Manuscript handled by: R. Medcalf
Systemic inhibition and liver-specific over-expression of PAI-1 failed to improve survival in all-inclusive populations or homogenous cohorts of CLP mice
Article first published online: 10 JUN 2014
© 2014 International Society on Thrombosis and Haemostasis
Journal of Thrombosis and Haemostasis
Volume 12, Issue 6, pages 958–969, June 2014
How to Cite
Systemic inhibition and liver-specific over-expression of PAI-1 failed to improve survival in all-inclusive populations or homogenous cohorts of CLP mice. J Thromb Haemost 2014; 12: 958–69., , , , , , , , , , , .
Final decision: P. H. Reitsma, 11 March 2014
- Issue published online: 10 JUN 2014
- Article first published online: 10 JUN 2014
- Accepted manuscript online: 21 MAR 2014 03:16AM EST
- Manuscript Accepted: 11 MAR 2014
- Manuscript Received: 1 OCT 2013
- WWTF. Grant Number: LS07-065
- EU Marie Curie IR. Grant Number: FP7-203685
- Scientific Research-Flanders (FWO-Vlaanderen). Grant Number: G.0594.13
The role of plasminogen activator inhibitor type-1 (PAI-1) in abdominal sepsis remains elusive.
To study the influence of inhibition and over-expression of PAI-1 upon survival in cecal ligation and puncture (CLP) sepsis.
(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.
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.
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.