CDDO-imidazolide ameliorates sepsis-induced ARDS by enhancing mitophagy via the Nrf2 pathway to prohibit alveolar macrophage pyroptosis and HMGB1 release

作者：Yajing Liu, Pengcheng Ye, Cijun Tang, Meiru Jiang, Yiru Shen, Xiangrui Wang, Lei Hou, Yupeng Zhao · 发表于：Acta Biochimica et Biophysica Sinica · 年份：2025 · DOI：10.3724/abbs.2025092 · 被引用次数：4 · 研究领域：Inflammasome and immune disorders、Advanced Glycation End Products research、Autophagy in Disease and Therapy

Accumulating evidence suggests that NLRP3-mediated alveolar macrophage (AM) pyroptosis and subsequent high mobility group box protein 1 (HMGB1) secretion play significant roles in the pathogenesis of acute respiratory distress syndrome (ARDS). Nrf2 has been shown to be individually involved in regulating pyroptosis. In this study, we investigate the ability of CDDO-imidazolide, a potent Nrf2 activator, to regulate AM pyroptosis and HMGB1 secretion in sepsis-associated ARDS, along with its underlying mechanism. The in vitro alveolar macrophage (AM) pyroptosis model, established by stimulating J774A.1 cells with LPS and ATP, was treated with CDDO-imidazolide or utilized Nrf2 -knockout cells. The mice are intraperitoneally administered with CDDO-imidazolide before the in vivo sepsis-associated ARDS model is constructed via caecal ligation perforation and the Nrf2 inhibitor, ML385. In vitro studies reveal that the use of 3-MA to prohibit PINK1/Parkin-dependent mitophagy aggravates NLRP3-mediated pyroptosis and HMGB1 release in J774A.1 cells via LPS and ATP exposure. CDDO-imidazolide also significantly prevents NLRP3-mediated pyroptosis and HMGB1 release to increase PINK1/Parkin-dependent mitophagy, but these effects are not detected in Nrf2 -knockout macrophages. Most importantly, CDDO-imidazolide significantly alleviates NLRP3 inflammasome protein expression in the lung tissues of septic mice and HMGB1 protein levels in the serum and bronchoalveolar lavage fluid (BALF), ...