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Division of Pediatric Surgery, Department of Surgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
Department of Surgery, The University of Oklahoma Health Sciences Center, 800 Research Parkway, Suite 449, Oklahoma City, OK 73104, USA.
Int J Mol Sci. 2025 Jun 25;26(13):6077. doi: 10.3390/ijms26136077.
Necrotizing enterocolitis (NEC) is a serious GI disease of premature infants, marked by intestinal inflammation and necrosis. Recent research has highlighted the potential role of oxidative stress (OS) and ferroptosis in its pathogenesis. We previously identified a deficiency in Glutathione Peroxidase (GPX) 4 and lipid radical accumulation, prompting further investigation. Human intestinal tissue from a prior study was processed, and it underwent RNA and protein isolation, Immunohistochemistry, Immunofluorescence, and acid digestion for iron and selenium analysis via Inductively coupled mass spectrometry (ICP-MS). NEC was induced in human enteroids using lipopolysaccharide (LPS) and hypoxia, followed by RNA/protein isolation and lipidomic analysis. Humans with NEC had significantly higher levels of GPX2 ( = 0.0003). Enteroids exposed to NEC conditions had significantly decreased amounts of NADPH compared to initial controls ( = 0.0091), but similar levels compared to post-24 h controls ( = 0.3520). Patients with NEC had significantly higher levels of iron compared to controls via the bathophenanthroline-based assay ( = 0.0102) and with ICP-MS ( = 0.0148). There were several significant alterations in lipid distribution between NEC and control patients, but not in the fatty acid profiles. Our study suggests that oxidative stress, iron dysregulation, and altered lipid metabolism contribute to NEC pathogenesis.
坏死性小肠结肠炎（NEC）是一种早产儿的严重胃肠道疾病，其特征为肠道炎症和坏死。最近的研究突出了氧化应激（OS）和铁死亡在其发病机制中的潜在作用。我们之前发现谷胱甘肽过氧化物酶（GPX）4缺乏和脂质自由基积累，促使进一步研究。对先前一项研究中的人体肠道组织进行处理，进行RNA和蛋白质分离、免疫组织化学、免疫荧光以及通过电感耦合质谱（ICP-MS）进行铁和硒分析的酸消化。使用脂多糖（LPS）和缺氧在人肠类器官中诱导NEC，随后进行RNA/蛋白质分离和脂质组学分析。患有NEC的人GPX2水平显著更高（P = 0.0003）。与初始对照组相比，暴露于NEC条件下的肠类器官中NADPH含量显著降低（P = 0.0091），但与24小时后对照组相比水平相似（P = 0.3520）。通过基于bathophenanthroline的测定法（P = 0.0102）和ICP-MS（P = 0.0148），NEC患者的铁水平显著高于对照组。NEC患者和对照患者之间的脂质分布存在若干显著改变，但脂肪酸谱没有改变。我们的研究表明，氧化应激、铁调节异常和脂质代谢改变促成了NEC的发病机制。
