Parthenolide alleviates sepsis-induced acute lung injury in rat models by regulating the ferroptosis pathway

Objective To explore the effect of parthenolide (PTL) on sepsis-induced acute lung injury (ALI) through nuclear factor erythroid 2-related factor 2-glutathione peroxidase 4 (Nrf2-GPX4) ferroptosis pathway. Methods The cecal ligation and puncture (CLP) method was used to construct an ALI rat model. Rats were randomly divided into control group, ALI group, ALI+PTL group, ALI+Nrf2 agonist (SFN) group, and ALI+PTL+Nrf2 inhibitor (ML385) group. Blood gas indicators and pulmonary edema were evaluated by Blood gas analyzer and lung wet/dry weight ratio. HE staining and Perls staining microscopy were used to identify the pathological characteristics. ELISA and immunofluorescence were performed to measure oxidative stress and iron metabolism indicators. Western blot was performed to detect the Nrf2-GPX4 pathway related proteins. Results ALI group, ALI+PTL group and ALI+SFN group all showed up-regulation of partial arterial pressure of oxygen(PaO2), superoxide dismutase(SOD) activity, glutathione peroxidase(GSH-Px) activity, glutathione peroxidase 4(GPX4) positive cell rate, p-Nrf2/Nrf2 ratio, and GPX4 protein, but down-regulation of partial arterial pressure of carbon dioxide(PaCO2), lung wet/dry weight ratio, lung tissue pathological injury score, iron deposition area percentage, 4-hydroxynonenal(4-HNE) content, 8-hydroxy-2-deoxyguanosine(8-OHdG) content, acyl-CoA synthetase long-chain family member 4(ACSL4) positive cell rate, ferritin positive cell rate and heme oxygenase-1(HO-1) protein(P＜0.05). In ALI+PTL group and ALI+PTL+ML385 group indicators mentioned above were all significantly reversed(P＜0.05). Conclusions PTL alleviates sepsis-induced ALI by a mechanism of activation of Nrf2-GPX4 pathway.