Systemic inhibition and liver-specific over-expression of PAI-1 failed to improve survival in all-inclusive populations or homogenous cohorts of CLP mice

Authors


  • Manuscript handled by: R. Medcalf
  • Final decision: P. H. Reitsma, 11 March 2014

Summary

Background

The role of plasminogen activator inhibitor type-1 (PAI-1) in abdominal sepsis remains elusive.

Objectives

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; < 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.

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