Department of Medicine, National Jewish Health, Denver, Colorado, United States of America.
PLoS One. 2011;6(7):e21958. doi: 10.1371/journal.pone.0021958. Epub 2011 Jul 6.
Acute respiratory distress syndrome (ARDS) is a poorly understood condition with greater than 30% mortality. Massive recruitment of neutrophils to the lung occurs in the initial stages of the ARDS. Significant variability in the severity and duration of ARDS-associated pulmonary inflammation could be linked to heterogeneity in the inflammatory capacity of neutrophils. Interferon-stimulated genes (ISGs) are a broad gene family induced by Type I interferons. While ISGs are central to anti-viral immunity, the potential exists for these genes to evoke extensive modification in cellular response in other clinical settings. In this prospective study, we sought to determine if ISG expression in circulating neutrophils from ARDS patients is associated with changes in neutrophil function. Circulating neutrophil RNA was isolated, and hierarchical clustering ranked patients' expression of three ISGs. Neutrophil response to pathogenic bacteria was compared between normal and high ISG-expressing neutrophils. High neutrophil ISG expression was found in 25 of 95 (26%) of ARDS patients and was associated with reduced migration toward interleukin-8, and altered responses to Staphylococcus aureus, but not Pseudomonas aeruginosa, which included decreased p38 MAP kinase phosphorylation, superoxide anion release, interleukin-8 release, and a shift from necrotic to apoptotic cell death. These alterations in response were reflected in a decreased capacity to kill S. aureus, but not P. aeruginosa. Therefore, the ISG expression signature is associated with an altered circulating neutrophil response phenotype in ARDS that may predispose a large subgroup of patients to increased risk of specific bacterial infections.
急性呼吸窘迫综合征（ARDS）是一种发病机制尚不完全明确的疾病，死亡率超过 30%。ARDS 的初始阶段，大量中性粒细胞被募集到肺部。ARDS 相关肺部炎症的严重程度和持续时间存在显著差异，这可能与中性粒细胞炎症能力的异质性有关。干扰素刺激基因（ISGs）是一类由 I 型干扰素诱导的广泛基因家族。虽然 ISGs 是抗病毒免疫的核心，但这些基因在其他临床环境中可能会引起细胞反应的广泛改变。在这项前瞻性研究中，我们试图确定 ARDS 患者循环中性粒细胞中的 ISG 表达是否与中性粒细胞功能的变化相关。分离循环中性粒细胞 RNA，对三种 ISG 的表达进行层次聚类，比较正常和高 ISG 表达中性粒细胞对致病菌的反应。在 95 例 ARDS 患者中，有 25 例（26%）发现中性粒细胞 ISG 高表达，与白细胞介素-8 趋化性降低以及对金黄色葡萄球菌反应改变有关，但对铜绿假单胞菌无影响，包括 p38 MAP 激酶磷酸化减少、超氧阴离子释放减少、白细胞介素-8 释放增加，以及从坏死性细胞死亡向凋亡性细胞死亡的转变。这些反应的改变反映在对金黄色葡萄球菌的杀伤能力降低，但对铜绿假单胞菌的杀伤能力没有降低。因此，ISG 表达谱与 ARDS 中循环中性粒细胞反应表型的改变有关，这可能使很大一部分患者易患特定细菌感染的风险增加。
