Patterns of gene expression among murine models of hemorrhagic shock/trauma and sepsis

Mira JC, Szpila BE, Nacionales DC, Lopez MC, Gentile LF, Mathias BJ, Vanzant EL, Ungaro R, Holden D, Rosenthal MD, Rincon J, Verdugo PT, Larson SD, Moore FA, Brakenridge SC, Mohr AM, Baker HV, Moldawer LL, Efron PA. Patterns of gene expression among murine models of hemorrhagic shock/trauma and sepsis. Physiol Genomics 48: 135-144, 2016. First published November 17, 2015; doi:10.1152/physiolgenomics.00072.2015.-Controversy remains whether the leukocyte genomic response to trauma or sepsis is dependent upon the initiating stimulus. Previous work illustrated poor correlations between historical models of murine trauma and sepsis (i.e., trauma-hemorrhage and lipopolysaccharide injection, respectively). The aim of this study is to examine the early genomic response in improved murine models of sepsis [cecal ligation and puncture (CLP)] and trauma [polytrauma (PT)] with and without pneumonia (PT + Pp). Groups of naive, CLP, PT, and PT + Pp mice were killed at 2 h, 1 or 3 days. Total leukocytes were isolated for genome-wide expression analysis, and genes that were found to differ from control (false discovery rate adjusted P < 0.001) were assessed for fold-change differences. Spearman correlations were also performed. For all time points combined (CLP, PT, PT + Pp), there were 10,426 total genes that were found to significantly differ from naive controls. At 2 h, the transcriptomic changes between CLP and PT showed a positive correlation (r(s)) of 0.446 (P < 0.0001) but were less positive thereafter. Correlations were significantly improved when we limited the analysis to common genes whose expression differed by a 1.5 fold-change. Both pathway and upstream analyses revealed the activation of genes known to be associated with pathogen-associated and damage-associated molecular pattern signaling, and early activation patterns of expression were very similar between polytrauma and sepsis at the earliest time points. This study demonstrates that the early leukocyte genomic response to sepsis and trauma are very similar in mice.