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 significantly 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 sponsored 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. 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 dysregulation of early immunity occurs is essential both to designing therapeutic strategies for ARDS, and to interpret response to treatment in this remarkably complex condition.
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