Neutrophilic granulocytes are required for antimicrobial defense, but they can also be harmful to the host organism. The current study demonstrates that disordered peptides in the 3-12 kDa size range in the plasma of septic patients alter effector functions of neutrophils from healthy donors. Those peptides stimulated exocytosis, increased extracellular release of reactive oxygen species (ROS), decreased ROS production in phagosomes, and impaired elimination of ROS-sensitive bacteria. Both the concentration of peptides in patients plasma and their effects on healthy cells were proportional to the clinical status of the patients. Proteomic analysis and in silico modeling indicate that multiple proteases generate the toxic peptides, with the greatest number of peptides cleaved by neutrophil elastase. We propose that neutrophils participate in an amplification loop in which proteolytic peptides stimulate extracellular release of proteases, resulting in production of more peptides. The enhanced extracellular ROS release contributes to tissue damage, while reduced intracellular ROS generation impairs elimination of certain bacteria. Breaking of this vicious cycle may offer a potential target for intervention.

中文翻译：

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肽紊乱会损害败血病患者的中性粒细胞细菌清除率并增强组织损伤

中性粒细胞是抗微生物防御所必需的，但它们也可能对宿主生物有害。当前的研究表明，败血症患者血浆中3-12 kDa大小的多肽紊乱会改变健康供体中性粒细胞的效应子功能。这些肽刺激胞吐作用，增加活性氧（ROS）的细胞外释放，减少吞噬体中ROS的产生以及削弱对ROS敏感细菌的清除。患者血浆中肽的浓度及其对健康细胞的影响均与患者的临床状况成正比。蛋白质组学分析和计算机模拟表明，多种蛋白酶可产生毒性肽，其中最大数量的肽可被嗜中性粒细胞弹性蛋白酶切割。我们建议中性粒细胞参与其中蛋白水解肽刺激蛋白酶胞外释放，从而产生更多肽的扩增环。增强的细胞外ROS释放有助于组织损伤，而减少的细胞内ROS生成则损害某些细菌的清除。打破这种恶性循环可能会提供潜在的干预目标。