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Molecular Medicine

, Volume 17, Issue 9–10, pp 1031–1038 | Cite as

Caspase-1 Is Hepatoprotective during Trauma and Hemorrhagic Shock by Reducing Liver Injury and Inflammation

  • Christoph L. Menzel
  • Qian Sun
  • Patricia A. Loughran
  • Hans-Christoph Pape
  • Timothy R. Billiar
  • Melanie J. Scott
Research Article

Abstract

Adaptive immune responses are induced in liver after major stresses such as hemorrhagic shock (HS) and trauma. There is emerging evidence that the inflammasome, the multiprotein platform that induces caspase-1 activation and promotes interleukin (IL)-1β and IL-18 processing, is activated in response to cellular oxidative stress, such as after hypoxia, ischemia and HS. Additionally, damage-associated molecular patterns, such as those released after injury, have been shown to activate the inflammasome and caspase-1 through the NOD-like receptor (NLR) NLRP3. However, the role of the inflammasome in organ injury after HS and trauma is unknown. We therefore investigated inflammatory responses and end-organ injury in wild-type (WT) and caspase-1−/− mice in our model of HS with bilateral femur fracture (HS/BFF). We found that caspase-1−/− mice had higher levels of systemic inflammatory cytokines than WT mice. This result corresponded to higher levels of liver damage, cell death and neutrophil influx in caspase-1−/− liver compared with WT, although there was no difference in lung damage between experimental groups. To determine if hepatoprotection also depended on NLRP3, we subjected NLRP3−/− mice to HS/BFF, but found inflammatory responses and liver damage in these mice was similar to WT. Hepatoprotection was also not due to caspase-1-dependent cytokines, IL-1β and IL-18. Altogether, these data suggest that caspase-1 is hepatoprotective, in part through regulation of cell death pathways in the liver after major trauma, and that caspase-1 activation after HS/BFF does not depend on NLRP3. These findings may have implications for the treatment of trauma patients and may lead to progress in prevention or treatment of multiple organ failure (MOF).

Notes

Acknowledgments

We thank Hong Liao, Lauryn Kohut, Alicia Frank, Meihua Bo, Derek Barclay, Richard Shapiro and Danielle Reiser for their help with this work. This work was supported through grants from the National Institutes of Health (P50-GM053789) and also by an award from the Surgical Infection Society (to MJ Scott).

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Copyright information

© The Feinstein Institute for Medical Research 2011
www.feinsteininstitute.org

Authors and Affiliations

  • Christoph L. Menzel
    • 1
    • 2
    • 3
  • Qian Sun
    • 2
  • Patricia A. Loughran
    • 2
  • Hans-Christoph Pape
    • 1
    • 4
  • Timothy R. Billiar
    • 2
  • Melanie J. Scott
    • 2
  1. 1.Department of Orthopedic SurgeryUniversity of Pittsburgh Medical CenterPittsburghUSA
  2. 2.Department of Surgery Labs, NW607MUHUniversity of Pittsburgh Medical CenterPittsburghUSA
  3. 3.Charité Medical UniversityBerlinGermany
  4. 4.Department of Orthopedics and Trauma SurgeryAachen UniversityAachenGermany

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