title: A non-lethal traumatic/hemorrhagic insult strongly modulates the compartment-specific PAI-1 response in the subsequent polymicrobial sepsis.
abstract: BACKGROUND
  Plasminogen activator inhibitor 1 (PAI-1) is a key factor in trauma- and sepsis-induced coagulopathy. We examined how trauma-hemorrhage (TH) modulates PAI-1 responses in subsequent cecal ligation and puncture (CLP)-induced sepsis, and the association of PAI-1 with septic outcomes.
  
  
  METHODS
  Mice underwent TH and CLP 48 h later in three separate experiments. In experiment 1, mice were sacrificed pre- and post-CLP to characterize the trajectory of PAI-1 in plasma (protein) and tissues (mRNA). Post-CLP dynamics in TH-CLP (this study) and CLP-Only mice (prior study) were then compared for modulatory effects of TH. In experiment 2, to relate PAI-1 changes to outcome, mice underwent TH-CLP and were sampled daily and followed for 14 days to compare non-survivors (DEAD) and survivors (SUR). In experiment 3, plasma and tissue PAI-1 expression were compared between mice predicted to die (P-DIE) and to live (P-LIVE).
  
  
  RESULTS
  In experiment 1, an early post-TH rise of circulating PAI-1 was contrasted by a delayed (post-TH) decrease of PAI-1 mRNA in organs. In the post-CLP phase, profiles of circulating PAI-1 were similar between TH-CLP and CLP-Only mice. Conversely, PAI-1 mRNA declined in the liver and heart of TH-CLP mice versus CLP-Only. In experiment 2, there were no DEAD/SUR differences in circulating PAI-1 prior to CLP. Post-CLP, circulating PAI-1 in DEAD was 2-4-fold higher than in SUR. PAI-1 increase heralded septic deaths up to 48 h prior but DEAD/SUR thrombomodulin (endothelial injury marker) levels were identical. In experiment 3, levels of circulating PAI-1 and its hepatic gene expression were higher in P-DIE versus P-LIVE mice and those increases closely correlated with liver dysfunction.
  
  
  CONCLUSIONS
  Trauma modulated septic PAI-1 responses in a compartment-specific fashion. Only post-CLP increases in circulating PAI-1 predicted septic outcomes. In posttraumatic sepsis, pre-lethal release of PAI-1 was mostly of hepatic origin and was independent of endothelial injury.
authors: Ludwig Boltzmann Institute for Experimental and Clinical Traumatology, Trauma Research Center of Allgemeine Unfallversicherungsanstalt, Vienna, Austria.
authors: Pierre
authors: P
authors: Raeven
authors: Alma
authors: A
authors: Salibasic
authors: Susanne
authors: S
authors: Drechsler
authors: Katrin Maria
authors: KM
authors: Weixelbaumer
authors: Mohammad
authors: M
authors: Jafarmadar
authors: Martijn
authors: M
authors: van Griensven
authors: Soheyl
authors: S
authors: Bahrami
authors: Marcin Filip
authors: MF
authors: Osuchowski
mesh_terms: D000818:Animals; D001483:Base Sequence; D017931:DNA Primers; D005260:Female; D006470:Hemorrhage / Q000503:physiopathology*; D051379:Mice; D017395:Plasminogen Activator Inhibitor 1 / Q000502:physiology*; D016133:Polymerase Chain Reaction; D018805:Sepsis / Q000276:immunology* / Q000382:microbiology / Q000503:physiopathology*; D014947:Wounds and Injuries / Q000503:physiopathology*
chemical_list: D017931:DNA Primers; D017395:Plasminogen Activator Inhibitor 1