Department of Emergency Medicine, Seoul National University College of Medicine, Seoul 03080, Republic of Korea;
Department of Emergency Medicine, Seoul National University Hospital, Seoul 03080, Republic of Korea.
Proc Natl Acad Sci U S A. 2021 Apr 27;118(17). doi: 10.1073/pnas.2018538118.
Secondary infections typically worsen outcomes of patients recovering from septic shock. Neutrophil [polymorphonuclear leukocytes (PMNs)] migration to secondarily inoculated sites may play a key role in inhibiting progression from local bacterial inoculation to secondary infection. Mitochondrial -formyl peptide (mtFP) occupancy of formyl peptide receptor-1 (FPR1) has been shown to suppress PMN chemotaxis. Therefore, we studied the association between circulating mtFPs and the development of secondary infection in patients with septic shock. We collected clinical data and plasma samples from patients with septic shock admitted to the intensive care unit for longer than 72 h. Impacts of circulating nicotinamide adenine dinucleotide dehydrogenase subunit-6 (ND6) upon clinical outcomes were analyzed. Next, the role of ND6 in PMN chemotaxis was investigated using isolated human PMNs. Studying plasma samples from 97 patients with septic shock, we found that circulating ND6 levels at admission were independently and highly associated with the development of secondary infection (odds ratio = 30.317, 95% CI: 2.904 to 316.407, = 0.004) and increased 90-d mortality (odds ratio = 1.572, 95% CI: 1.002 to 2.465, = 0.049). In ex vivo experiments, ND6 pretreatment suppressed FPR1-mediated PMN chemotactic responses to bacterial peptides in the presence of multiple cytokines and chemokines, despite increased nondirectional PMN movements. Circulating mtFPs appear to contribute to the development of secondary infection and increased mortality in patients with septic shock who survive their early hyperinflammatory phase. The increased susceptibility to secondary infection is probably partly mediated by the suppression of FPR1-mediated PMN chemotaxis to secondary infected sites.
继发性感染通常会使脓毒性休克患者的康复结果恶化。中性粒细胞[多形核白细胞（PMN）]向继发性接种部位的迁移可能在抑制局部细菌接种向继发性感染的进展中起关键作用。已经表明，线粒体形式肽（mtFP）占据形式肽受体-1（FPR1）可抑制PMN趋化性。因此，我们研究了循环 mtFP 与脓毒性休克患者继发性感染发展之间的关系。我们从入住重症监护病房超过 72 小时的脓毒性休克患者中收集临床数据和血浆样本。分析循环烟酰胺腺嘌呤二核苷酸脱氢酶亚基-6（ND6）对临床结果的影响。接下来，使用分离的人 PMN 研究了 ND6 在 PMN 趋化性中的作用。研究了 97 例脓毒性休克患者的血浆样本，我们发现入院时的循环 ND6 水平与继发性感染的发展独立且高度相关（优势比=30.317，95%CI：2.904 至 316.407，=0.004），并增加了 90 天死亡率（优势比=1.572，95%CI：1.002 至 2.465，=0.049）。在体外实验中，尽管 PMN 无定向运动增加，但 ND6 预处理在存在多种细胞因子和趋化因子的情况下抑制了 FPR1 介导的 PMN 对细菌肽的趋化反应。循环 mtFP 似乎有助于存活其早期高炎症期的脓毒性休克患者继发性感染的发生和死亡率的增加。对继发性感染的易感性增加可能部分是通过抑制 FPR1 介导的PMN 向继发性感染部位的趋化作用来介导的。
