Wang Wei, Xu Rongli, He Ping, Xiong Yuqing, Zhao Haomiao, Fu Xuewei, Lin Jie, Ye Lijiao
Geriatric Medicine Department, the Fifth Affiliated Hospital of Southern Medical University, Guangzhou, Guangdong Province, P.R.China.
Department of Cardiology, Hainan General Hospital, Hainan Affiliated Hospital of Hainan Medical University, Haikou, Hainan Province, P.R.China.
J Infect Dis. 2024 Feb 14;229(2):522-534. doi: 10.1093/infdis/jiad337.
Patients with sepsis resulting in acute lung injury (ALI) usually have increased mortality. Ferroptosis is a vital regulator in sepsis-induced ALI. Exploring the association of ferroptosis and sepsis-induced ALI is crucial for the management of sepsis-induced ALI.
Whole blood was collected from sepsis patients. Mice were treated with cecal ligation and puncture (CLP) to model sepsis. Primary murine pulmonary microvascular endothelial cells were treated with lipopolysaccharide as a cell model. Ferroptosis was evaluated by analyzing levels of iron, malonaldehyde, glutathione, nonheme iron, ferroportin, ferritin, and GPX4. Hematoxylin and eosin and Masson's trichrome staining were applied to examine lung injury and collagen deposition. Cell apoptosis was analyzed by caspase-3 activity and TUNEL assays. Gene regulatory relationship was verified using RNA pull-down and immunoprecipitation assays.
CircEXOC5 was highly expressed in sepsis patients and CLP-treated mice, in which knockdown alleviated CLP-induced pulmonary inflammation and injury, and ferroptosis. CircEXOC5 recruited IGF2BP2 to degrade ATF3 mRNA. The demethylase ALKBH5 was responsible for circEXOC5 upregulation through demethylation. CircEXOC5 silencing significantly improved sepsis-induced ALI and survival rate of mice by downregulating ATF3.
ALKBH5-mediated upregulation of circEXOC5 exacerbates sepsis-induced ALI by facilitating ferroptosis through IGF2BP2 recruitment to degrade ATF3 mRNA.
脓毒症导致急性肺损伤（ALI）的患者通常死亡率会升高。铁死亡是脓毒症诱导的ALI中的一个重要调节因子。探索铁死亡与脓毒症诱导的ALI之间的关联对于脓毒症诱导的ALI的管理至关重要。
从脓毒症患者中采集全血。用盲肠结扎和穿刺（CLP）处理小鼠以建立脓毒症模型。用脂多糖处理原代小鼠肺微血管内皮细胞作为细胞模型。通过分析铁、丙二醛、谷胱甘肽、非血红素铁、铁转运蛋白、铁蛋白和GPX4的水平来评估铁死亡。应用苏木精-伊红染色和Masson三色染色来检查肺损伤和胶原沉积。通过caspase-3活性和TUNEL测定法分析细胞凋亡。使用RNA下拉和免疫沉淀测定法验证基因调控关系。
CircEXOC5在脓毒症患者和CLP处理的小鼠中高表达，其中敲低可减轻CLP诱导的肺部炎症、损伤和铁死亡。CircEXOC5招募IGF2BP2来降解ATF3 mRNA。去甲基化酶ALKBH5通过去甲基化负责CircEXOC5的上调。CircEXOC5沉默通过下调ATF3显著改善了脓毒症诱导的ALI和小鼠的存活率。
ALKBH5介导的CircEXOC5上调通过招募IGF2BP2降解ATF3 mRNA促进铁死亡，从而加剧脓毒症诱导的ALI。
