Bactericidal/permeability-increasing protein ameliorates hypercoagulability after hemorrhagic shock.

We recently showed that both plasminogen activator inhibitor-1 (PAI-1) and tissue factor (TF) are induced after a massive hemorrhage. In this study, we determined if bactericidal/permeability-increasing protein (BPI) has any effects on the induction of these factors after hemorrhagic shock. Three days after cannulation, rats were bled and maintained at a mean blood pressure of 40 mmHg for 60 min, and then were resuscitated with the shed blood and an equal volume of saline over 60 min. Rats in the BPI group were given at 6 mg/kg of rBPI21 (XOMA, Berkeley, CA; a 3-mg/kg dose at the beginning of hemorrhage followed by two doses of 1.5 mg/kg at the end of shock and at the end of resuscitation). The control group was treated similarly to the BPI group, but received control protein in the same dose as rBPI21. Plasma endotoxin concentration, whole blood clotting time (WBCT) and plasma PAI activity were measured at times 0, 2, 4, 6, and 8 h. The time-course changes in mRNA of TF, PAI-1, tumor necrosis factor alpha (TNF alpha), interleukin-1 beta (IL-1 beta), and interleukin-6 (IL-6) were also detected in the liver by reverse transcription and polymerase chain reaction. The plasma endotoxin levels increased after hemorrhagic shock and showed a peak at 2 h in the control group. These increases were significantly neutralized by rBPI21 treatment at 2 h in the BPI group. WBCT decreased and PAI activity increased rapidly after hemorrhagic shock in the control group. These changes were significantly smaller in the BPI group at 6 and 8 h. The increases in mRNA of TF, PAI-1, TNF alpha, and IL-6 were also attenuated by rBPI21 treatment. These results show that BPI ameliorates hypercoagulability after hemorrhagic shock and suggest that endotoxin plays a role in the pathogenesis of thrombogenic responses after hemorrhagic shock.