TP-235

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.

Activation of nuclear factor erythroid 2–related factor 2 (Nrf2) has shown protective effects in experimental models of acute kidney injury and nonproteinuric chronic kidney disease. However, the efficacy of Nrf2 activation for proteinuric chronic kidney disease with glomerular injury is controversial, as a transient increase in proteinuria is observed. Here, we identified a potent Nrf2 activator UD-051, which inhibits the interaction between Kelch-like ECH-associated protein 1 (Keap1) and Nrf2. UD-051 significantly ameliorated the progressive phenotype of Alport syndrome mouse model in an Nrf2-dependent manner, accompanied by increased proteinuria. Mild Nrf2 activation by geneticKeap1knockdown or pharmacological Keap1 inhibition with CDDO-imidazolide did not attenuate Alport kidney disease, suggesting that strong Nrf2 activation is essential for clear therapeutic efficacy. In-depth analysis revealed that UD-051 suppressed tubular injury, including oxidative stress, inflammation, and dysregulated metabolism. UD-051 with losartan, a renin–angiotensin system inhibitor that targets glomerular dysfunction, vastly ameliorated Alport kidney disease. Our study provides a comprehensive insight into the efficacy of Nrf2 activation in Alport syndrome and provides a rationale for adding a Keap1-Nrf2 interaction inhibitor to a renin–angiotensin system inhibitor.