Abstract：
Both sepsis and acute respiratory distress syndrome (ARDS) rely on imprecise clinical definitions leading to heterogeneity, which has contributed to negative trials. Because circulating protein/DNA complexes have been implicated in sepsis and ARDS, we aimed to develop a proteomic signature of DNA-bound proteins to discriminate between children with sepsis with and without ARDS. We performed a prospective case-control study in 12 children with sepsis with ARDS matched to 12 children with sepsis without ARDS on age, severity of illness score, and source of infection. We performed co-immunoprecipitation and downstream proteomics in plasma collected ≤ 24 h of intensive care unit admission. Expression profiles were generated, and a random forest classifier was used on differentially expressed proteins to develop a signature which discriminated ARDS. The classifier was tested in six independent blinded samples. Neutrophil and nucleosome proteins were over-represented in ARDS, including two S100A proteins, superoxide dismutase (SOD), and three histones. Random forest produced a 10-protein signature that accurately discriminated between children with sepsis with and without ARDS. This classifier perfectly assigned six independent blinded samples as having ARDS or not. We validated higher expression of the most informative discriminating protein, galectin-3-binding protein, in children with ARDS. Our methodology has applicability to isolation of DNA-bound proteins from plasma. Our results support the premise of a molecular definition of ARDS, and give preliminary insight into why some children with sepsis, but not others, develop ARDS.
摘要：
脓毒症和急性呼吸窘迫综合征（ARDS）都依赖于不精确的临床定义，导致异质性。这导致了阴性试验。因为循环蛋白/DNA复合物与脓毒症和ARDS有关,我们的目的是建立DNA结合蛋白的蛋白质组学特征,以区分有和无ARDS的脓毒症患儿.我们进行了一项前瞻性病例对照研究，研究对象为12例合并ARDS的脓毒症患儿与12例无ARDS的脓毒症患儿的年龄相匹配，疾病严重程度评分，和感染源。我们在重症监护病房入院后≤24小时收集的血浆中进行了免疫共沉淀和下游蛋白质组学。产生表达谱,并在差异表达的蛋白质上使用随机森林分类器来开发区分ARDS的签名。在六个独立的盲化样品中测试分类器。中性粒细胞和核小体蛋白在ARDS中过度表达，包括两种S100A蛋白,超氧化物歧化酶（SOD），和三个组蛋白。随机森林产生了一个10蛋白签名，可以准确区分有和没有ARDS的脓毒症儿童。该分类器完美地将六个独立的盲化样品分配为是否具有ARDS。我们验证了信息最丰富的区别蛋白的更高表达，半乳糖凝集素-3结合蛋白，患有ARDS的儿童。我们的方法适用于从血浆中分离DNA结合的蛋白质。我们的结果支持ARDS分子定义的前提，并初步了解为什么一些患有败血症的儿童，但不是其他人，发展ARDS。
