GDF3 alleviates sepsis-induced acute lung injury by regulating ferroptosis through NRF2/GPX4
Objective:To investigate the mechanism of growth differentiation factor-3(GDF3)in alleviating sepsis-induced acute lung injury in mice by regulating ferroptosis.Methods:Thirty male C57BL/6 mice were randomly divided into three groups:the control group,the cecal ligation and puncture(CLP)CLP group,and the CLP+GDF3 group,with 10 mice in each group.The septic lung injury mouse model was established using the CLP method.In the CLP+GDF3 group,GDF3(20 μg/kg)was administered via tail vein injection before CLP modeling.Tissue samples were collected 24 hours af-ter modeling.Lung tissue pathological morphology was observed and scored through HE staining,and the wet-to-dry weight ratio of lung tissue was calculated.The inflammatory cell count in the bron-choalveolar lavage fluid(BALF)of each group of mice was assessed using Wright's Giemsa staining method.The levels of inflammatory cytokines TNF-α and IL-1β in the serum and BALF of each group,as well as the levels of MDA,GSH,and Fe2+in lung tissue,were measured by ELISA.GPX4,HO-1,and NRF2 expression levels at the mRNA and protein levels in lung tissue were evalu-ated using q-PCR and Western Blot.GPX4 expression was detected using immunohistochemistry and immunofluorescence staining.Results:Compared with the control group,the CLP group exhibited significant exacerbation of lung tissue injury,a notable increase in the wet-to-dry weight ratio of the lungs,an elevated count of inflammatory cells in BALF,increased levels of TNF-α and IL-1β in both serum and BALF,elevated levels of MDA and Fe2+in lung tissue,decreased GSH content,and a downregulation of GPX4,HO-1 and NRF2 expression at both mRNA and protein levels in lung tis-sue(P<0.05).In comparison to the CLP group,the CLP+GDF3 group demonstrated significant at-tenuation of lung tissue injury,including a remarkable decrease in the wet-to-dry weight ratio,a reduc-tion in the count of inflammatory cells in BALF,decreased levels of TNF-α and IL-1β in both serum and BALF,decreased levels of MDA and Fe2+,increased GSH content,and upregulation of GPX4,HO-1 and NRF2 expression at both mRNA and protein levels in lung tissue(P<0.05).Conclusion:GDF3 can improve CLP-induced septic ALI in mice,and its mechanism of action may be related to the activation of the NRF2/GPX4 signaling pathway and the inhibition of ferroptosis.
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