Limits...
Host responses to sepsis vary in different low-lethality murine models.

Gentile LF, Nacionales DC, Lopez MC, Vanzant E, Cuenca A, Szpila BE, Cuenca AG, Joseph A, Moore FA, Leeuwenburgh C, Baker HV, Moldawer LL, Efron PA - PLoS ONE (2014)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Departments of Surgery, University of Florida College of Medicine, Gainesville, Florida, United States of America.

ABSTRACT

Introduction: Animal 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.

Methods: Six 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.

Results: The 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.

Conclusion: These 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.

Show MeSH

Related in: MedlinePlus

The CLP and CS models of murine intra-abdominal sepsis each induce a distinct genomic response after sepsis.A. Unsupervised cluster analysis with a coefficient of variation of >0.5 reveals that the expression of 19,071 probe sets (12,838 genes) varied after sepsis, and segregated based on the type of sepsis model employed. B. A supervised analysis shows that there were 11,612 probesets (7,581 genes) differentially expressed after sepsis (p<0.001) and the expression patterns from these two models appear distinct from one another.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4006924&req=5

pone-0094404-g002: The CLP and CS models of murine intra-abdominal sepsis each induce a distinct genomic response after sepsis.A. Unsupervised cluster analysis with a coefficient of variation of >0.5 reveals that the expression of 19,071 probe sets (12,838 genes) varied after sepsis, and segregated based on the type of sepsis model employed. B. A supervised analysis shows that there were 11,612 probesets (7,581 genes) differentially expressed after sepsis (p<0.001) and the expression patterns from these two models appear distinct from one another.

Mentions: Using a simple unsupervised analysis, we first asked whether the two models of sepsis altered the gene expression of blood leukocytes at either two hours, one day or three days. Using cluster analysis and an individual probe set coefficient of variance threshold of greater than 0.5, we found that there were 19,071 probe sets (representing 12,838 genes) whose expression varied. Surprisingly, when these genes were clustered, the main node of separation was the sepsis model employed rather than timing of sample (Figure 2A). Using a supervised analysis, and setting the threshold at p<0.001 by F test, there were 11,612 probe sets (representing 7,581 genes) that were significantly altered after sepsis, and by examining the heat map (Figure 2B), one can see that the genomic response induced by the CS model of intra-abdominal sepsis appears distinct from that induced by the CLP model of sepsis. These differences in gene expression between the three classes (CLP, CS and healthy control) could be used to identify the source of the sample (p<0.01), as confirmed by leave-one out cross validation analysis with Monte Carlo simulation.


Host responses to sepsis vary in different low-lethality murine models.

Gentile LF, Nacionales DC, Lopez MC, Vanzant E, Cuenca A, Szpila BE, Cuenca AG, Joseph A, Moore FA, Leeuwenburgh C, Baker HV, Moldawer LL, Efron PA - PLoS ONE (2014)

The CLP and CS models of murine intra-abdominal sepsis each induce a distinct genomic response after sepsis.A. Unsupervised cluster analysis with a coefficient of variation of >0.5 reveals that the expression of 19,071 probe sets (12,838 genes) varied after sepsis, and segregated based on the type of sepsis model employed. B. A supervised analysis shows that there were 11,612 probesets (7,581 genes) differentially expressed after sepsis (p<0.001) and the expression patterns from these two models appear distinct from one another.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4006924&req=5

pone-0094404-g002: The CLP and CS models of murine intra-abdominal sepsis each induce a distinct genomic response after sepsis.A. Unsupervised cluster analysis with a coefficient of variation of >0.5 reveals that the expression of 19,071 probe sets (12,838 genes) varied after sepsis, and segregated based on the type of sepsis model employed. B. A supervised analysis shows that there were 11,612 probesets (7,581 genes) differentially expressed after sepsis (p<0.001) and the expression patterns from these two models appear distinct from one another.
Mentions: Using a simple unsupervised analysis, we first asked whether the two models of sepsis altered the gene expression of blood leukocytes at either two hours, one day or three days. Using cluster analysis and an individual probe set coefficient of variance threshold of greater than 0.5, we found that there were 19,071 probe sets (representing 12,838 genes) whose expression varied. Surprisingly, when these genes were clustered, the main node of separation was the sepsis model employed rather than timing of sample (Figure 2A). Using a supervised analysis, and setting the threshold at p<0.001 by F test, there were 11,612 probe sets (representing 7,581 genes) that were significantly altered after sepsis, and by examining the heat map (Figure 2B), one can see that the genomic response induced by the CS model of intra-abdominal sepsis appears distinct from that induced by the CLP model of sepsis. These differences in gene expression between the three classes (CLP, CS and healthy control) could be used to identify the source of the sample (p<0.01), as confirmed by leave-one out cross validation analysis with Monte Carlo simulation.

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Departments of Surgery, University of Florida College of Medicine, Gainesville, Florida, United States of America.

ABSTRACT

Introduction: Animal 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.

Methods: Six 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.

Results: The 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.

Conclusion: These 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.

Show MeSH
Related in: MedlinePlus