Acute lung injury (ALI) affects over 10% of patients hospitalised in critical care, with acute respiratory distress syndrome (ARDS) being the most severe form of ALI and having a mortality rate in the region of 40%. There has been slow but incremental progress in identification of biomarkers that contribute to the pathophysiology of ARDS, have utility in diagnosis and monitoring, and that are potential therapeutic targets (Calfee CS, Delucchi K, Parsons PE, Thompson BT, Ware LB, Matthay MA, Thompson T, Ware LB, Matthay MA, Lancet Respir Med 2014, 2:611--620). However, a major issue is that ARDS is such a heterogeneous, multi-factorial, end-stage condition that the strategies for "lumping and splitting" are critical (Prescott HC, Calfee CS, Thompson BT, Angus DC, Liu VX, Am J Respir Crit Care Med 2016, 194:147--155). Nevertheless, sequencing of the human genome, the availability of improved methods for analysis of transcription to mRNA (gene expression), and development of sensitive immunoassays has allowed the application of network biology to ARDS, with these biomarkers offering potential for personalised or precision medicine (Sweeney TE, Khatri P, Toward precision medicine Crit Care Med; 2017 45:934-939). Biomarker panels have potential applications in molecular phenotyping for identifying patients at risk of developing ARDS, diagnosis of ARDS, risk stratification and monitoring. Two subphenotypes of ARDS have been identified on the basis of blood biomarkers: hypo-inflammatory and hyper-inflammatory. The hyper-inflammatory subphenotype is associated with shock, metabolic acidosis and worst clinical outcomes. Biomarkers of particular interest have included interleukins (IL-6 and IL-8), interferon gamma (IFN-γ), surfactant proteins (SPD and SPB), von Willebrand factor antigen, angiopoietin 1/2 and plasminogen activator inhibitor-1 (PAI-1). In terms of gene expression (mRNA) in blood there have been found to be increases in neutrophil-related genes in sepsis-induced and influenza-induced ARDS, but whole blood expression does not give a robust diagnostic test for ARDS. Despite improvements in management of ARDS on the critical care unit, this complex disease continues to be a major life-threatening event. Clinical trials of β2-agonists, statins, surfactants and keratinocyte growth factor (KGF) have been disappointing. In addition, monoclonal antibodies (anti-TNF) and TNFR fusion protein have also been unconvincing. However, there have been major advances in methods of mechanical ventilation, a neuromuscular blocker (cisatracurium besilate) has shown some benefit, and stem cell therapy is being developed. In the future, by understanding the role of biomarkers in the pathophysiology of ARDS and lung injury, it is hoped that this will provide rational therapeutic targets and ultimately improve clinical care (Seymour CW, Gomez H, Chang CH, Clermont G, Kellum JA, Kennedy J, Yende S, Angus DC, Crit Care 2017, 21:257).

中文翻译：

---

急性呼吸窘迫综合征的生物标志物和个性化医学的前景。

急性肺损伤（ALI）影响超过10％的危重病住院患者，其中急性呼吸窘迫综合征（ARDS）是ALI的最严重形式，死亡率约为40％。在鉴定有助于ARDS病理生理，在诊断和监测中有用并可能成为潜在治疗靶点的生物标志物的鉴定中，进展缓慢但逐渐发展（Calfee CS，Delucchi K，Parsons PE，Thompson BT，Ware LB，Matthay MA ，Thompson T，Ware LB，Matthay MA，Lancet Respir Med 2014，2：611--620）。但是，一个主要问题是，ARDS如此异质，多因素，处于最终阶段，因此“集结和分裂”策略至关重要（Prescott HC，Calfee CS，Thompson BT，Angus DC，Liu VX，Am J呼吸急救医学2016，194：147--155）。不过，人类基因组测序，改进的分析mRNA转录（基因表达）的方法的可用性以及灵敏免疫分析方法的发展使网络生物学得以应用于ARDS，这些生物标志物为个性化或精密医学提供了潜力（Sweeney TE ，Khatri P，迈向精准医学Crit Care Med; 2017 45：934-939）。生物标志物检测小组在分子表型分析中具有潜在的应用潜力，可用于识别有发展为ARDS风险的患者，ARDS的诊断，风险分层和监测。根据血液生物标志物已鉴定出ARDS的两种亚表型：低炎症性和高炎症性。高炎症亚型与休克，代谢性酸中毒和最差的临床结果有关。特别感兴趣的生物标志物包括白介素（IL-6和IL-8），干扰素γ（IFN-γ），表面活性剂蛋白（SPD和SPB），von Willebrand因子抗原，血管生成素1/2和纤溶酶原激活物抑制剂1（PAI） -1）。在血液中的基因表达（mRNA）方面，已发现败血症诱导和流感诱导的ARDS中与中性粒细胞相关的基因增加，但是全血表达并未提供针对ARDS的可靠诊断测试。尽管重症监护病房对ARDS的管理有所改善，但这种复杂的疾病仍然是威胁生命的重大事件。β2-激动剂，他汀类药物，表面活性剂和角质形成细胞生长因子（KGF）的临床试验令人失望。此外，单克隆抗体（抗TNF）和TNFR融合蛋白也令人信服。然而，机械通气方法已取得重大进展，神经肌肉阻滞剂（顺式阿曲库铵）显示出一定的益处，并且正在开发干细胞疗法。将来，通过了解生物标志物在ARDS和肺损伤的病理生理学中的作用，希望这将提供合理的治疗靶点并最终改善临床护理（Seymour CW，Gomez H，Chang CH，Clermont G，Kellum JA， Kennedy J，Yende S，Angus DC，Crit Care 2017，21：257）。