术后多器官功能障碍（MOD）与显着的死亡率和发病率相关。坏死性凋亡与不同类型的实体器官损伤有关。然而，坏死性凋亡与炎症的联系机制需要进一步阐明。本研究探讨了坏死性凋亡和 NLR 家族包含热蛋白结构域 3 (NLRP3) 炎性体在创伤手术后小肠损伤中的参与情况。以大鼠肾移植和小鼠肾缺血再灌注（I/R）作为创伤和剖腹手术模型，研究术后小肠坏死性凋亡和炎症小体激活；其他组还接受受体相互作用蛋白激酶 1 (RIPK1) 抑制剂 necrostatin-1s (Nec-1s)。为了研究坏死性凋亡是否在体外调节炎症小体活性，通过肿瘤坏死因子-α (TNFα)、SMAC 模拟物 LCL-161 和泛半胱天冬酶抑制剂 Q-VD 的组合在人结肠上皮癌细胞 (Caco-2) 中诱导坏死性凋亡-Oph（统称为 TLQ）和坏死性凋亡被 Nec-1 或混合谱系激酶结构域样 (MLK​​L) 抑制剂 necrosulfonamide (NSA) 阻断。 24 岁时，肾移植和肾缺血再灌注 (I/R) 上调小肠中坏死性凋亡介质（RIPK1；RIPK3；磷酸化-MLKL）和炎症小体成分（P2X 嘌呤受体亚家族 7、P2X7R；NLRP3；caspase-1）的表达h和Nec-1s抑制炎症小体成分的表达。 TLQ 治疗诱导 NLRP3 炎症小体，促进 caspase-1 和白细胞介素 1β (IL-1β) 的裂解，并刺激 Caco-2 细胞释放细胞外 ATP，MLKL 抑制剂 NSA 阻止 TLQ 诱导的炎症小体活性和 Caco-2 细胞的 ATP 释放。 2 个细胞。我们的工作表明，坏死性凋亡和炎症小体至少部分通过 ATP 嘌呤能信号相互作用促进远端术后小肠损伤。坏死性凋亡-炎性体轴可被视为在重症监护环境中解决术后 MOD 的新治疗靶点。© 2023。作者。

Postoperative multi-organ dysfunction (MOD) is associated with significant mortality and morbidity. Necroptosis has been implicated in different types of solid organ injury; however, the mechanisms linking necroptosis to inflammation require further elucidation. The present study examines the involvement of necroptosis and NLR family pyrin domain containing 3 (NLRP3) inflammasome in small intestine injury following traumatic surgery. Kidney transplantation in rats and renal ischaemia-reperfusion (I/R) in mice were used as traumatic and laparotomic surgery models to study necroptosis and inflammasome activation in the small intestinal post-surgery; additional groups also received receptor-interacting protein kinase 1 (RIPK1) inhibitor necrostatin-1s (Nec-1s). To investigate whether necroptosis regulates inflammasome activity in vitro, necroptosis was induced in human colonic epithelial cancer cells (Caco-2) by a combination of tumour necrosis factor-alpha (TNFα), SMAC mimetic LCL-161 and pan-caspase inhibitor Q-VD-Oph (together, TLQ), and necroptosis was blocked by Nec-1s or mixed lineage kinase-domain like (MLKL) inhibitor necrosulfonamide (NSA). Renal transplantation and renal ischaemia-reperfusion (I/R) upregulated the expression of necroptosis mediators (RIPK1; RIPK3; phosphorylated-MLKL) and inflammasome components (P2X purinoceptor subfamily 7, P2X7R; NLRP3; caspase-1) in the small intestines at 24 h, and Nec-1s suppressed the expression of inflammasome components. TLQ treatment induced NLRP3 inflammasome, promoted cleavage of caspase-1 and interleukin-1 beta (IL-1β), and stimulated extracellular ATP release from Caco-2 cells, and MLKL inhibitor NSA prevented TLQ-induced inflammasome activity and ATP release from Caco-2 cells. Our work suggested that necroptosis and inflammasome interactively promote remote postoperative small intestinal injury, at least in part, through ATP purinergic signalling. Necroptosis-inflammasome axis may be considered as novel therapeutic target for tackling postoperative MOD in the critical care settings.© 2023. The Author(s).