创伤感染的预防和治疗策略通常集中在抗生素的使用上,避免细菌的联合治疗,他们的毒素,和炎症介质。这可能是伤口受害者的预后没有改善的主要原因。尽管我们以前的工作发现吲哚美辛(IND)和环丙沙星(CIP)的组合可以促进皮肤伤口修复并增强免疫功能,该策略对严重创伤性感染介导的并发症的有效性和安全性尚不清楚.此外,目前尚无相关靶细胞和分子机制的研究。在这项研究中,对C57BL/6成年雄性小鼠进行严重创伤性感染建模,并确定了单独IND和CIP的最佳剂量。之后,探讨INDplusCIP在创伤性感染小鼠中的疗效和安全性。然后通过转录组学方法和常规实验技术对活化巨噬细胞在此过程中的差异表达基因进行分析和验证。评估了候选信号通路(PI3K/Akt)在调节巨噬细胞功能和药物组合治疗中的作用。结果表明,INDplusCIP提高了生存率,降低炎症反应的程度,增强了创伤感染小鼠的抑菌效果。这种联合疗法不会对重要器官(肝脏,肾,心)。此外,IND联合CIP诱导的巨噬细胞显著改变其几种细胞因子的表达水平,包括白细胞介素(IL)-1β,IL-6、IL-10、IL-22、IL-23A、IL-17A,IL-17F,分化簇(CD)11b和其他基因/编码蛋白质。进一步的研究表明,PI3K抑制剂LY294002的干预调节了上述巨噬细胞的分泌功能和Akt活化(在丝氨酸473处的磷酸化)。INDplusCIP可以通过PI3K/Akt信号通路调节巨噬细胞功能,改善严重创伤感染小鼠的预后。这可能是预防和治疗严重创伤性感染的一种新的治疗策略。
The prevention and treatment strategies for traumatic infection often focus on the use of antibiotics, while eschew the combined treatment of the bacteria, their toxins, and inflammatory mediators. This might be a main reason the prognosis of wound victims has not improved. Although our previous work found that the combination of indomethacin (IND) and ciprofloxacin (
CIP) could promote skin wound repair and enhance the immune function, the efficacy and safety of this strategy for severe traumatic infection-mediated complications remain unknown. Additionally, there is no study on the relevant target cells and molecular mechanisms. In this study, C57BL/6 adult male mice were modeled for severe traumatic infection, and the optimal doses of IND and
CIP alone were determined. After that, the efficacy and safety of IND plus
CIP in traumatic infection mice were explored. Then the differentially expressed genes of activated macrophages in this process were analysed and verified by transcriptomic methods and conventional experimental techniques. The role of a candidate signalling pathway (PI3K/Akt) in regulating macrophage function and drug combination therapy was evaluated. The results showed that IND plus
CIP increased the survival rate, reduced the degree of inflammatory response, and enhanced the bacteriostatic effect in mice under traumatic infection. This combined therapy did not cause significant damage to the functions of important organs (liver, kidney, heart). In addition, IND combined with CIP induced macrophages to significantly change their expression levels of several cytokines, including interleukin (IL) -1β, IL-6, IL-10, IL-22, IL-23A, IL-17A, IL-17F, cluster of differentiation (CD) 11b and other genes/encode proteins. Further study showed that intervention with the PI3K inhibitor LY294002 modulated the secretion function of the above-mentioned macrophages and Akt activation (phosphorylation at serine 473). IND plus
CIP can regulate macrophage function through the PI3K/Akt signalling pathway and improve the prognosis of severe traumatic infected mice. This may be a new therapeutic strategy for the prevention and treatment of severe traumatic infection.