尽管脓毒症死亡率很高，但有效且有针对性的治疗方法仍然很少。由于细菌耐药性不断增加，TIENAM（注射用亚胺培南西司他丁钠，TIE）等传统抗生素的使用具有挑战性，这会降低其疗效并导致不良反应。我们之前的研究表明，乌司他丁 (UTI) 通过减少全身炎症和调节免疫反应对脓毒症发挥治疗作用。在这项研究中，我们检查了使用盲肠结扎穿刺 (CLP) 在小鼠模型中诱导败血症后施用 UTI 和 TIE 的可能性。我们评估了存活率、炎症细胞因子水平、组织损伤程度、免疫细胞群、腹水中的微生物群以及重要的信号通路。 UTI 和 TIE 的组合显着提高了脓毒症小鼠的存活率并减少了炎症和细菌负荷，表明其具有有效的抗菌特性。值得注意的是，与接受 CLP 的小鼠相比，接受 UTI TIE 治疗的小鼠的存活率在 168 小时内从 10% 增加到 75%。双重治疗通过减少 B 细胞、自然杀伤细胞和 TNFR2 Treg 细胞，成功调节炎症指标（白细胞介素 [IL]-6、IL-1β 和肿瘤坏死因子 [TNF]-α）和免疫细胞数量的水平。增加 CD8 T 细胞。此外，UTI 和 TIE 的结合减轻了组织损伤，减少了腹膜腔中的细菌负荷，并抑制了 NF-κB 信号通路。我们的研究结果表明，UTI 和 TIE 联合疗法可以通过减少炎症和增强免疫系统来显着改善脓毒症的结局。该结果为未来脓毒症治疗提供了一种有前景的治疗方法。版权所有 © 2024 Elsevier B.V. 保留所有权利。

Despite the high mortality associated with sepsis, effective and targeted treatments remain scarce. The use of conventional antibiotics such as TIENAM (imipenem and cilastatin sodium for injection, TIE) is challenging because of the increasing bacterial resistance, which diminishes their efficacy and leads to adverse effects. Our previous studies demonstrated that ulinastatin (UTI) exerts a therapeutic impact on sepsis by reducing systemic inflammation and modulating immune responses. In this study, we examined the possibility of administering UTI and TIE after inducing sepsis in a mouse model using cecal ligation and puncture (CLP). We assessed the rates of survival, levels of inflammatory cytokines, the extent of tissue damage, populations of immune cells, microbiota in ascites, and important signaling pathways. The combination of UTI and TIE significantly improved survival rates and reduced inflammation and bacterial load in septic mice, indicating potent antimicrobial properties. Notably, the survival rates of UTI+TIE-treated mice increased from 10 % to 75 % within 168 h compared to those of mice that were subjected to CLP. The dual treatment successfully regulated the levels of inflammatory indicators (interleukin [IL]-6, IL-1β, and tumor necrosis factor [TNF]-α) and immune cell numbers by reducing B cells, natural killer cells, and TNFR2+ Treg cells and increasing CD8+ T cells. Additionally, the combination of UTI and TIE alleviated tissue damage, reduced bacterial load in the peritoneal cavity, and suppressed the NF-κB signaling pathway. Our findings indicate that UTI and TIE combination therapy can significantly enhance sepsis outcomes by reducing inflammation and boosting the immune system. The results offer a promising therapeutic approach for future sepsis treatment.Copyright © 2024 Elsevier B.V. All rights reserved.