Abstract

OBJECTIVE Sepsis-induced acute lung injury (ALI) is characterized by mitochondrial dysfunction and oxidative stress, contributing to high mortality rates. This study investigates the protective effects of astragaloside II (ASII)-preconditioned bone marrow mesenchymal stem cells (BMSCs) on sepsis-induced ALI and explores the underlying mechanism. METHODS BMSCs were isolated from C57BL/6 mice and preconditioned with ASII. The viability, migration, and apoptosis of these BMSCs were assessed. LPS-injured MLE-12 cells were co-cultured with ASII-preconditioned BMSCs to evaluate their protective effects on cell survival, apoptosis, mitochondrial membrane potential, and oxidative stress markers. A cecal ligation and puncture (CLP)-induced sepsis model in mice was used to assess the in vivo efficacy of ASII-preconditioned BMSCs on lung injury, pulmonary edema, inflammation, and apoptosis. The involvement of the NRF2 pathway was confirmed using a specific inhibitor, ML385. RESULTS BMSCs pretreated with ASII exhibited enhanced viability, migration, and resistance to apoptosis. In LPS-injured MLE-12 cells, ASII-preconditioned BMSCs improved cell survival, reduced apoptosis, and restored mitochondrial membrane potential by modulating mitochondrial dynamics (increasing Mfn2 and decreasing Fis1 expression) and promoting mitochondrial biogenesis via the NRF2/PGC-1α/Nrf1/Tfam signaling axis. These protective effects were attenuated upon NRF2 inhibition with ML385, confirming NRF2 pathway involvement. In a CLP-induced sepsis model, ASII-preconditioned BMSCs significantly reduced lung injury, pulmonary edema, and apoptosis, while lowering inflammatory cytokine levels (TNF-α, IL-1β, IL-6) and increasing TIPE2 in bronchoalveolar lavage fluid. CONCLUSIONS