title: Systemic inhibition and liver-specific over-expression of PAI-1 failed to improve survival in all-inclusive populations or homogenous cohorts of CLP mice.
abstract: BACKGROUND
  The role of plasminogen activator inhibitor type-1 (PAI-1) in abdominal sepsis remains elusive.
  
  
  OBJECTIVE
  To study the influence of inhibition and over-expression of PAI-1 upon survival in cecal ligation and puncture (CLP) sepsis.
  
  
  METHODS
  (i) Mice underwent moderate CLP and received 10 mg kg(-1) of either monoclonal anti-PAI-1 (MA-MP6H6) or control (MA-Control) antibody intravenously at 0, 18 or 30 h post-CLP. The 30-h treatment group was additionally stratified into mice predicted to survive (P-SUR) or die (P-DIE) based on IL 6 measured at 24 h post-CLP. (ii) PAI-1 expression was induced with pLIVE.PAI-1 plasmid administered 72 h pre-CLP. Blood was sampled for 5 days and survival was monitored for 28 days.
  
  
  RESULTS
  MA-MP6H6 effectively neutralized active PAI-1 and fully restored fibrinolysis while PAI-1 over-expression was liver-specific and correlated with PAI-1 increase in the blood. Without stratification, MA-MP6H6 co-/post-treatment conferred no survival benefit. Prospective stratification (IL-6 cut-off: 14 ng mL(-1) ) suggested increased mortality by MA-MP6H6 treatment in P-SUR that reached 30% difference (vs. MA-Control; P < 0.05) after a retrospective cut-off readjustment to 3.3 ng mL(-1) for better P-SUR homogeneity. Subsequent prospective anti-PAI-1 treatment in P-SUR mice with 3.3 ng mL(-1) cut-off demonstrated a negative but statistically insignificant effect: mortality was higher by 17% after MA-MP6H6 vs. MA-Control. Over-expression of PAI 1 did not alter post-CLP survival. Neither PAI-1 inhibition nor over-expression meaningfully modified inflammatory response and/or organ function.
  
  
  CONCLUSIONS
  Restoration of fibrinolysis in early abdominal sepsis was not beneficial and it may prove detrimental in subjects with the lowest risk of death, while preemptive PAI-1 up-regulation at the current magnitude was not protective.
authors.affiliation: Ludwig Boltzmann Institute for Experimental and Clinical Traumatology in the Trauma Research Center of the AUVA, Vienna, Austria; Department of Anesthesiology, University Medical Center, Regensburg, Germany.
authors.forename: P
authors.initials: P
authors.lastname: Raeven
authors.forename: S
authors.initials: S
authors.lastname: Drechsler
authors.forename: K M
authors.initials: KM
authors.lastname: Weixelbaumer
authors.forename: D
authors.initials: D
authors.lastname: Bastelica
authors.forename: F
authors.initials: F
authors.lastname: Peiretti
authors.forename: A
authors.initials: A
authors.lastname: Klotz
authors.forename: M
authors.initials: M
authors.lastname: Jafarmadar
authors.forename: H
authors.initials: H
authors.lastname: Redl
authors.forename: S
authors.initials: S
authors.lastname: Bahrami
authors.forename: M C
authors.initials: MC
authors.lastname: Alessi
authors.forename: P J
authors.initials: PJ
authors.lastname: Declerck
authors.forename: M F
authors.initials: MF
authors.lastname: Osuchowski
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity; D015415:Biomarkers / Q000097:blood; D002432:Cecum / Q000382:microbiology / Q000601:surgery*; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D005260:Female; D005342:Fibrinolysis / Q000187:drug effects / Q000235:genetics; D015316:Genetic Therapy; D018836:Inflammation Mediators / Q000097:blood; D007275:Injections, Intravenous; D015850:Interleukin-6 / Q000097:blood; D008026:Ligation; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000382:microbiology; D051379:Mice; D010538:Peritonitis / Q000097:blood / Q000235:genetics / Q000382:microbiology / Q000628:therapy*; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D011677:Punctures; D018805:Sepsis / Q000097:blood / Q000235:genetics / Q000382:microbiology / Q000628:therapy*; D013997:Time Factors; D015854:Up-Regulation
chemical_list: D000911:Antibodies, Monoclonal; D015415:Biomarkers; D018836:Inflammation Mediators; D015850:Interleukin-6; D017395:Plasminogen Activator Inhibitor 1; C577686:interleukin-6, mouse
keywords: fibrinolysis; heterogeneity; outbred; peritonitis; plasmid