Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, the Netherlands.
Center of Experimental &Molecular Medicine, Division of Infectious Diseases, Amsterdam Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
Nat Immunol. 2016 Apr;17(4):406-13. doi: 10.1038/ni.3398. Epub 2016 Mar 7.
The acute phase of sepsis is characterized by a strong inflammatory reaction. At later stages in some patients, immunoparalysis may be encountered, which is associated with a poor outcome. By transcriptional and metabolic profiling of human patients with sepsis, we found that a shift from oxidative phosphorylation to aerobic glycolysis was an important component of initial activation of host defense. Blocking metabolic pathways with metformin diminished cytokine production and increased mortality in systemic fungal infection in mice. In contrast, in leukocytes rendered tolerant by exposure to lipopolysaccharide or after isolation from patients with sepsis and immunoparalysis, a generalized metabolic defect at the level of both glycolysis and oxidative metabolism was apparent, which was restored after recovery of the patients. Finally, the immunometabolic defects in humans were partially restored by therapy with recombinant interferon-γ, which suggested that metabolic processes might represent a therapeutic target in sepsis.
脓毒症的急性期以强烈的炎症反应为特征。在一些患者的后期阶段，可能会出现免疫麻痹，这与不良预后有关。通过对脓毒症患者的转录组和代谢组学分析，我们发现从氧化磷酸化到有氧糖酵解的转变是宿主防御初始激活的一个重要组成部分。用二甲双胍阻断代谢途径会减少细胞因子的产生，并增加系统性真菌感染小鼠的死亡率。相比之下，在因接触脂多糖而耐受或从脓毒症和免疫麻痹患者中分离出来的白细胞中，糖酵解和氧化代谢水平的广泛代谢缺陷是明显的，在患者康复后得到恢复。最后，用重组干扰素-γ治疗部分恢复了人类的免疫代谢缺陷，这表明代谢过程可能是脓毒症的一个治疗靶点。
