Human placental mesenchymal stem cells and their derived exosomes alleviate oxidative stress and ferroptosis via the Nrf2/GPX4 pathway in hemorrhagic shock-induced acute lung injury

Hemorrhagic shock (HS) induces acute lung injury (ALI) in the early phase. Mesenchymal stem cells (MSCs) have shown potential in ameliorating HS-induced ALI; however, the mechanisms involved remain unclear. Our study investigated the therapeutic effects of human placental MSCs (hPMSCs) on HS-induced ALI and explored the underlying mechanisms. Male Sprague-Dawley rats were used to establish a model of HS, and the treatment group received injected hPMSCs. The biodistribution of hPMSCs in various organs of rats was imaged with the in vivo imaging system (IVIS) spectrum. The therapeutic effect of hPMSCs on HS-induced ALI was evaluated, and the underlying mechanisms were investigated. The lungs and livers of HS rats were the main migration targets after hPMSC transplantation. hPMSCs markedly mitigated lung pathological damage and diminished the levels of reactive oxygen species (ROS), malondialdehyde (MDA), and ferrous ions (Fe 2+ ) in the lungs of HS rats, while also enhancing glutathione peroxidase 4 (GPX4) protein expression. Exosomes derived from hPMSCs were taken up by rat alveolar type II epithelial (AT2) cells to inhibit ferroptosis by promoting the overexpression of nuclear factor erythroid 2-related factor 2 (Nrf2). Our study demonstrates the potential of hPMSC transplantation as a treatment for HS-induced ALI. The protective mechanism of hPMSCs in HS-induced ALI may include the regulation of oxidative stress and ferroptosis.