Neutrophils are a main source of circulating suPAR predicting outcome in critical illness
Neutrophils are a main source of circulating suPAR predicting outcome in critical illness
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DOI：
10.1186/s40560-019-0381-5
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发表时间：
2019-04-27
影响因子：
7.1
通讯作者：
Tacke, Frank
中科院分区：
文献类型：
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作者：
Gussen, Hendrik;Hohlstein, Philipp;Tacke, Frank
背景可溶性尿激酶纤溶酶原激活受体（suPAR）的循环水平已被提议作为危重疾病和脓毒症患者的预后生物标志物。然而，脓毒症中suPAR的起源仍不清楚。我们通过分析膜结合尿激酶纤溶酶原激活剂受体（uPAR、CD87）来研究 suPAR 的潜在细胞来源，并评估其在危重患者中的临床相关性。方法我们在一项前瞻性单中心非干预性队列研究中研究了来自医疗重症监护病房 (ICU) 的 87 名危重患者（44 名脓毒症患者，43 名无脓毒症患者），与 48 名标准护理感染患者和 27 名健康对照者进行比较。在入ICU时和第3天测定不同免疫细胞亚群的细胞uPAR表达（通过外周血流式细胞术）和相应的血清suPAR浓度。此外，我们分析了脓毒症患者血清对体外原代人中性粒细胞和巨噬细胞激活和uPAR裂解的影响。结果在健康对照中，几乎所有血液中性粒细胞和单核细胞都检测到uPAR（CD87）表达，但很少在淋巴细胞上检测到。虽然 ICU 患者中单核细胞上的 uPAR 表达得以维持，但危重患者中只有 58% 的中性粒细胞表达 uPAR，显着低于健康对照或标准护理患者。与此同时，ICU 患者的血清 suPAR 水平显着升高。我们注意到，在标准护理和 ICU 患者中，低中性粒细胞 uPAR 与高血清 suPAR 之间存在明显的负相关，表明激活的中性粒细胞中 uPAR 的脱落是全身炎症中 suPAR 的主要来源。低uPAR和高suPAR均与危重患者的死亡率密切相关。此外，脓毒症患者的血清在体外诱导分离的原代中性粒细胞（而非巨噬细胞）上的uPAR蛋白表达和随后的受体脱落。结论中性粒细胞上低uPAR表面表达与危重患者血清中高suPAR之间的负相关性支持中性粒细胞是全身炎症中脱落的suPAR蛋白的主要来源。此外，高suPAR水平和低中性粒细胞uPAR表达可预测ICU患者的死亡率。
BackgroundCirculating levels of soluble urokinase plasminogen activation receptor (suPAR) have been proposed as a prognostic biomarker in patients with critical illness and sepsis. However, the origin of suPAR in sepsis has remained obscure. We investigated the potential cellular sources of suPAR by analyzing membrane-bound urokinase plasminogen activator receptor (uPAR, CD87) and evaluated its clinical relevance in critically ill patients.MethodsWe studied 87 critically ill patients (44 with sepsis, 43 without sepsis) from the medical intensive care unit (ICU) in comparison to 48 standard care patients with infections and 27 healthy controls in a prospective single-center non-interventional cohort study. Cellular uPAR expression of different immune cell subsets (by flow cytometry from peripheral blood) and corresponding serum suPAR concentrations were determined upon ICU admission and at day 3. Furthermore, we analyzed the effects of serum from sepsis patients on the activation and uPAR cleavage of primary human neutrophils and macrophages in vitro.ResultsIn healthy controls, uPAR (CD87) expression was detected on nearly all blood neutrophils and monocytes, but only scarcely on lymphocytes. While uPAR expression on monocytes was maintained in ICU patients, only 58% of neutrophils from critically ill patients expressed uPAR, which was significantly lower than in healthy controls or standard care patients. Concomitantly, serum suPAR levels were significantly increased in ICU patients. We noted a clear inverse correlation between low neutrophilic uPAR and high serum suPAR in standard care and ICU patients, indicating that shedding of uPAR from activated neutrophils represents a main source of suPAR in systemic inflammation. Both low uPAR and high suPAR were closely associated with mortality in critically ill patients. Furthermore, serum from sepsis patients induced uPAR protein expression and subsequent receptor shedding on isolated primary neutrophils, but not on macrophages, in vitro.ConclusionsThe inverse correlation between low uPAR surface expression on neutrophils and high serum suPAR in critically ill patients supports that neutrophils are a main source of shed suPAR proteins in systemic inflammation. Furthermore, high suPAR levels and low neutrophilic uPAR expression predict mortality in ICU patients.