Transcriptomic Profiling of CD66b+ Neutrophils from Healthy Controls and Cardiac Surgery Patients with Vasoplegic and Septic Shock Syndromes Across Multiple Timepoints

Background: The systemic response to inflammation involves massive reorganization of gene expression which contributes to protection from infection but can also precipitate septic shock and organ failure. Understanding the early molecular events of systemic inflammation in sepsis is complicated by variance in both host-pathogen interactions and responses over time. Vasoplegic syndrome after cardiac surgery resembles septic shock but lacks pathogen-related variables and proceeds over a defined, reproducible time course. Analysis of a single leukocyte cell type further enhances signal-to-noise. We hypothesized that human neutrophil transcriptomic changes in sterile vasoplegic syndrome would resemble neutrophil transcriptomic changes in one or more molecular subtypes of septic shock. Results: We enrolled seven patients with vasoplegic syndrome after cardiac surgery, eight cardiac surgical controls, and 12 patients with septic shock. In principal component analysis, isolated neutrophil transcriptomes from surgical patients clustered together by timepoint and demonstrated core dynamic gene expression changes in response to cardiac surgery that were independent of outcome. Additionally, among vasoplegic syndrome patients, two marked and consistent neutrophil transcriptomic phenotypes were observed and associated with distinct clinical phenotypes. A subset of dynamic expression changes in severe vasoplegic syndrome which were not seen in surgical controls instead resembled expression in patients with septic shock characterized by increased MMP8 mRNA. Similar results were obtained for plasma cytokine levels. Conclusions: Dynamic gene expression in neutrophils from patients with severe vasoplegic syndrome includes both expression changes in response to surgery, and development of a phenotype resembling septic shock with elevated MMP8 expression. Molecular events in severe vasoplegic syndrome may provide insights into the early mechanisms driving both septic and sterile inflammatory shock. Keywords: Sepsis, Surgical Trauma, Traumatic Injury