Fresh Frozen Plasma Modulates Brain Gene Expression in a Swine Model of Traumatic Brain Injury and Shock: A Network Analysis

Abstract

Resuscitation with fresh frozen plasma (FFP) decreases brain lesion size and swelling in a swine model of traumatic brain injury and hemorrhagic shock. We hypothesized that brain gene expression profiles after traumatic brain injury and hemorrhagic shock would be modulated by FFP resuscitation. Fifteen swine underwent a protocol of traumatic brain injury and hemorrhagic shock and 2hours of shock followed by resuscitation with FFP, normal saline, or hetastarch (5/group). After 6 hours, brain RNA was isolated and hybridized onto a porcine gene ST 1.1 microarray. Weighted gene correlation network analysis was used to identify clusters of highly coexpressed genes. Principal component analysis identified cluster eigenvectors, indicating overall direction and magnitude of cluster gene expression. Using linear regression, cluster eigenvectors were associated with treatment as well as brain lesion size and swelling. Results were post-hoc corrected using false discovery rate. Relevant gene clusters were subjected to pathway analysis using the Reactome tool. Network analysis identified 322 gene expression clusters (total of 12,462 coexpressed genes). Fresh frozen plasma resuscitation (but not normal saline or hetastarch) was positively associated with 2 distinct gene clusters (termed A and B) comprising 493 genes. Gene expression in both clusters was negatively associated with brain swelling, and cluster B was also negatively associated with lesion size. Pathway analysis revealed an upregulation of genes involved in metabolic and platelet signaling, as well as collagen formation and downregulation of inflammation. Fresh frozen plasma resuscitation in this model was associated with downregulation of inflammatory pathway genes and expression of gene clusters mapping to increased metabolic and platelet signaling, which, in turn, was reversely associated with brain swelling.