Inhibition of Gpx4-mediated ferroptosis by curcumin attenuates acute lung injury in rats with sepsis
Objective:To investigate the involvement of ferroptosis mediated by glutathione peroxidase 4(Gpx4)in acute lung injury in rats with sepsis,as well as the intervention mechanism of curcumin(Cur).Methods:Twenty-four rats were randomly divided into three groups,with 8 rats in each group:Sham group,Sepsis group and Cur group.The rat model of acute lung injury in sepsis was established by cecal ligation and puncture(CLP).The Sham group only underwent laparotomy and closure.Both Sepsis group and Cur group underwent CLP,Cur group was injected with curcumin(200 mg/kg)intraperitoneally 1 hour after modeling,and the administra-tion was repeated 24 hours later.The lung tissues of the rats were sampled 48 hours after surgery,and the wet/dry weight of lung tissue ratio(W/D)of lung tissues in each group was measured.Morphological changes of lung tissues were observed by HE staining.The con-tents of GSH,MDA,and Fe2+and the levels of inflammatory factors including TNF-α,IL-6,and IL-1β in the lung tissues were mea-sured using test kits.Western blot was used to detect the expressions of nuclear factor E2-related factor 2(Nrf2)and the key regulatory protein of ferroptosis Gpx4.Apoptosis of alveolar epithelial cells was detected by TUNEL method.Ultrastructural changes of alveolar epithelial cells were observed by transmission electron microscopy.Results:Compared with the Sham group,lung tissues in the Sepsis group showed an increased W/D(P<0.05),significantly higher levels of inflammatory factors TNF-α,IL-6,and IL-1β and contents of MDA and Fe2+(P<0.05),decreased content of GSH,up-regulated expression of Nrf2,and down-regulated expression of Gpx4(P<0.05),the type Ⅱ alveolar epithelial cells were seen to be edematous,congested,and infiltrated with inflammatory cells via light microscopy,and ferroptosis signs such as mitochondrial crinkling,thickened bilayer membrane density,and reduced or broken cristae were seen via transmission electron microscopy.Compared with Sepsis group,lung tissues in the Cur group showed decreased W/D(P<0.05),lower levels of TNF-α,IL-6 and IL-1β,lower contents of MDA and Fe2+,increased content of GSH,down-regulated expression of Nrf2,and up-regulated expression of Gpx4(P<0.05),the pathological changes of lung tissues were significantly reduced.Conclusion:Curcumin reduces sepsis-induced acute lung injury in rats,and the mechanism is related to inhibiting inflamma-tory response and GPX4-mediated ferroptosis.
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