Department of Pediatric Intensive Care Unit, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangdong Provincial Clinical Research Center for Child Health, Guangzhou 510623, China.
The School of Clinical Medicine, Fujian Medical University, Fuzhou 350007, China; Department of Pediatrics, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361003, China.
Int Immunopharmacol. 2024 Nov 15;141:112935. doi: 10.1016/j.intimp.2024.112935. Epub 2024 Aug 18.
Sepsis-induced intestinal injury is a common complication that increases the morbidity and mortality associated with sepsis. UCP2, a mitochondrial membrane protein, is involved in numerous cellular processes, including metabolism, inflammation, and pyroptosis. According to our previous studies, UCP2 expression increases in septic intestinal tissue. However, its function in intestinal damage is not known. This work investigated UCP2's role in intestinal injury caused by sepsis. A sepsis mouse model was established in wild-type and UCP2-knockout (UCP2-KO) animals using cecal ligation and puncture (CLP). MCC950, an NLRP3 inflammasome inhibitor, was injected intraperitoneally 3 h before CLP surgery. Overall, significantly higher levels of UCP2 were observed in the intestines of septic mice. UCP2-KO mice subjected to CLP exhibited exacerbated intestinal damage, characterized by enhanced mucosal erosion, inflammatory cell infiltration, and increased intestinal permeability. Furthermore, UCP2 knockout significantly increased oxidative stress, inflammation, and pyroptosis in the CLP mouse intestines. Interestingly, MCC950 not only inhibited pyroptosis but also reversed inflammation, oxidative stress as well as damage to intestinal tissues as a result of UCP2 knockout. Our results highlighted the protective functions of UCP2 in sepsis-associated intestinal injury through modulation of inflammation and oxidative stress via NLRP3 inflammasome-induced pyroptosis.
脓毒症诱导的肠道损伤是一种常见的并发症，会增加与脓毒症相关的发病率和死亡率。UCP2 是一种线粒体膜蛋白，参与许多细胞过程，包括代谢、炎症和细胞焦亡。根据我们之前的研究，UCP2 在脓毒症肠道组织中的表达增加。然而，其在肠道损伤中的功能尚不清楚。本研究探讨了 UCP2 在脓毒症引起的肠道损伤中的作用。使用盲肠结扎穿孔术（CLP）在野生型和 UCP2 敲除（UCP2-KO）动物中建立脓毒症小鼠模型。在 CLP 手术前 3 小时，通过腹腔内注射 MCC950，一种 NLRP3 炎性小体抑制剂。总的来说，脓毒症小鼠的肠道中观察到 UCP2 的水平显著升高。在接受 CLP 的 UCP2-KO 小鼠中，肠道损伤明显加重，表现为黏膜糜烂、炎症细胞浸润和肠道通透性增加。此外，UCP2 敲除显著增加了 CLP 小鼠肠道中的氧化应激、炎症和细胞焦亡。有趣的是，MCC950 不仅抑制了细胞焦亡，还逆转了 UCP2 敲除引起的炎症、氧化应激以及肠道组织损伤。我们的研究结果表明，UCP2 通过 NLRP3 炎性小体诱导的细胞焦亡来调节炎症和氧化应激，从而在脓毒症相关的肠道损伤中发挥保护作用。
