Ma Gang, Ma Jie, Qu Baofu, Zhang Caixia, Zhu Jinyuan, Chen Yi, Ma Yujie, Meng Xiangkun
Department of Anesthesia and Perioperative Medicine, General Hospital of Ningxia Medical University (The First Clinical Medical College of Ningxia Medical University), 750004 Yinchuan, China.
Department of Intensive Care Unit, General Hospital of Ningxia Medical University (The First Clinical Medical College of Ningxia Medical University), 750004 Yinchuan, China.
Cytokine. 2025 Mar;187:156872. doi: 10.1016/j.cyto.2025.156872. Epub 2025 Jan 28.
Sepsis is an infection-related systemic inflammation with high mortality rates. Activation of formyl peptide receptor 1 (FPR1) in immune cells can promote their chemotaxis and inflammatory response, which imbalances immune response during the process of sepsis. FPR1 blockade did diminish systemic inflammatory response during bacterial infection. Accordingly, this study tested the hypothesis that knockout or treatment with an antagonist of FPR1 could protect animals from sepsis-related death.
Wild-type (WT) or Fpr1 gene knockout (Fpr1) C57BL/6 mice were subjected to the process of cecal ligation and puncture (CLP) to induce different grades of sepsis. Some WT mice were treated with cinnamoylphenylalanine-(D)leucine-phenylalanine-(D)leucine-phenylalanine (cFLFLF), a FPR1 antagonist. Their survival rate was evaluated, their blood and peritoneal flushing samples were collected at 6 and 24 h after the induction of sepsis for biochemical analyses. We also enrolled 143 sepsis patients, their blood and neutrophil samples were collected for analysis of FPR1 expression by RT-qPCR, and their 28-day survival was recorded.
All mice died by day 6 after high grade sepsis regardless of Fpr1 or cFLFLF treatment. Fpr1 gene knockout or cFLFLF treatment increased the survival rate of mice with a mid-to-low grade of sepsis, accompanied by a significant decrease in the levels of serum and peritoneal inflammatory markers (IL-6, IL-1β and TNF-α). Induction of sepsis increased the percentages of blood neutrophils, and the counts of peritoneal bacterial colony forming units, but decreased body temperature in WT mice, but not in the Fpr1 mice or cFLFLF-treated sepstic mice. Analysis of clinical data indicated that sequential organ failure assessment score and old age were independent risk factors for 28-day mortality.
Fpr1 gene knockout or cFLFLF treatment increased the survival rate of animals with a mid-to-low grade of sepsis, in part by inhibiting abdominal and systemic inflammation during the early period of sepsis. FPR1 protein level in neutrophils was not an independent risk factor of 28-day mortality in sepsis patients.
脓毒症是一种与感染相关的全身炎症反应，死亡率很高。免疫细胞中甲酸肽受体1（FPR1）的激活可促进其趋化性和炎症反应，这在脓毒症过程中使免疫反应失衡。FPR1阻断确实能减轻细菌感染期间的全身炎症反应。因此，本研究检验了以下假设：敲除FPR1基因或用FPR1拮抗剂治疗可保护动物免于脓毒症相关死亡。
野生型（WT）或Fpr1基因敲除（Fpr1）的C57BL/6小鼠接受盲肠结扎和穿刺（CLP）过程以诱导不同程度的脓毒症。一些WT小鼠用肉桂酰苯丙氨酸-（D）亮氨酸-苯丙氨酸-（D）亮氨酸-苯丙氨酸（cFLFLF），一种FPR1拮抗剂进行治疗。评估它们的存活率，在诱导脓毒症后6小时和24小时收集它们的血液和腹腔冲洗液样本进行生化分析。我们还纳入了143例脓毒症患者，收集他们的血液和中性粒细胞样本，通过逆转录定量聚合酶链反应（RT-qPCR）分析FPR1表达，并记录他们的28天生存率。
无论是否进行Fpr1或cFLFLF治疗，所有小鼠在重度脓毒症后第6天死亡。Fpr1基因敲除或cFLFLF治疗提高了中低度脓毒症小鼠的存活率，同时血清和腹腔炎症标志物（白细胞介素-6、白细胞介素-1β和肿瘤坏死因子-α）水平显著降低。脓毒症的诱导增加了血液中性粒细胞的百分比和腹腔细菌菌落形成单位的数量，但降低了WT小鼠的体温，但Fpr1小鼠或接受cFLFLF治疗的脓毒症小鼠体温未降低。临床数据分析表明，序贯器官衰竭评估评分和年龄是28天死亡率的独立危险因素。
Fpr1基因敲除或cFLFLF治疗提高了中低度脓毒症动物的存活率，部分原因是在脓毒症早期抑制了腹部和全身炎症。中性粒细胞中FPR1蛋白水平不是脓毒症患者28天死亡率的独立危险因素。
