OBJECTIVE: Although
thrombin-activatable fibrinolysis inhibitor (
TAFI) has been implicated as a negative regulator of
fibrinolysis, its pathophysiological significance remains to be unveiled. We performed the
pharmacologic study to assess the effect of EF6265, a specific inhibitor of activated form of
TAFI (TAFIa) on sepsis-induced
organ dysfunction models. DESIGN: A controlled, in vivo laboratory study. SETTING: Company research laboratory. SUBJECTS: Wistar and
Sprague-Dawley rats. INTERVENTIONS:
Endotoxemia and
sepsis models were induced by
intravenous injection of
lipopolysaccharide and
Pseudomonas aeruginosa, respectively. MEASUREMENTS AND MAIN RESULTS: In the
endotoxemia model, posttreatment (1 hour) with EF6265 reduced
fibrin deposits in
the kidney and
liver accompanied by no significant changes in
platelet count and
fibrinogen concentration in plasma. This compound also significantly decreased levels of plasma
lactate dehydrogenase and
aspartate aminotransferase, markers of
organ dysfunction. In the
sepsis model, EF6265, simultaneously administered with
ceftazidime (CAZ) 2 hours after
Pseudomonas aeruginosa injection, showed no influence on the
antibiotic activity of CAZ. Meanwhile, it dramatically potentiated the interleukin-6-reducing effect of CAZ in plasma, suggesting that inhibition of TAFIa leads to the reduction in systemic
inflammatory response associated with
bacterial infection. This combined treatment also lowered plasma
lactate dehydrogenase and
blood urea nitrogen more potently than single treatment with CAZ. CONCLUSIONS: These results clearly suggest that
TAFI plays an important role in the deterioration of
organ dysfunction in
sepsis and the inhibitor of TAFIa protects against sepsis-induced tissue damage through regulation of
fibrinolysis and
inflammation.
