创伤中 NETosis 的蛋白质组学分析：丝氨酸蛋白酶抑制剂 B1 的出现成为关键因素。
A proteomic analysis of NETosis in trauma: Emergence of serpinB1 as a key player.
机构信息
From the Department of Surgery/Trauma Research Center (T.R.S.Jr, E.E.M., A.S., M.D.B., O.T., W.H., S.M., A.B., K.J., C.C.S., M.J.C.), Department of Biochemistry and Molecular Genetics (I.L.C., K.C.H., A.D'A., M.D., C.E.), University of Colorado Denver, School of Medicine, Aurora; Department of Surgery (E.E.M., A.L.C.), Denver Health Medical Center, Denver; Department of Health Systems, Management, and Policy (A.S.), University of Colorado Denver, School of Medicine, Aurora; Vitalant Research Institute (C.C.S.), Denver; and Department of Pediatrics (C.C.S.), University of Colorado Denver, School of Medicine, Aurora, CO.
出版信息
J Trauma Acute Care Surg. 2023 Mar 1;94(3):361-370. doi: 10.1097/TA.0000000000003849. Epub 2022 Nov 28.
BACKGROUND
Release of neutrophil extracellular traps (NETosis) may mediate postinjury organ dysfunction, but mechanisms remain unclear. The intracellular serine protease inhibitor (serpin) B1 is vital to neutrophil function and has been shown to restrict NETosis in inflammatory settings. In this study, we used discovery proteomics to identify the proteomic signature of trauma-induced NETosis. We hypothesized that serpinB1 would be a major component of this NET protein profile and associated with adverse outcomes.
METHODS
This was a post hoc analysis of data collected as part of the COMBAT randomized clinical trial. Blood was collected from injured patients at a single Level I Trauma Center. Proteomic analyses were performed through targeted liquid chromatography coupled with mass spectrometry. Abundances of serpinB1 and known NETosis markers were analyzed with patient and injury characteristics, clinical data, and outcomes.
RESULTS
SerpinB1 levels on emergency department (ED) arrival were significantly correlated with proteomic markers of NETosis, including core histones, transketolase, and S100A8/A9 proteins. More severely injured patients had elevated serpinB1 and NETosis markers on ED arrival. Levels of serpinB1 and top NETosis markers were significantly elevated on ED arrival in nonsurvivors and patients with fewer ventilator- and ICU-free days. In proteome-wide receiver operating characteristic analysis, serpinB1 was consistently among the top proteins associated with adverse outcomes. Among NETosis markers, levels of serpinB1 early in the patient's course exhibited the greatest separation between patients with fewer and greater ventilator- and ICU-free days. Gene Ontology analysis of top predictors of adverse outcomes further supports NETosis as a potential mediator of postinjury organ dysfunction.
CONCLUSION
We have identified a proteomic signature of trauma-induced NETosis, and NETosis is an early process following severe injury that may mediate organ dysfunction. In addition, serpinB1 is a major component of this NET protein profile that may serve as an early marker of excessive NETosis after injury.
背景
中性粒细胞胞外诱捕网（NETosis）的释放可能介导损伤后器官功能障碍，但机制尚不清楚。细胞内丝氨酸蛋白酶抑制剂（serpin）B1 对中性粒细胞功能至关重要，并已被证明可在炎症环境中限制 NETosis。在这项研究中，我们使用发现蛋白质组学来鉴定创伤诱导的 NETosis 的蛋白质组特征。我们假设 serpinB1 将是该 NET 蛋白图谱的主要组成部分，并与不良结局相关。
方法
这是 COMBAT 随机临床试验数据的事后分析。在一级创伤中心从受伤患者采集血液。通过靶向液相色谱与质谱联用进行蛋白质组学分析。分析了 serpinB1 和已知的 NETosis 标志物与患者和损伤特征、临床数据和结局的相关性。
结果
急诊室（ED）到达时的 serpinB1 水平与 NETosis 的蛋白质组标志物显著相关，包括核心组蛋白、转酮醇酶和 S100A8/A9 蛋白。ED 到达时，受伤更严重的患者 serpinB1 和 NETosis 标志物水平升高。在 ED 到达时，非幸存者和机械通气和 ICU 天数更少的患者中，serpinB1 和顶级 NETosis 标志物的水平显著升高。在蛋白质组学宽接收器操作特征分析中，serpinB1 一直是与不良结局相关的顶级蛋白之一。在 NETosis 标志物中，患者早期的 serpinB1 水平在机械通气和 ICU 天数较少和较多的患者之间有最大的分离。不良结局的顶级预测因子的基因本体分析进一步支持 NETosis 是损伤后器官功能障碍的潜在介质。
结论
我们已经确定了创伤诱导的 NETosis 的蛋白质组特征，NETosis 是严重损伤后的早期过程，可能介导器官功能障碍。此外，serpinB1 是该 NET 蛋白图谱的主要组成部分，可能是损伤后过度 NETosis 的早期标志物。
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