In this ICI-LI model, high levels of caspase-3/gasdermin E (GSDME) were detected in the lung tissue of mice, and the JNK inhibitor SP600125 mitigated lung damage by inhibiting GSDME-mediated pyroptosis. Consistent with the findings in the animal model, immunofluorescence and RNA sequencing of lung tissue from ICI-LI patients revealed upregulation of the expression of genes related to the GSDME-related pyroptosis pathway. Our results suggest that GSDME-mediated pyroptosis may be associated with the pathogenesis of ICI-LI, indicating that targeting GSDME could be a potential therapeutic strategy for treating ICI-LI.