CDDO-imidazolide ameliorates sepsis-induced ARDS by enhancing mitophagy via the Nrf2 pathway to prohibit alveolar macrophage pyroptosis and HMGB1 release
机构：[1]Department of Anesthesiology and Critical Care Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China.[2]Jinzhou Medical University, Jinzhou 121001, China.[3]Department of Anesthesiology, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200336, China.[4]Department of Anesthesiology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China.
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), which can be reversed by ML385. Taken together, our results demonstrate that CDDO-imidazolide prominently protects the lungs by promoting Nrf2 activation and enhancing PINK1/Parkin mitophagy to inhibit AM pyroptosis and HMGB1 release. These findings provide novel insights for therapeutic strategies for sepsis-associated ARDS.
基金：
the National Natural Science Foundation of China (Nos. 81900081 and 82170089).
语种：
外文
PubmedID：
中科院(CAS)分区：
出版当年[2025]版：
大类|2 区生物学
小类|2 区生化与分子生物学2 区生物物理
最新[2025]版：
大类|2 区生物学
小类|2 区生化与分子生物学2 区生物物理
第一作者：
第一作者机构：[1]Department of Anesthesiology and Critical Care Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China.[2]Jinzhou Medical University, Jinzhou 121001, China.
共同第一作者：
通讯作者：
通讯机构：[1]Department of Anesthesiology and Critical Care Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China.[4]Department of Anesthesiology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China.
推荐引用方式(GB/T 7714)：
Liu Yajing,Ye Pengcheng,Tang Cijun,et al.CDDO-imidazolide ameliorates sepsis-induced ARDS by enhancing mitophagy via the Nrf2 pathway to prohibit alveolar macrophage pyroptosis and HMGB1 release[J].Acta Biochimica Et Biophysica Sinica.2025,doi:10.3724/abbs.2025092.
APA：
Liu Yajing,Ye Pengcheng,Tang Cijun,Jiang Meiru,Shen Yiru...&Zhao Yupeng.(2025).CDDO-imidazolide ameliorates sepsis-induced ARDS by enhancing mitophagy via the Nrf2 pathway to prohibit alveolar macrophage pyroptosis and HMGB1 release.Acta Biochimica Et Biophysica Sinica,,
MLA：
Liu Yajing,et al."CDDO-imidazolide ameliorates sepsis-induced ARDS by enhancing mitophagy via the Nrf2 pathway to prohibit alveolar macrophage pyroptosis and HMGB1 release".Acta Biochimica Et Biophysica Sinica .(2025)
