可溶性程序性细胞死亡受体-1（sPD-1）：人类和实验性急性呼吸窘迫综合征（ARDS）中具有抗炎特性的潜在生物标志物。
Soluble programmed cell death receptor-1 (sPD-1): a potential biomarker with anti-inflammatory properties in human and experimental acute respiratory distress syndrome (ARDS).
作者信息
Monaghan Sean F, Chung Chun-Shiang, Chen Yaping, Lomas-Neira Joanne, Fairbrother William G, Heffernan Daithi S, Cioffi William G, Ayala Alfred
机构信息
Division of Surgical Research, Department of Surgery, Alpert School of Medicine at Brown University and Rhode Island Hospital, 593 Eddy Street, Providence, RI, 02903, USA.
MCB Department, Brown University, 70 Ship Street, Providence, RI, 02903, USA.
出版信息
J Transl Med. 2016 Nov 11;14(1):312. doi: 10.1186/s12967-016-1071-x.
BACKGROUND
Acute respiratory distress syndrome (ARDS) remains a common organ dysfunction in the critically ill patient. Mechanisms for its development have focused on immune mediated causes, aspects of our understanding are not complete, and we lack biomarkers.
DESIGN, SETTING, AND SUBJECTS: Blood and bronchial alveolar lavage fluid (BAL) from humans (n = 10-13) with ARDS and controls (n = 5-10) as well as a murine model of ARDS (n = 5-6) with controls (n = 6-7) were studied.
METHODS
ARDS was induced in mice by hemorrhagic shock (day 1) followed by poly-microbial sepsis (day 2). Samples were then collected on the third day after the animals were euthanized. Ex vivo experiments used splenocytes from animals with ARDS cultured with and without soluble programmed death receptor-1 (sPD-1).
RESULTS
Levels of sPD-1 are increased in both the serum (11,429.3 pg/mL(SD 2133.3) vs. 8061.4(SD 4187.8), p = 0.036) and bronchial alveolar lavage (BAL) fluid (6,311.1 pg/mL(SD 3758.0) vs. 90.7 pg/mL(SD 202.8), p = 0.002) of humans with ARDS. Similar results are seen in the serum (9396.1 pg/mL(SD 1546.0) vs. 3464.5 pg/mL(SD 2511.8), p = 0.001) and BAL fluid (2891.7 pg/mL(SD 868.1) vs. 1385.9 pg/mL(SD 927.8), p = 0.012) of mice. sPD-1 levels in murine blood (AUC = 1(1-1), p = 0.006), murine BAL fluid (AUC = 0.905(0.717-1.093), p = 0.015), and human BAL (AUC = 1(1-1), p = 0.001) fluid predicted ARDS. To assess the importance of sPD-1 in ARDS, ex vivo experiments were undertaken. BAL fluid from mice with ARDS dampens the TNF-α production compared to cells cultured with BAL lacking sPD-1 (2.7 pg/mL(SD 3.8) vs. 52.38 pg/mL(SD 25.1), p = 0.002).
CONCLUSIONS
This suggests sPD-1 is elevated in critical illness and may represent a potential biomarker for ARDS. In addition, sPD-1 has an anti-inflammatory mechanism in conditions of marked stress and aids in the resolution of severe inflammation. sPD-1 could be used to not only diagnose ARDS, but may be a potential therapy.
背景
急性呼吸窘迫综合征（ARDS）仍是危重症患者常见的器官功能障碍。其发病机制主要集中在免疫介导的病因上，但我们的理解并不完整，且缺乏生物标志物。
设计、研究场所和研究对象：对患有ARDS的人类（n = 10 - 13）和对照组（n = 5 - 10）以及ARDS小鼠模型（n = 5 - 6）和对照组（n = 6 - 7）的血液和支气管肺泡灌洗液（BAL）进行了研究。
方法
通过出血性休克（第1天）诱导小鼠发生ARDS，随后进行多微生物败血症（第2天）。然后在动物安乐死后第三天采集样本。体外实验使用来自患有ARDS的动物的脾细胞，分别在有和没有可溶性程序性死亡受体-1（sPD-1）的情况下进行培养。
结果
ARDS患者血清中sPD-1水平升高（11,429.3 pg/mL（标准差2133.3）对8061.4（标准差4187.8），p = 0.036），支气管肺泡灌洗液（BAL）中sPD-1水平也升高（6,311.1 pg/mL（标准差3758.0）对90.7 pg/mL（标准差202.8），p = 0.002）。在小鼠的血清（9396.1 pg/mL（标准差1546.0）对3464.5 pg/mL（标准差2511.8），p = 0.001）和BAL液（2891.7 pg/mL（标准差868.1）对1385.9 pg/mL（标准差927.8），p = 0.012）中也观察到类似结果。小鼠血液中sPD-1水平（AUC = 1（1 - 1），p = 0.006）、小鼠BAL液中sPD-1水平（AUC = 0.905（0.717 - 1.093），p = 0.015）以及人类BAL液中sPD-1水平（AUC = 1（1 - 1），p = 0.001）可预测ARDS。为评估sPD-1在ARDS中的重要性，进行了体外实验。与用缺乏sPD-1的BAL培养的细胞相比，来自患有ARDS的小鼠的BAL液可抑制TNF-α的产生（2.7 pg/mL（标准差3.8）对52.38 pg/mL（标准差25.1），p = 0.002）。
结论
这表明sPD-1在危重症中升高，可能是ARDS的潜在生物标志物。此外，sPD-1在明显应激状态下具有抗炎机制，有助于缓解严重炎症。sPD-1不仅可用于诊断ARDS，还可能是一种潜在的治疗方法。
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