Cardiac arrest disrupts caspase-1 and patterns of inflammatory mediators differently in skin and muscle following localized tissue injury in rats: Insights from data-driven modeling

Ravi Starzl, Dolores Wolfram, Ruben Zamora, Bahiyyah Jefferson, Derek Barclay, Chien Ho, Vijay Gorantla, Gerald Brandacher, Stefan Schneeberger, W. P. Andrew Lee, Jaime Carbonell, Yoram Vodovotz

Research output: Contribution to journalArticle

3 Scopus citations

Abstract

Background: Trauma often cooccurs with cardiac arrest and hemorrhagic shock. Skin and muscle injuries often lead to significant inflammation in the affected tissue. The primary mechanism by which inflammation is initiated, sustained, and terminated is cytokine-mediated immune signaling, but this signaling can be altered by cardiac arrest. The complexity and context sensitivity of immune signaling in general has stymied a clear understanding of these signaling dynamics. Methodology/principal findings: We hypothesized that advanced numerical and biological function analysis methods would help elucidate the inflammatory response to skin and muscle wounds in rats, both with and without concomitant shock. Based on the multiplexed analysis of inflammatory mediators, we discerned a differential interleukin (IL)-1α and IL-18 signature in skin vs. muscle, which was suggestive of inflammasome activation in the skin. Immunoblotting revealed caspase-1 activation in skin but not muscle. Notably, IL-1α and IL-18, along with caspase-1, were greatly elevated in the skin following cardiac arrest, consistent with differential inflammasome activation. Conclusion/significance: Tissue-specific activation of caspase-1 and the NLRP3 inflammasome appear to be key factors in determining the type and severity of the inflammatory response to tissue injury, especially in the presence of severe shock, as suggested via data-driven modeling.

Original languageEnglish (US)
Article number587
JournalFrontiers in immunology
Volume6
Issue numberNOV
DOIs
StatePublished - 2015

Keywords

  • Cardiac arrest and trauma
  • Computational modeling
  • Data driven modeling
  • Hemorrhagic shock
  • Immunoregulatory
  • Inflammasome
  • Inflammatory mediators
  • Localized tissue injury

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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    Starzl, R., Wolfram, D., Zamora, R., Jefferson, B., Barclay, D., Ho, C., Gorantla, V., Brandacher, G., Schneeberger, S., Andrew Lee, W. P., Carbonell, J., & Vodovotz, Y. (2015). Cardiac arrest disrupts caspase-1 and patterns of inflammatory mediators differently in skin and muscle following localized tissue injury in rats: Insights from data-driven modeling. Frontiers in immunology, 6(NOV), [587]. https://doi.org/10.3389/fimmu.2015.00587