Viral-induced Adaptation of Neutrophil Response in ARDS

摘要 急性呼吸窘迫综合征(ARDS)是对广泛的 一系列具有感染力的侮辱。然而，疾病发生和严重程度的巨大差异 在具有明显相似风险因素的个人之间被看到。快速和大规模 中性粒细胞聚集到空气中是最早可识别的事件之一 ARDS的发病机制，以及过度兴奋、无效和/或对 细菌感染可能随之而来。我们假设病毒感染可以间接引起 中性粒细胞对病原菌的一过性反应受损，导致 中性粒细胞介导的肺部炎症和损伤。病毒诱导I型病毒的释放 干扰素(IFNA/？)，它反过来上调一个被称为 干扰素刺激基因(ISG)。在初步研究中，我们发现了大约一个 四分之一的有ARDS风险的患者的ISG表达显著升高 循环中的中性粒细胞，ISG上调与中性粒细胞受损有关 患者的体外反应表型和更严重的临床结果。这一假设 将在分离的中性粒细胞和ARDS患者的全血研究中进行测试，这将是 参加了由NHLBI ARDS临床网络赞助的两项即将进行的治疗试验。 其具体目的是：1)前瞻性地测试中性粒细胞对ARDS患者的影响 干扰素刺激基因(ISG)上调疾病严重程度和临床参数 结果。2)在ARDS患者分离的中性粒细胞中前瞻性检测ISG的作用 上调细胞对促炎刺激和活细菌的反应。3)前瞻性 全血ISG升高作为急性呼吸窘迫综合征生物标志物的预测价值 病毒感染和更严重的临床病程。分离的中性粒细胞和中性粒细胞的ISG上调 全血将通过实时定量聚合酶链式反应检测原型ISG，并分析 中性粒细胞信号转导和功能特性对有效的先天反应至关重要 细菌感染。由于必须对中性粒细胞的反应进行分析，因此该提议具有时间敏感性。 在分离时有活细胞。叙述性 持续、解决或未诊断的病毒感染的能力，使患者容易患上 严重且往往致命的细菌感染长期以来一直被观察到，但其机制 这些事件在很大程度上是未知的。如果成功，这项提议将通过以下方式确定一种机制 哪些病毒可以在ARDS中调解更严重的结果，并将测试升高的 ISG表达可作为预后较差的标志物。确定病毒诱导的机制 早期免疫的调节对于设计治疗策略是必不可少的。 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.