Patterns of gene expression among murine models of hemorrhagic shock trauma and sepsis
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE69345 | GEO | 2016/07/10
SECONDARY ACCESSION(S): PRJNA285259
REPOSITORIES: GEO
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Project description:The CS and CLP murine models of intra-abdominal sepsis have unique transcriptomic respones 2 hrs, 1 and 3 days after sepsis We used mouse microarrays to detail the molecular profile of the events that occur following infection in two different sepsis models Infection protocol: Used the Cecal Ligation and Puncture (CLP) model and Cecal Slurry (CS) method in young mice.
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Project description: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 naïve, 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 naïve controls. At 2 h, the transcriptomic changes between CLP and PT showed a positive correlation (rs) 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.
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Project description:We previously demonstrated in rodents that T/HS results in liver injury that can be prevented by IL-6 administration at the start of resuscitation, however the mechanism(s) for the IL-6 protective effect is not fully known. We used microarrays to detail the global gene expression in response to T/HS and the effect of IL-6 on this model with and without pharmacologic blockade of Stat3-mediated IL-6 and identified distinct members of the inflammasome de-regulated during T/HS that normalized with IL-6 administration during resuscitation.
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Project description:The etiology of trauma-hemorrhage shock-induced acute lung injury has been difficult to elucidate due, at least in part, to the inability of in vivo studies to separate the non-injurious pulmonary effects of trauma-hemorrhage from the tissue injurious ones. To circumvent this in vivo limitation, we utilized a model of trauma-hemorrhagic shock (T/HS) in which T/HS-lung injury was abrogated by dividing the mesenteric lymph duct. In this way, it was possible to separate the pulmonary injurious response from the non-injurious systemic response to T/HS by comparing the pulmonary molecular response of rats subjected to T/HS which did and did not develop lung injury as well as to non-shocked rats. Utilizing high-density oligonucleotide arrays and treatment group comparisons of whole lung tissue collected at 3 hours after the end of the shock or sham-shock period, 139 of the 8,799 assessed genes were differentially expressed. Experiment Overall Design: Four groups of rats (n=3) were studied in order to identify changes in pulmonary gene expression associated with T/HS, both in the presence and absence of lung injury. These included trauma-sham shock (T/SS) rats which had a laparotomy (trauma) but were not subjected to hemorrhagic shock. These rats had no lung injury and served as controls for rats which were subjected to T/HS (laparotomy plus 90 min of shock) and had lung injury. Differences in gene expression between these two groups would represent both the effects of hemorrhagic shock as well as lung injury. To distinguish the gene response of hemorrhagic shock from the gene response associated with lung injury, gene expression was also compared between T/HS rats (hemorrhage and lung injury) and rats subjected to T/HS plus lymph duct ligation (T/HS-LDL), since the T/HS-LDL rats experienced hemorrhagic shock but had no measurable lung injury. Lastly, to identify hemorrhagic shock- modified genes, the pulmonary gene response of T/HS-LDL (hemorrhage without lung injury) were compared to rats subjected to T/SS plus LDL (no hemorrhage or lung injury). Three hours after the end of the 90 min shock or sham-shock period (i.e. 4.5 hrs after the induction of T/HS), the rats were sacrificed and specimens harvested for genechip analysis and histology.
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Project description:The etiology of trauma-hemorrhage shock-induced acute lung injury has been difficult to elucidate due, at least in part, to the inability of in vivo studies to separate the non-injurious pulmonary effects of trauma-hemorrhage from the tissue injurious ones. To circumvent this in vivo limitation, we utilized a model of trauma-hemorrhagic shock (T/HS) in which T/HS-lung injury was abrogated by dividing the mesenteric lymph duct. In this way, it was possible to separate the pulmonary injurious response from the non-injurious systemic response to T/HS by comparing the pulmonary molecular response of rats subjected to T/HS which did and did not develop lung injury as well as to non-shocked rats. Utilizing high-density oligonucleotide arrays and treatment group comparisons of whole lung tissue collected at 3 hours after the end of the shock or sham-shock period, 139 of the 8,799 assessed genes were differentially expressed. Keywords: Treatment response to shock
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2015-11-17 | GSE74697 | GEO
Project description:Trauma complicated by hemorrhagic shock (T/HS) is the leading cause of morbidity and mortality in the United States for individuals under the age of 44 years. Initial survivors are susceptible to developing multiple organ failure (MOF), which is thought to be caused, at least in part, by excessive or maladaptive activation of inflammatory pathways. We previously demonstrated in rodents that T/HS results in liver injury that can be prevented by IL-6 administration at the start of resuscitation; however, the contribution of the severity of HS to the extent of liver injury, whether or not resuscitation is required, and the mechanism(s) for the IL-6 protective effect have not been reported. In the experiments described here, we demonstrated that the extent of liver inflammation induced by T/HS depends on the duration of hypotension and requires resuscitation. We established that IL-6 administration at the start of resuscitation is capable of completely reversing liver inflammation and is associated with increased Stat3 activation. Global assessment of the livers showed that the main effect of IL-6 was to normalize the T/HS-induced inflammation transcriptome. Pharmacological inhibition of Stat3 activity within the liver blocked the ability of IL-6 to prevent liver inflammation and to normalize the T/HS-induced liver inflammation transcriptome. Genetic deletion of a Stat3?, a naturally occurring, dominant-negative isoform of the Stat3, attenuated T/HS-induced liver inflammation, confirming a role for Stat3, especially Stat3?, in preventing T/HS-mediated liver inflammation. Thus, T/HS-induced liver inflammation depends on the duration of hypotension and requires resuscitation; IL-6 administration at the start of resuscitation reverses T/HS-induced liver inflammation, through activation of Stat3?, which normalized the T/HS-induced liver inflammation transcriptome.
| S-EPMC3127578 | biostudies-literature
Project description:Trauma is a major cause of mortality in the United States. Death among those surviving the initial insult is caused by multiple organ failure (MOF) with the liver among the organs most frequently affected. We previously demonstrated in rodents that trauma complicated by hemorrhagic shock (trauma/HS) results in liver injury that can be prevented by IL-6 administration at the start of resuscitation; however, the contribution of the severity of HS to the extent of liver injury, whether or not resuscitation is required and the mechanism for the IL-6 protective effect have not been reported. In the experiments reported here, we demonstrated that the extent of liver apoptosis induced by trauma/HS depends on the duration of hypotension and requires resuscitation. We established that IL-6 administration at the start of resuscitation is capable of completely reversing liver apoptosis and is associated with increased Stat3 activation. Microarray analysis of the livers showed that the main effect of IL-6 was to normalize the trauma/HS-induced apoptosis transcriptome. Pharmacological inhibition of Stat3 activity within the liver blocked the ability of IL-6 to prevent liver apoptosis and to normalize the trauma/HS- induced liver apoptosis transcriptome. Genetic deletion of a Stat3beta, a naturally occurring, dominant-negative isoform of the Stat3, attenuated trauma/HS-induced liver apoptosis, confirming a role for Stat3, especially Stat3alpha, in preventing trauma/HS-mediated liver apoptosis. Thus, trauma/HS-induced liver apoptosis depends on the duration of hypotension and requires resuscitation. IL-6 administration at the start of resuscitation reverses HS-induced liver apoptosis, through activation of Stat3alpha, which normalizes the trauma/HS-induced liver apoptosis transcriptome.
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