Protective Effect Of Hepcidin On Acute Respiratory Distress Syndrome By Regulating Iron Metabolism

Background and ObjectiveAcute respiratory distress syndrome（ARDS）is still faced with limited effective therapeutic drugs and high mortality.In particular,the mortality rate of COVID-19 related ARDS has reached as high as 61.5%with the global pandemic of Coronavirus disease 2019（COVID-19）pneumonia.Ferroptosis is an iron-dependent cell death,and its effect on ARDS is not clear.Hepcidin can affect inflammation and iron homeostasis.The purpose of this study was to investigate the protective effects and mechanisms of hepcidin on ferroptosis in ARDS induced by lipopolysaccharide（LPS）.Methods1.The ARDS mouse model was established by intratracheal instillations of LPS.ARDS mice were treated with or without Ferrostatin-1（Fer-1）,an inhibitor of ferroptosis.Next,ferroptosis,lung injury,inflammation was detected to explore the role of ferroptosis in LPS induced ARDS mice.2.The different expression genes（DEGs）and their biological functions involved in ARDS mice were analyzed by R with GEO database.We found that hepcidin was involved in iron metabolism,inflammation and immune process.3.Clinically,the level of serum hepcidin was verified in ARDS patients.4.ARDS mice were treated with or without hepcidin,and ferroptosis,lung injury,inflammatory factor release,immune infiltration and iron metabolism of lung tissues were detected.5.In vitro,A549 cells were treated with or without LPS or（and）hepcidin,and A549 cell ferroptosis,inflammatory factors,and iron metabolism were detected.6.FTH was silenced by si RNA-FTH and A549 ferroptosis was detected to explore the potential mechanism of the protective effect of hepcidin.Results1.Ferroptosis occurred in lung tissues of LPS induced ARDS mice,and ferroptosis aggravated lung injury and lung inflammation.2.Bioinformatics analysis showed that Hamp was up-regulated in the lung tissue of early ARDS mice and was involved in the regulation of immunity,inflammation and iron metabolism.3.The level of serum hepcidin in patients with ARDS was reduced.4.Supplementing exogenous hepcidin to ARDS mice reduced lung iron deposition,increased FTH expression,inhibited ferroptosis and alleviated lung inflammation,immune infiltration,and lung injury.5.Hepcidin inhibited A549 cell ferroptosis by regulating the iron metabolism,increasing intracellular FTH level and reducing free Fe²⁺.6.Silencing the expression of FTH in A549 cells blocked the protective effect of hepcidin on A549 cell ferroptosis.Conclusions1.Ferroptosis has occurred in LPS induced ARDS mice.2.Decreased hepcidin level has been associated with ARDS.3.Hepcidin has alleviated ferroptosis and inflammation in LPS induced ARDS mice and LPS treated A549 cells.4.Hepcidin has inhibited ferroptosis by up-regulating FTH level.