Fujian Key Laboratory of Innate Immune Biology, Biomedical Research Center of South China, College of Life Science, Fujian Normal University, Fuzhou, Fujian Province 350117, PR China.
Fujian Key Laboratory of Innate Immune Biology, Biomedical Research Center of South China, College of Life Science, Fujian Normal University, Fuzhou, Fujian Province 350117, PR China.
Int Immunopharmacol. 2024 Nov 15;141:112927. doi: 10.1016/j.intimp.2024.112927. Epub 2024 Aug 19.
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 T 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.
尽管脓毒症的死亡率很高，但有效的靶向治疗方法仍然稀缺。由于细菌耐药性的增加，传统抗生素（如 TIENAM[注射用亚胺培南西司他丁钠，TIE]）的使用受到挑战，因为这会降低它们的疗效并导致不良反应。我们之前的研究表明，乌司他丁（UTI）通过减轻全身炎症和调节免疫反应对脓毒症产生治疗作用。在这项研究中，我们使用盲肠结扎穿孔（CLP）在小鼠模型中诱导脓毒症后，检查了给予 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、免疫细胞群体、腹水微生物群和重要信号通路。UTI 和 TIE 的联合使用显著提高了脓毒症小鼠的存活率，降低了炎症和细菌负荷，表明具有强大的抗菌特性。值得注意的是，与接受 CLP 的小鼠相比，UTI+TIE 治疗的小鼠在 168 小时内的存活率从 10%增加到 75%。双重治疗通过减少 B 细胞、自然杀伤细胞和 TNFR2 T 细胞并增加 CD8 T 细胞成功调节了炎症指标（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。此外，UTI 和 TIE 的联合使用减轻了组织损伤，减少了腹腔内的细菌负荷，并抑制了 NF-κB 信号通路。我们的研究结果表明，UTI 和 TIE 联合治疗通过减轻炎症和增强免疫系统可以显著改善脓毒症的结局。这些发现为未来的脓毒症治疗提供了一种有前途的治疗方法。
