Blunt trauma induces a proinvasive transcriptional program in isolated circulating human neutrophils

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BACKGROUND: Trauma induces a "genomic storm" of gene expression in circulating leukocytes. We hypothesized that the neutrophil contribution to this response after blunt trauma varies with the magnitude of physiologic insult. METHODS: Blunt trauma patients had blood samples taken at 0 hour, 8 hours, 24 hours, and 72 hours postinjury. Clinical data on injury pattern, treatment, and outcomes were collected. Circulating neutrophils were isolated for whole transcriptome RNAseq. Over the 72-hour study period, differentially expressed genes were compared in trauma patients with and without admission lactate levels ≥3 mmol/L. Clinical outcomes and plasma effectors of neutrophil function were correlated with transcriptomic signatures. RESULTS: Nineteen patients were enrolled (median Injury Severity Score, 25; interquartile range, 14-36) with 14,517 genes analyzed. Admission serum lactate correlated with Injury Severity Score, organ failure at 72 hours postinjury, and distinct transcriptional changes, with 108 genes differentially expressed in neutrophils of high vs. low admission serum lactate patients. Top biological processes associated with high admission lactate included cAMP response element binding protein, rat sarcoma viral oncogene homolog/mitogen-activated protein kinase and nitric oxide pathways. Differentially expressed genes were clustered by dynamic expression. The largest cluster of differentially expressed genes in high vs. low admission lactate patients was associated with multiple pathways involved in neutrophil migration and extravasation. Similar to septic shock, the expression of a proinvasive transcriptional transcriptome was identified following injury and was most pronounced in patients with high admission serum lactate. CONCLUSION: Cell type-specific analysis teases out the time- and insult-dependent neutrophil signal from the circulating leukocyte "storm." Neutrophil activation by severe trauma induces a proinvasive transcriptome signal, a potential link between the circulating and tissue phenotypes associated with poor clinical outcomes. LEVEL OF EVIDENCE: Prognostic and Epidemiologic; Level III.

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