Department of Veterinary Pharmacology, Graduate School of Agriculture and Life Sciences, The University of Tokyo, Tokyo, Japan.
Department of Pharmacology, School of Veterinary Medicine, Azabu University, Kanagawa, Japan.
J Vet Med Sci. 2022 Apr 15;84(4):610-617. doi: 10.1292/jvms.22-0014. Epub 2022 Mar 7.
Postoperative ileus (POI) is a postsurgical gastrointestinal motility dysfunction caused by mechanical stress to the intestine during abdominal surgery. POI leads to nausea and vomiting reduced patient quality of life, as well as high medical costs and extended hospitalization. Intestinal inflammation caused by macrophages and neutrophils is thought to be important in the mechanism of POI. Surgery-associated tissue injury and inflammation induce the release of adenosine triphosphate (ATP) from injured cells. Released ATP binds the purinergic P2X7 receptor (P2X7R) expressed on inflammatory cells, inducing the secretion of inflammatory mediators. P2X7R antagonists are thought to be important mediators of the first step in the inflammation process, and studies in chemically induced colitis models confirmed that P2X7R antagonists exhibit anti-inflammatory effects. Therefore, we hypothesized that P2X7R plays an important role in POI. POI models were generated from C57BL/6J mice. Mice were treated with P2X7R antagonist A438079 (34 mg/kg) 30 min before and 2 hr after intestinal manipulation (IM). Inflammatory cell infiltration and gastrointestinal transit were measured. A438079 ameliorated macrophage and neutrophil infiltration in the POI model. Impaired intestinal transit improved following A438079 treatment. P2X7R was expressed on both infiltrating and resident macrophages in the inflamed ileal muscle layer. The P2X7R antagonist A438079 exhibits anti-inflammatory effects via P2X7R expressed on macrophages and therefore could be a target in the treatment of POI.
术后肠麻痹（POI）是一种腹部手术后由于肠道机械性应激引起的胃肠道动力功能障碍。POI 导致恶心和呕吐，降低了患者的生活质量，同时也增加了医疗费用和延长了住院时间。巨噬细胞和中性粒细胞引起的肠道炎症被认为是 POI 发生机制中的重要因素。手术相关的组织损伤和炎症诱导损伤细胞释放三磷酸腺苷（ATP）。释放的 ATP 与炎症细胞上表达的嘌呤能 P2X7 受体（P2X7R）结合，诱导炎症介质的分泌。P2X7R 拮抗剂被认为是炎症过程中第一步的重要介质，化学诱导结肠炎模型的研究证实 P2X7R 拮抗剂具有抗炎作用。因此，我们假设 P2X7R 在 POI 中发挥重要作用。使用 C57BL/6J 小鼠生成 POI 模型。在肠道操作（IM）前 30 分钟和后 2 小时，用 P2X7R 拮抗剂 A438079（34mg/kg）处理小鼠。测量炎症细胞浸润和胃肠传输。A438079 改善了 POI 模型中的巨噬细胞和中性粒细胞浸润。A438079 治疗后，受损的肠道传输得到改善。P2X7R 在炎症性回肠肌层浸润的巨噬细胞和固有巨噬细胞上均有表达。P2X7R 拮抗剂 A438079 通过巨噬细胞上表达的 P2X7R 发挥抗炎作用，因此可能成为 POI 治疗的靶点。
