Abstract
IntroductionAnimal models for the study of sepsis are being increasingly scrutinized, despite their essential role for early translational research. In particular, recent studies have suggested that at the level of the leukocyte transcriptome, murine models of burns, trauma and endotoxemia markedly differ from their human equivalents, and are only weakly similar amongst themselves. We compared the plasma cytokine and leukocyte transcriptome responses between two different low-lethality murine models of polymicrobial intra-abdominal sepsis.MethodsSix to ten week male C57BL/6j mice underwent either the ‘gold standard’ cecal ligation and puncture (CLP) model of intra-abdominal sepsis or administration of a cecal slurry (CS), where cecal contents are injected intraperitoneally. Surviving mice were euthanized at two hours, one or three days after sepsis.ResultsThe murine leukocyte transcriptomic response to the CLP and CS models of sepsis was surprisingly dissimilar at two hours, one, and three days after sepsis. The Pearson correlation coefficient for the maximum change in expression for the entire leukocyte transcriptome that changed significantly over time (n = 19,071) was R = 0.54 (R2 = 0.297). The CS model resulted in greater magnitude of early inflammatory gene expression changes in response to sepsis with associated increased production of inflammatory chemokines and cytokines. Two hours after sepsis, CLP had more significant expression of genes associated with IL-10 signaling pathways, whereas CS had greater expression of genes related to CD28, apoptosis, IL-1 and T-cell receptor signaling. By three days, the changes in gene expression in both sepsis models were returning to baseline in surviving animals.ConclusionThese analyses reveal that the murine blood leukocyte response to sepsis is highly dependent on which model of intra-abdominal sepsis is employed, despite their similar lethality. It may be difficult to extrapolate findings from one murine model to another, let alone to human sepsis.
Highlights
Animal models for the study of sepsis are being increasingly scrutinized, despite their essential role for early translational research
The cecal slurry (CS) model of sepsis is similar in scope to the newer colon ascendans peritoneal stent (CASP) model of intra-abdominal sepsis which is thought to more closely mimic a human generalized peritonitis response, in that it represents acute generalized peritonitis
It is helpful in those mice where a cecal ligation and puncture (CLP) is not feasible, such as neonatal mice [14]
Summary
Animal models for the study of sepsis are being increasingly scrutinized, despite their essential role for early translational research. Recent studies have suggested that at the level of the leukocyte transcriptome, murine models of burns, trauma and endotoxemia markedly differ from their human equivalents, and are only weakly similar amongst themselves. Even with recent improvements in outcomes due to changes in practice, the incidence and mortality from sepsis is increasing, in the elderly population, and sepsis continues to remain the leading cause of ICU mortality, prolonged ICU stays and multiple organ failure (MOF)[3,4,5]. A recent controversial report has revealed that at the level of the blood leukocyte transcriptome, the human response to trauma, burns and endotoxicosis is remarkably similar, whereas the comparison of the human response to murine models of injury was surprisingly poor (9). The murine transcriptomic responses to burn, trauma and endotoxicosis exhibited very little similarity among themselves
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