Compartment-specific expression of plasminogen activator inhibitor-1 correlates with severity/outcome of murine polymicrobial sepsis

Introduction: Plasminogen activator inhibitor type 1 (PAI-1) co-induces septic coagulopathy. We aimed to characterize spatiotemporal PAI-1 gene/protein changes occurring in acute sepsis and tested whether PAI-1 fluctuations correlate with sepsis severity and early outcome. Materials and Methods: Female mice underwent cecal ligation and puncture (CLP) in three experiments. I: mild (23G needle) CLP to compare circulating PAI-1 to its organ gene expression within 0-24 h. II: mild or severe (17G) CLP to asses differences in PAI-1 organ-specific expression and in coagulation/fibrinolysis. III: moderate (18G) CLP to characterize circulating PAI-1 in survivors (SUR), and to retrospectively compare it to dying (DIE) mice. Results: In mild sepsis, the trajectory of circulating PAI-1 (1089 ng/ml peak at 24 h) was identical to PAI-1 gene expression in the left cranial vena cava (LCVC; 39-fold peak at 24 h). PAI-1 expression rise was immediate (60-fold at 6 h) and sustained in the liver, but marginal in the kidney, lungs and heart. Body temperature decrease correlated with the PAI-1 expression increase in the liver (rho=-0.79), and blood (protein, rho=-0.53). Regardless of severity, PAI-1 gene expression remained unaltered except the LCVC where it was > 3-fold higher in 17G (vs. 23G). Severe sepsis extended activated partial thromboplastin/pro-thrombin time and increased circulating PAI-1, while antithrombin and fibrinogen decreased at 6 and/or 24 h (vs. 23G). Within 24 h of death, circulating PAI-1 in DIE was > 3-fold higher versus SUR. Conclusions: Polymicrobial sepsis caused a gradual circulating PAI-1 release and highly variable gene expression response pattern in organs. Only circulating PAI-1 and PAI-1 expression in the LCVC correlated with response severity and/or outcome. (C) 2012 Elsevier Ltd. All rights reserved.