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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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Diagram of simplified Interleukin-10 (IL-10) pathway.A hyperosmotic condition induces cellular shrinkage and activates tyrosine phosphorylation of Janus kinases (JAK) to subsequently phosphorylate STAT3 and IL-10 production.
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pone-0100088-g011: Diagram of simplified Interleukin-10 (IL-10) pathway.A hyperosmotic condition induces cellular shrinkage and activates tyrosine phosphorylation of Janus kinases (JAK) to subsequently phosphorylate STAT3 and IL-10 production.

Mentions: The full molecular mechanisms behind the proposed state are not fully elucidated however several components are understood. One direct result of cellular shrinkage is vasodilation potentially mediating the no-reflow condition. Furthermore, cellular shrinkage is a consequence of hypertonic treatments which have been shown mitigate inflammation following shock [46], [47]. The hyperosmotic environment causes cellular shrinkage which activates the tyrosine phosphorylation of Janus kinases. These kinases activate the transcription factor STAT3 [48] which ultimately stimulates Interleukin 10 (IL-10) production while simultaneously inhibiting pro-inflammatory cytokines (e.g. IL-1β, TNF-α, and intercellular adhesion molecules) by inhibiting the transcription factor NF-κB [49], [50] (Figure 11). Although IL-10 was not individually identified, the anti-inflammatory state of the FS is supported as several pro-inflammatory genes are elevated in CPF animals (Figure 8). Further research on the anti-inflammatory properties of cellular shrinkage is required.


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)

Diagram of simplified Interleukin-10 (IL-10) pathway.A hyperosmotic condition induces cellular shrinkage and activates tyrosine phosphorylation of Janus kinases (JAK) to subsequently phosphorylate STAT3 and IL-10 production.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0100088-g011: Diagram of simplified Interleukin-10 (IL-10) pathway.A hyperosmotic condition induces cellular shrinkage and activates tyrosine phosphorylation of Janus kinases (JAK) to subsequently phosphorylate STAT3 and IL-10 production.
Mentions: The full molecular mechanisms behind the proposed state are not fully elucidated however several components are understood. One direct result of cellular shrinkage is vasodilation potentially mediating the no-reflow condition. Furthermore, cellular shrinkage is a consequence of hypertonic treatments which have been shown mitigate inflammation following shock [46], [47]. The hyperosmotic environment causes cellular shrinkage which activates the tyrosine phosphorylation of Janus kinases. These kinases activate the transcription factor STAT3 [48] which ultimately stimulates Interleukin 10 (IL-10) production while simultaneously inhibiting pro-inflammatory cytokines (e.g. IL-1β, TNF-α, and intercellular adhesion molecules) by inhibiting the transcription factor NF-κB [49], [50] (Figure 11). Although IL-10 was not individually identified, the anti-inflammatory state of the FS is supported as several pro-inflammatory genes are elevated in CPF animals (Figure 8). Further research on the anti-inflammatory properties of cellular shrinkage is required.

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