Genetic Contribution to the Septic Response in a Mouse Model

Stewart, Dylan; Fulton, William B.; Wilson, Chad; Monitto, Constance L.; Paidas, Charles N.; Reeves, Roger H.; Maio, Antonio De

doi:10.1097/00024382-200210000-00009

Cited by 67 publications

(58 citation statements)

References 29 publications

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“…Furthermore, this study uses C57BL/6 mice, a Th1 dominant strain (44). It is well known that different inbred mouse strains can have a different response to injury (39,44). A Th1 dominant strain has predominant interferon-␥ cytokine production leading to immune activation via a macrophage dominant response (44), thus favoring the innate immune response.…”

Section: Discussionmentioning

confidence: 99%

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

Mira

Szpila

Nacionales

et al. 2016

Physiological Genomics

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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 doi:10. /physiolgenomics.00072.2015 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 (PTϩPp). Groups of naïve, CLP, PT, and PTϩPp 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 Ͻ 0.001) were assessed for fold-change differences. Spearman correlations were also performed. For all time points combined (CLP, PT, PTϩPp), there were 10,426 total genes that were found to significantly differ from naïve controls. At 2 h, the transcriptomic changes between CLP and PT showed a positive correlation (r s) of 0.446 (P Ͻ 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.

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Section: Discussionmentioning

confidence: 99%

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

Mira

Szpila

Nacionales

et al. 2016

Physiological Genomics

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“…We have correlated a hyperinflammatory response, in particular IL-10 levels, with an increase in mortality of B6 mice after endotoxic (6) and septic shock (8,9), respectively. Other investigations have shown a correlation between overexpression of IL-10 and a detrimental outcome after infection (30).…”

Section: Figurementioning

confidence: 99%

“…The genetic contribution to sepsis has been further supported by studies using a model of polymicrobial sepsis (8,9). A direct correlation between extremely elevated anti-inflammatory (IL-10) cytokine levels and increased mortality has been observed after peritonitis (8,9). Such studies, conducted on animals housed in identical environments and subjected to the same initiating insult, clearly illustrate that the genetic background is an important modifier of the inflammatory response and outcome.…”

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confidence: 95%

“…The frequency of mortality was also different among inbred mouse strains following injection of LPS (6). The genetic contribution to sepsis has been further supported by studies using a model of polymicrobial sepsis (8,9). A direct correlation between extremely elevated anti-inflammatory (IL-10) cytokine levels and increased mortality has been observed after peritonitis (8,9).…”

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confidence: 96%

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A Quantitative Trait Loci Analysis to Map Genes Involved in Lipopolysaccharide-Induced Inflammatory Response: Identification of Macrophage Scavenger Receptor 1 as a Candidate Gene

Fulton¹,

Reeves

Takeya

et al. 2006

The Journal of Immunology

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Septic shock, which is a major complication observed after trauma and other human diseases, is likely the product of a prolonged and poorly controlled systemic inflammatory response. Symptoms of sepsis can be partially reproduced by injection of bacterial LPS in mice. Differences in mortality between C57BL/6Jhigh and A/Jlow mice after LPS injection have been previously observed and correlated with differences in the inflammatory response between these two inbred strains. In the present study, we have mapped four loci responsible for differences in levels of LPS-induced IL-10, named modifier of IL-10, between the two strains. A locus within mouse chromosome 8 was confirmed using chromosome 8 consomic mice. This locus was further reduced in size by haplotype analysis and evaluated by the presence of potential candidate genes. The macrophage scavenger receptor 1 (Msr1) within this locus emerged as a candidate gene based on differences at the expression and structural levels between C57BL/6J and A/J mice. In comparison with wild-type (C57BL/6J) mice, Msr1 knockout mice displayed reduced levels of LPS-induced IL-10, but not of TNF-α or IL-6, confirming a specific role for this gene in the regulation of IL-10. These results suggest that Msr1 is involved in the regulation of the anti-inflammatory process, thus offering a new perspective on the molecular mechanisms involved in endotoxemia and sepsis.

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“…fluid resuscitation), many of which are not taken into account or are technically challenging in murine research models exploring trauma/sepsis. Nevertheless, even allowing for genetic variability amongst murine strains which influence survival, 24,25 other major physiologic differences in metabolism, 26 cardiovascular control 27 and gut flora 28 suggest that cautious extrapolation is clearly warranted. However, the detection of tissue injury through Pattern recognition receptors (PRR) 29,30 and antimicrobial arsenal 31 also differ between the two species.…”

Section: Diagnostic Uncertainty Confounds the Study Of Sepsis Syndromementioning

confidence: 99%

Man is the new mouse: Elective surgery as a key translational model for multi-organ dysfunction and sepsis

Cain

Arroyo

Ackland

2015

Journal of the Intensive Care Society

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Translational research in critically ill human patients presents many methodological challenges. Diagnostic uncertainty, coupled with poorly defined comorbidities, make the identification of a suitable control population for case-control investigations an arguably insurmountable challenge. Healthy volunteer experiments using endotoxin infusion as an inflammatory model are methodologically robust, but fail to replicate the onset of, and diverse therapeutic interventions associated with, sepsis/trauma. Animal models are also limited by many of these issues. Major elective surgery addresses many of these shortfalls and offers a key model for exploring the human biology underlying the sepsis syndrome. Surgery triggers highly conserved features of the human inflammatory response that are common to both tissue damage and infection. Surgical patients sustain a predictable and relatively high incidence of sepsis, particularly within the 'higher risk' group. The collection of preoperative samples enables each patient to act as their own control. Thus, the surgical model offers unique and elegant experimental design features that provide an important translational bridge between the basic biological understanding afforded by animal laboratory models and the de novo presentation of human sepsis.

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Genetic Contribution to the Septic Response in a Mouse Model

Cited by 67 publications

References 29 publications

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

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

A Quantitative Trait Loci Analysis to Map Genes Involved in Lipopolysaccharide-Induced Inflammatory Response: Identification of Macrophage Scavenger Receptor 1 as a Candidate Gene

Man is the new mouse: Elective surgery as a key translational model for multi-organ dysfunction and sepsis

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