Amplification of the proinflammatory transcription factor cascade increases with severity of uncontrolled hemorrhage in swine

Susan I. Brundage, Martin Schreiber, John B. Holcomb, Nathan Zautke, Mary Ann Mastrangelo, Xu Xq, Joe Macaitis, David J. Tweardy

    Research output: Contribution to journalArticle

    20 Citations (Scopus)

    Abstract

    Introduction. Hypotension causes diffuse liver injury accompanied by increased local production of interleukin-6 (IL-6) in swine models of uncontrolled hemorrhagic shock (HS). IL-6 is transcriptionally up-regulated by nuclear factor (NF)-κB and results in activation of signal transducer and activator of transcription-3 (Stat3) in a murine model of controlled HS. Our objectives were: 1) to determine if increased IL-6 production and NF-κB and Stat3 activation occurs in a swine model of uncontrolled HS, and 2) to assess whether or not levels of IL-6 mRNA and activity of NF-κB and Stat3 correlate with shock severity. Materials and methods. Swine were assigned to four groups: 1) control animals (n = 6): no intervention, 2) sham operation (n = 6): celiotomy and splenectomy, 3) uncontrolled hemorrhagic shock (UHS) (n = 6): sham plus grade V vascular liver injury and resuscitation, 4) profound uncontrolled hemorrhagic shock (PUHS) (n = 8): UHS after dilutional hypothermia. Following euthanasia at 2 h, livers were harvested, total RNA isolated, and IL-6 mRNA levels quantified by Q-RT-PCR (ABI Prism 7700, Applied Biosystems International, Foster City, CA). Protein was extracted for measurement of NF-κB and Stat3 activity by electrophoretic mobility shift assay (EMSA). Results. Compared to shams, IL-6 mRNA levels increased 4.5-fold in UHS and 90-fold in PUHS (P <0.001). Compared with shams; NF-κB activity increased 2-fold in both UHS and PUHS (P <0.05). Stat3 activity was equivalent (not significant) in UHS when compared with shams but increased 5.3-fold in PUHS. (P <0.05). Conclusion. These findings suggest that regional proinflammatory cytokine production results from and perpetuates a proinflammatory transcription factor cascade in a swine model of uncontrolled hemorrhagic shock and indicate that this process is proportional to the severity of shock.

    Original languageEnglish (US)
    Pages (from-to)74-80
    Number of pages7
    JournalJournal of Surgical Research
    Volume113
    Issue number1
    DOIs
    StatePublished - Jul 2003

    Fingerprint

    Hemorrhagic Shock
    Transcription Factors
    Swine
    Hemorrhage
    STAT3 Transcription Factor
    Interleukin-6
    Messenger RNA
    Liver
    Shock
    CCAAT-Enhancer-Binding Protein-beta
    Euthanasia
    Vascular System Injuries
    Electrophoretic Mobility Shift Assay
    Splenectomy
    Hypothermia
    Resuscitation
    Hypotension
    Transcriptional Activation

    Keywords

    • Hemorrhage
    • Inflammatory cascade
    • Interleukin-6
    • Nuclear factor-κB
    • Proinflammatory cytokines
    • Shock, ischemia/reperfusion injury
    • Signal transducer and activator of transcription-3 (Stat3)
    • Signal transduction
    • Transcription factors
    • Trauma

    ASJC Scopus subject areas

    • Surgery

    Cite this

    Amplification of the proinflammatory transcription factor cascade increases with severity of uncontrolled hemorrhage in swine. / Brundage, Susan I.; Schreiber, Martin; Holcomb, John B.; Zautke, Nathan; Mastrangelo, Mary Ann; Xq, Xu; Macaitis, Joe; Tweardy, David J.

    In: Journal of Surgical Research, Vol. 113, No. 1, 07.2003, p. 74-80.

    Research output: Contribution to journalArticle

    Brundage, Susan I. ; Schreiber, Martin ; Holcomb, John B. ; Zautke, Nathan ; Mastrangelo, Mary Ann ; Xq, Xu ; Macaitis, Joe ; Tweardy, David J. / Amplification of the proinflammatory transcription factor cascade increases with severity of uncontrolled hemorrhage in swine. In: Journal of Surgical Research. 2003 ; Vol. 113, No. 1. pp. 74-80.
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    abstract = "Introduction. Hypotension causes diffuse liver injury accompanied by increased local production of interleukin-6 (IL-6) in swine models of uncontrolled hemorrhagic shock (HS). IL-6 is transcriptionally up-regulated by nuclear factor (NF)-κB and results in activation of signal transducer and activator of transcription-3 (Stat3) in a murine model of controlled HS. Our objectives were: 1) to determine if increased IL-6 production and NF-κB and Stat3 activation occurs in a swine model of uncontrolled HS, and 2) to assess whether or not levels of IL-6 mRNA and activity of NF-κB and Stat3 correlate with shock severity. Materials and methods. Swine were assigned to four groups: 1) control animals (n = 6): no intervention, 2) sham operation (n = 6): celiotomy and splenectomy, 3) uncontrolled hemorrhagic shock (UHS) (n = 6): sham plus grade V vascular liver injury and resuscitation, 4) profound uncontrolled hemorrhagic shock (PUHS) (n = 8): UHS after dilutional hypothermia. Following euthanasia at 2 h, livers were harvested, total RNA isolated, and IL-6 mRNA levels quantified by Q-RT-PCR (ABI Prism 7700, Applied Biosystems International, Foster City, CA). Protein was extracted for measurement of NF-κB and Stat3 activity by electrophoretic mobility shift assay (EMSA). Results. Compared to shams, IL-6 mRNA levels increased 4.5-fold in UHS and 90-fold in PUHS (P <0.001). Compared with shams; NF-κB activity increased 2-fold in both UHS and PUHS (P <0.05). Stat3 activity was equivalent (not significant) in UHS when compared with shams but increased 5.3-fold in PUHS. (P <0.05). Conclusion. These findings suggest that regional proinflammatory cytokine production results from and perpetuates a proinflammatory transcription factor cascade in a swine model of uncontrolled hemorrhagic shock and indicate that this process is proportional to the severity of shock.",
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    T1 - Amplification of the proinflammatory transcription factor cascade increases with severity of uncontrolled hemorrhage in swine

    AU - Brundage, Susan I.

    AU - Schreiber, Martin

    AU - Holcomb, John B.

    AU - Zautke, Nathan

    AU - Mastrangelo, Mary Ann

    AU - Xq, Xu

    AU - Macaitis, Joe

    AU - Tweardy, David J.

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    N2 - Introduction. Hypotension causes diffuse liver injury accompanied by increased local production of interleukin-6 (IL-6) in swine models of uncontrolled hemorrhagic shock (HS). IL-6 is transcriptionally up-regulated by nuclear factor (NF)-κB and results in activation of signal transducer and activator of transcription-3 (Stat3) in a murine model of controlled HS. Our objectives were: 1) to determine if increased IL-6 production and NF-κB and Stat3 activation occurs in a swine model of uncontrolled HS, and 2) to assess whether or not levels of IL-6 mRNA and activity of NF-κB and Stat3 correlate with shock severity. Materials and methods. Swine were assigned to four groups: 1) control animals (n = 6): no intervention, 2) sham operation (n = 6): celiotomy and splenectomy, 3) uncontrolled hemorrhagic shock (UHS) (n = 6): sham plus grade V vascular liver injury and resuscitation, 4) profound uncontrolled hemorrhagic shock (PUHS) (n = 8): UHS after dilutional hypothermia. Following euthanasia at 2 h, livers were harvested, total RNA isolated, and IL-6 mRNA levels quantified by Q-RT-PCR (ABI Prism 7700, Applied Biosystems International, Foster City, CA). Protein was extracted for measurement of NF-κB and Stat3 activity by electrophoretic mobility shift assay (EMSA). Results. Compared to shams, IL-6 mRNA levels increased 4.5-fold in UHS and 90-fold in PUHS (P <0.001). Compared with shams; NF-κB activity increased 2-fold in both UHS and PUHS (P <0.05). Stat3 activity was equivalent (not significant) in UHS when compared with shams but increased 5.3-fold in PUHS. (P <0.05). Conclusion. These findings suggest that regional proinflammatory cytokine production results from and perpetuates a proinflammatory transcription factor cascade in a swine model of uncontrolled hemorrhagic shock and indicate that this process is proportional to the severity of shock.

    AB - Introduction. Hypotension causes diffuse liver injury accompanied by increased local production of interleukin-6 (IL-6) in swine models of uncontrolled hemorrhagic shock (HS). IL-6 is transcriptionally up-regulated by nuclear factor (NF)-κB and results in activation of signal transducer and activator of transcription-3 (Stat3) in a murine model of controlled HS. Our objectives were: 1) to determine if increased IL-6 production and NF-κB and Stat3 activation occurs in a swine model of uncontrolled HS, and 2) to assess whether or not levels of IL-6 mRNA and activity of NF-κB and Stat3 correlate with shock severity. Materials and methods. Swine were assigned to four groups: 1) control animals (n = 6): no intervention, 2) sham operation (n = 6): celiotomy and splenectomy, 3) uncontrolled hemorrhagic shock (UHS) (n = 6): sham plus grade V vascular liver injury and resuscitation, 4) profound uncontrolled hemorrhagic shock (PUHS) (n = 8): UHS after dilutional hypothermia. Following euthanasia at 2 h, livers were harvested, total RNA isolated, and IL-6 mRNA levels quantified by Q-RT-PCR (ABI Prism 7700, Applied Biosystems International, Foster City, CA). Protein was extracted for measurement of NF-κB and Stat3 activity by electrophoretic mobility shift assay (EMSA). Results. Compared to shams, IL-6 mRNA levels increased 4.5-fold in UHS and 90-fold in PUHS (P <0.001). Compared with shams; NF-κB activity increased 2-fold in both UHS and PUHS (P <0.05). Stat3 activity was equivalent (not significant) in UHS when compared with shams but increased 5.3-fold in PUHS. (P <0.05). Conclusion. These findings suggest that regional proinflammatory cytokine production results from and perpetuates a proinflammatory transcription factor cascade in a swine model of uncontrolled hemorrhagic shock and indicate that this process is proportional to the severity of shock.

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    KW - Shock, ischemia/reperfusion injury

    KW - Signal transducer and activator of transcription-3 (Stat3)

    KW - Signal transduction

    KW - Transcription factors

    KW - Trauma

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