title: 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.
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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Language Technologies Institute, Carnegie Mellon University , Pittsburgh, PA , USA ; Department of Plastic and Reconstructive Surgery, University of Pittsburgh , Pittsburgh, PA , USA ; Department of Plastic and Reconstructive Surgery, Johns Hopkins Medicine , Baltimore, MD , USA.
authors.forename: Ravi
authors.initials: R
authors.lastname: Starzl
authors.affiliation: Department of Plastic and Reconstructive Surgery, Innsbruck Medical University , Innsbruck , Austria.
authors.forename: Dolores
authors.initials: D
authors.lastname: Wolfram
authors.affiliation: Department of Surgery, University of Pittsburgh , Pittsburgh, PA , USA ; Center for Inflammation and Regenerative Modeling, McGowan Institute for Regenerative Medicine, University of Pittsburgh , Pittsburgh, PA , USA.
authors.forename: Ruben
authors.initials: R
authors.lastname: Zamora
authors.affiliation: Department of Surgery, University of Pittsburgh , Pittsburgh, PA , USA.
authors.forename: Bahiyyah
authors.initials: B
authors.lastname: Jefferson
authors.affiliation: Department of Surgery, University of Pittsburgh , Pittsburgh, PA , USA.
authors.forename: Derek
authors.initials: D
authors.lastname: Barclay
authors.affiliation: Department of Biological Sciences, Carnegie Mellon University , Pittsburgh, PA , USA.
authors.forename: Chien
authors.initials: C
authors.lastname: Ho
authors.affiliation: Department of Plastic and Reconstructive Surgery, University of Pittsburgh , Pittsburgh, PA , USA.
authors.forename: Vijay
authors.initials: V
authors.lastname: Gorantla
authors.affiliation: Department of Plastic and Reconstructive Surgery, Johns Hopkins Medicine , Baltimore, MD , USA.
authors.forename: Gerald
authors.initials: G
authors.lastname: Brandacher
authors.affiliation: Department of Plastic and Reconstructive Surgery, Johns Hopkins Medicine , Baltimore, MD , USA.
authors.forename: Stefan
authors.initials: S
authors.lastname: Schneeberger
authors.affiliation: Department of Plastic and Reconstructive Surgery, Johns Hopkins Medicine , Baltimore, MD , USA.
authors.forename: W P
authors.initials: WP
authors.lastname: Andrew Lee
authors.affiliation: Language Technologies Institute, Carnegie Mellon University , Pittsburgh, PA , USA.
authors.forename: Jaime
authors.initials: J
authors.lastname: Carbonell
authors.affiliation: Department of Surgery, University of Pittsburgh , Pittsburgh, PA , USA ; Center for Inflammation and Regenerative Modeling, McGowan Institute for Regenerative Medicine, University of Pittsburgh , Pittsburgh, PA , USA.
authors.forename: Yoram
authors.initials: Y
authors.lastname: Vodovotz
keywords: Inflammasome; cardiac arrest and trauma; computational modeling; data driven modeling; hemorrhagic shock; immunoregulatory; inflammatory mediators; localized tissue injury