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Fed state prior to hemorrhagic shock and polytrauma in a porcine model results in altered liver transcriptomic response.

Determan C, Anderson R, Becker A, Witowski N, Lusczek E, Mulier K, Beilman GJ - PLoS ONE (2014)

Bottom Line: Resuscitation often results in reperfusion injury and survivors are susceptible to developing multiple organ failure (MOF).Our findings also suggest that the fasting state, relative to a carbohydrate prefed state, displays decreased carbohydrate metabolism, increased cytoskeleton reorganization and decreased inflammation in response to hemorrhagic shock and reperfusion.Evidence suggests that this is a consequence of a shrunken, catabolic state of the liver cells which provides an anti-inflammatory condition that partially mitigates hepatocellar damage.

View Article: PubMed Central - PubMed

Affiliation: Department of Surgery, Division of Critical Care and Acute Care Surgery, University of Minnesota, Minneapolis, Minnesota, United States of America.

ABSTRACT
Hemorrhagic shock is a leading cause of trauma-related mortality in both civilian and military settings. Resuscitation often results in reperfusion injury and survivors are susceptible to developing multiple organ failure (MOF). The impact of fed state on the overall response to shock and resuscitation has been explored in some murine models but few clinically relevant large animal models. We have previously used metabolomics to establish that the fed state results in a different metabolic response in the porcine liver following hemorrhagic shock and resuscitation. In this study, we used our clinically relevant model of hemorrhagic shock and polytrauma and the Illumina HiSeq platform to determine if the liver transcriptomic response is also altered with respect to fed state. Functional analysis of the response to shock and resuscitation confirmed several typical responses including carbohydrate metabolism, cytokine inflammation, decreased cholesterol synthesis, and apoptosis. Our findings also suggest that the fasting state, relative to a carbohydrate prefed state, displays decreased carbohydrate metabolism, increased cytoskeleton reorganization and decreased inflammation in response to hemorrhagic shock and reperfusion. Evidence suggests that this is a consequence of a shrunken, catabolic state of the liver cells which provides an anti-inflammatory condition that partially mitigates hepatocellar damage.

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Heatmap of log2 fold changes of genes associated with peptidase activity in carbohydrate prefed (CPF) animals at each resuscitation timepoint (2, 8, and 20 hours) relative to Baseline (B).Rows are differentially expressed genes (DEGs) following RNA sequencing. Columns denote the respective timepoints Baseline (B), 2 hours full resuscitation change from Baseline (FR2vB), 8 hours full resuscitation change from Baseline (FR8vB), and 20 hours full resuscitation change from Baseline (FR20vB). Green denotes increased mRNA expression with respect to Baseline whereas red denotes the opposite.
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pone-0100088-g006: Heatmap of log2 fold changes of genes associated with peptidase activity in carbohydrate prefed (CPF) animals at each resuscitation timepoint (2, 8, and 20 hours) relative to Baseline (B).Rows are differentially expressed genes (DEGs) following RNA sequencing. Columns denote the respective timepoints Baseline (B), 2 hours full resuscitation change from Baseline (FR2vB), 8 hours full resuscitation change from Baseline (FR8vB), and 20 hours full resuscitation change from Baseline (FR20vB). Green denotes increased mRNA expression with respect to Baseline whereas red denotes the opposite.

Mentions: Continued resuscitation in CPF animals continued to identify gene expression characteristic of the response to hemorrhagic shock and resuscitation. Functional clusters identified included altered cytokine production (Figure 4), lipid metabolism (Figure 5), oxidation-reduction processes, hormone responses, and peptidase activity (Figure 6) (Supplementary File 5). Genes associated with cytokine production included heat shock 60 kDa protein 1 (HSPD1) and myeloid differentiation primary response 88 (MyD88) which both induce pro-inflammatory cytokines [25]–[27]. Analysis of specific genes within categories suggested decreased cholesterol synthesis, decreased fatty acid beta-oxidation and apoptosis. All processes are typical following ischemia-reperfusion [28], [29]. No genes were found to be significant when comparing FR20 to baseline, possibly a consequence of the small sample size in the CPF group.


Fed state prior to hemorrhagic shock and polytrauma in a porcine model results in altered liver transcriptomic response.

Determan C, Anderson R, Becker A, Witowski N, Lusczek E, Mulier K, Beilman GJ - PLoS ONE (2014)

Heatmap of log2 fold changes of genes associated with peptidase activity in carbohydrate prefed (CPF) animals at each resuscitation timepoint (2, 8, and 20 hours) relative to Baseline (B).Rows are differentially expressed genes (DEGs) following RNA sequencing. Columns denote the respective timepoints Baseline (B), 2 hours full resuscitation change from Baseline (FR2vB), 8 hours full resuscitation change from Baseline (FR8vB), and 20 hours full resuscitation change from Baseline (FR20vB). Green denotes increased mRNA expression with respect to Baseline whereas red denotes the opposite.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4061062&req=5

pone-0100088-g006: Heatmap of log2 fold changes of genes associated with peptidase activity in carbohydrate prefed (CPF) animals at each resuscitation timepoint (2, 8, and 20 hours) relative to Baseline (B).Rows are differentially expressed genes (DEGs) following RNA sequencing. Columns denote the respective timepoints Baseline (B), 2 hours full resuscitation change from Baseline (FR2vB), 8 hours full resuscitation change from Baseline (FR8vB), and 20 hours full resuscitation change from Baseline (FR20vB). Green denotes increased mRNA expression with respect to Baseline whereas red denotes the opposite.
Mentions: Continued resuscitation in CPF animals continued to identify gene expression characteristic of the response to hemorrhagic shock and resuscitation. Functional clusters identified included altered cytokine production (Figure 4), lipid metabolism (Figure 5), oxidation-reduction processes, hormone responses, and peptidase activity (Figure 6) (Supplementary File 5). Genes associated with cytokine production included heat shock 60 kDa protein 1 (HSPD1) and myeloid differentiation primary response 88 (MyD88) which both induce pro-inflammatory cytokines [25]–[27]. Analysis of specific genes within categories suggested decreased cholesterol synthesis, decreased fatty acid beta-oxidation and apoptosis. All processes are typical following ischemia-reperfusion [28], [29]. No genes were found to be significant when comparing FR20 to baseline, possibly a consequence of the small sample size in the CPF group.

Bottom Line: Resuscitation often results in reperfusion injury and survivors are susceptible to developing multiple organ failure (MOF).Our findings also suggest that the fasting state, relative to a carbohydrate prefed state, displays decreased carbohydrate metabolism, increased cytoskeleton reorganization and decreased inflammation in response to hemorrhagic shock and reperfusion.Evidence suggests that this is a consequence of a shrunken, catabolic state of the liver cells which provides an anti-inflammatory condition that partially mitigates hepatocellar damage.

View Article: PubMed Central - PubMed

Affiliation: Department of Surgery, Division of Critical Care and Acute Care Surgery, University of Minnesota, Minneapolis, Minnesota, United States of America.

ABSTRACT
Hemorrhagic shock is a leading cause of trauma-related mortality in both civilian and military settings. Resuscitation often results in reperfusion injury and survivors are susceptible to developing multiple organ failure (MOF). The impact of fed state on the overall response to shock and resuscitation has been explored in some murine models but few clinically relevant large animal models. We have previously used metabolomics to establish that the fed state results in a different metabolic response in the porcine liver following hemorrhagic shock and resuscitation. In this study, we used our clinically relevant model of hemorrhagic shock and polytrauma and the Illumina HiSeq platform to determine if the liver transcriptomic response is also altered with respect to fed state. Functional analysis of the response to shock and resuscitation confirmed several typical responses including carbohydrate metabolism, cytokine inflammation, decreased cholesterol synthesis, and apoptosis. Our findings also suggest that the fasting state, relative to a carbohydrate prefed state, displays decreased carbohydrate metabolism, increased cytoskeleton reorganization and decreased inflammation in response to hemorrhagic shock and reperfusion. Evidence suggests that this is a consequence of a shrunken, catabolic state of the liver cells which provides an anti-inflammatory condition that partially mitigates hepatocellar damage.

Show MeSH
Related in: MedlinePlus