Li Ya, Pan Deng, Liu Huifeng, Xie Wenya, Li Xiaoyong, Mu Xin, Chen Li, Yang Min, Wang Xianliang, Li Xianxiao, Li Jianhui, Zhang Bianhong, Guan Fangxia, Aziz Faisal, Cao Jingyu, Zhu Xiangzhan
Henan Key Laboratory of Rehabilitation Medicine, Henan Joint International Research Laboratory of Chronic Liver Injury, Zhengzhou, China.
Henan Provincial Outstanding Overseas Scientists Chronic Liver Injury Workshop, the Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
Inflammation. 2024 Dec 10. doi: 10.1007/s10753-024-02203-2.
Necrotizing enterocolitis (NEC) stands as the most prevalent and severe gastrointestinal ailment affecting premature newborns, particularly those with extremely low birth weights. Intestinal barrier dysfunction emerges as a crucial factor in NEC's pathogenesis. REGγ predominantly manifests in the intestinal epithelium and has shown to regulate experimental colitis. However, the potential correlation between REGγ and NEC remains ambiguous. This study reveals that REGγ is notably overexpressed in both human and murine NEC samples. REGγ-deficient mice displayed improvements in intestinal mucosal inflammation and reduced NEC severity. Additionally, REGγ deficiency notably lowered the expression of phosphorylated transcription factor p65 and inflammatory factors in intestinal epithelial cells of NEC-afflicted mice. REGγ exacerbates the local inflammation by triggering the degradation of IκBɛ, a negative regulator of NFκB. Clinically, REGγ and p65 expression levels exhibit a positive correlation in NEC specimens. Moreover, pre-treatment of mice with a p65 inhibitor effectively suppressed the expression of inflammatory mediators and alleviated REGγ-mediated NEC development. These findings underscore that abnormal upregulation of REGγ triggers NEC development by enhancing NF-κB activity and exacerbating epithelial barrier dysfunction. Thus, novel therapeutic approaches targeting REGγ inhibition may offer enhanced treatment for NEC.
坏死性小肠结肠炎（NEC）是影响早产儿尤其是极低出生体重儿最常见且最严重的胃肠道疾病。肠道屏障功能障碍是NEC发病机制中的一个关键因素。REGγ主要在肠道上皮中表达，并已显示出可调节实验性结肠炎。然而，REGγ与NEC之间的潜在关联仍不明确。本研究表明，REGγ在人类和小鼠NEC样本中均显著过表达。REGγ缺陷小鼠的肠道黏膜炎症有所改善，NEC严重程度降低。此外，REGγ缺陷显著降低了患NEC小鼠肠道上皮细胞中磷酸化转录因子p65和炎症因子的表达。REGγ通过触发NFκB的负调节因子IκBɛ的降解来加剧局部炎症。临床上，NEC标本中REGγ和p65的表达水平呈正相关。此外，用p65抑制剂预处理小鼠可有效抑制炎症介质的表达，并减轻REGγ介导的NEC发展。这些发现强调，REGγ的异常上调通过增强NF-κB活性和加剧上皮屏障功能障碍来触发NEC的发展。因此，针对REGγ抑制的新型治疗方法可能为NEC提供更好的治疗。
