Viral-induced Adaptation of Neutrophil Response in ARDS

摘要 急性呼吸窘迫综合征（ARDS）是一种对广泛的呼吸道疾病的失调反应。 一系列的传染病。然而，疾病发生和严重程度的巨大变化 在具有明显相似风险因素的个体之间可见。迅速而庞大 中性粒细胞在空域的积累是第一个可识别的事件之一， 急性呼吸窘迫综合征的发病机制，过度兴奋，无效，和/或不适当的反应， 细菌感染可能随之发生。我们假设病毒感染可以间接引起 中性粒细胞对病原菌的反应暂时受损，导致增强 嗜中性粒细胞介导的肺部炎症和损伤。病毒诱导I型 干扰素（IFNa/？），这反过来又上调了一个基因家族的表达， 干扰素刺激基因（Interferon Stimulated Genes，ISG）在初步研究中，我们发现大约有一个 四分之一的有ARDS风险的患者在其组织中ISG表达显著升高， 循环中性粒细胞，并且ISG上调与中性粒细胞受损相关。 反应表型离体和更严重的患者的临床结果。这一假设 将在ARDS患者的分离中性粒细胞和全血研究中进行测试， 参加了由NHLBI ARDS临床网络赞助的两项即将进行的治疗试验。 本研究的具体目的是：（1）检测中性粒细胞在ARDS患者中的作用， 干扰素刺激基因（ISG）上调对疾病严重程度和 结果。2)急性呼吸窘迫综合征患者中性粒细胞的促红细胞生成试验及ISG的影响 上调对促炎刺激和活细菌的细胞应答。3)前瞻性 在ARDS患者中测试全血中ISG上调作为ARDS的生物标志物的预测价值， 病毒感染和更严重的临床过程。ISG在分离的中性粒细胞中上调， 将通过原型ISG的真实的时间PCR定量测定全血，并分析 中性粒细胞信号传导和功能特性的中心，有效的先天反应， 细菌感染该提案具有时间敏感性，因为必须分析中性粒细胞反应 在分离时用活细胞。叙事 正在进行的、正在消退的或未确诊的病毒感染使患者易患以下疾病的能力 长期以来一直观察到严重且通常致命的细菌感染，但 这些事件在很大程度上是未知的。如果成功，该提案将确定一个机制， 哪些病毒可以介导ARDS中更严重的结果，并将测试升高 ISG表达是预后不良的标志。确定病毒诱导的 早期免疫失调的发生对于设计治疗策略 ARDS，并解释在这种非常复杂的情况下对治疗的反应。

Abstract The Acute Respiratory Distress Syndrome (ARDS) is a dysregulated response to a broad range of infectious insults. However, tremendous variability in disease occurrence and severity is seen between individuals with apparently similar risk factors. Rapid and massive accumulation of neutrophils to the airspace is one of the first identifiable events in the pathogenesis of ARDS, and overexuberant, ineffective, and/or inappropriate responses to a bacterial infection may ensue. We hypothesize that viral infections can indirectly evoke a transient impairment of the neutrophil response to pathogenic bacteria, resulting in enhanced neutrophil-mediated lung inflammation and injury. Viruses induce the release of Type I Interferons (IFNa/?), which in turn upregulate expression of a family of genes referred to as the Interferon Stimulated Genes (ISG). In preliminary studies, we have found approximately one quarter of patients at risk for ARDS demonstrate signficantly elevated ISG expression in their circulating neutrophils, and that ISG upregulation is associated with an impaired neutrophil response phenotype ex vivo and a more severe clinical outcome in patients. This hypothesis will be tested in studies of isolated neutrophils and whole blood from ARDS patients that will be enrolled in two upcoming therapeutic trials sponosored by the NHLBI ARDS Clinical Network. The specific aims are to 1) Prospectively test in ARDS patients the effect of neutrophil Interferon Stimulated Gene (ISG) upregulation on clinical parameters of disease severity and outcome. 2) Prospectively test in neutrophils isolated from ARDS patients the effect of ISG upregulation on cellular response to pro-inflammatory stimuli and live bacteria. 3) Prospectively test in ARDS patients the predictive value of ISG upregulation in whole blood as a biomarker of viral infection and a more severe clinical course. ISG upregulation in isolated neutrophils and whole blood will be determined by real time PCR quantification of prototypical ISG, and analysis of neutrophil signaling and functional properties central to an effective innate response to bacterial infection. The proposal is ¿time sensitive¿, as neutrophil response must be analyzed with viable cells at the time of isolation. Narrative The capacity of ongoing, resolving or undiagnosed viral infections to predispose patients to severe and often lethal bacterial infections has long been observed, but the mechanisms of these events are largely unknown. If successful, this proposal will identify a mechanism by which viruses can mediate a more severe outcome in ARDS, and will test the utility of elevated ISG expression as a marker of worse prognosis. Identifying mechanisms by which viral-induced dsyregulation of early immunity occurs is essential both to designing therapeutic strategies for ARDS, and to interpret response to treatment in this remarkably complex condition.