The future of murine sepsis and trauma research models

Abstract

Recent comparisons of the murine and human transcriptome in health and disease have called into question the appropriateness of the use of murine models for human sepsis and trauma research. More specifically, researchers have debated the suitability of mouse models of severe inflammation that is intended for eventual translation to human patients. This mini-review outlines this recent research, as well as specifically defines the arguments for and against murine models of sepsis and trauma research based on these transcriptional studies. In addition, we review newer advancements in murine models of infection and injury and define what we envision as an evolving but viable future for murine studies of sepsis and trauma. J. Leukoc. Biol. 98: 945-952;

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

“…Interestingly, the genomic responses to these various stressors were very similar in humans, but not in mice (38). One explanation is that the current murine models are poor representations of the human condition (9,10). In support of that conclusion, we have reported that increasing injury severity in a murine trauma model produced a modest but significant improvement in correlation between patterns of human and murine gene expression (16).…”

“…In contrast, the failure of murine models to recapitulate the human response may well be due to the nature of the injury models and time periods selected (10,16). Although the response to a 30% burn injury, administration of endotoxin, and hemorrhagic shock with a laparotomy were transcriptomically dissimilar, it can be argued that these murine models are suboptimal representations of human infection and injury (10).…”

“…Murine models remain the bedrock for preclinical mechanistic and therapeutic studies. Recent studies examining the host genomic responses to injury and sepsis have increased the scrutiny of a murine model's capacity to recapitulate the human processes (10). Recently, we reported that the leukocyte genomic response to human models of injury showed significant overlap, while comparable murine models demonstrated little to no correlation among themselves (38).…”

“…Recently, murine models of sepsis and trauma have received scrutiny for their failure to fully recapitulate comparable human responses at the level of the leukocyte transcriptome (10,38). Interestingly, the genomic responses to these various stressors were very similar in humans, but not in mice (38).…”

An Immunological Perspective on Neonatal Sepsis

“…However, major differences in the nature of the transcriptome responses depend on the model used [105], and well-recognized differences between humans and mice may limit the application of findings across species. This justifies direct observations in humans [106]. Most recently, two important genome-wide gene expression studies have provided insights into the molecular pathways activated in newborns with severe infections [88,107].…”